propylthiouracil and Body-Weight

Genetic sensitivity to the bitter taste of phenylthiocarbamide and 6-n-propylthiouracil (PROP) is a well-studied human trait. It has been hypothesized that this phenotype is a marker for individual differences in taste perception that influence food preferences and dietary behavior with subsequent links to body weight and chronic disease risk. Steady progress has been made over the past several decades in defining the involvement of this phenotype and its underlying gene, TAS2R38, in this complex behavioral pathway. However, more work needs to be done to fully determine its overall nutritional and health significance. The primary goal of this review is to assess our current understanding of the role of the PROP bitter taste phenotype in food selection and body weight in both children and adults. A brief history of the field is included and controversies surrounding the use of different PROP screening methods are addressed. The contribution of other receptors (both bitter and nonbitter) to human taste variation is also discussed.

Topics: Body Weight; Food Preferences; Genetic Variation; Humans; Propylthiouracil; Taste; Taste Threshold; Tongue

Topics: Amino Acids; Animals; Behavior, Animal; Body Weight; Brain; Carbon Isotopes; DNA; Humans; Learning; Myelin Sheath; Nerve Tissue Proteins; Neuroglia; Nucleic Acids; Organ Size; Propylthiouracil; Rats; RNA; Thyroid Gland; Thyroid Hormones; Thyroidectomy; Thyroxine

1. The present study was conducted to examine the effects of α-lipoic acid on hypothyroidism-induced negative growth performance and whether α-lipoic acid alleviates acute heat stress in relation to hypothyroid status. 2. Female broiler chickens (14 d-old) were fed diets supplemented with α-lipoic acid (100 mg/kg) and an antithyroid substance, propylthiouracil (200 mg/kg), for 20 d under thermoneutral conditions (25°C). At 42 d of age, chickens were exposed to a high ambient temperature (36°C, 60% RH) for 4 h. 3. Under the thermoneutral condition, propylthiouracil administration decreased feed efficiency and concomitantly increased adipose tissue and thyroid gland weights. Plasma nonesterified fatty acids and triacylglycerol were also increased by propylthiouracil administration. However, α-lipoic acid supplementation did not affect the hypothyroidism-induced effects. 4. In hypothyroid chickens, the rise in respiratory rate induced by heat exposure was greatly inhibited by α-lipoic acid administration at 1 h, but this effect had disappeared at 4 h. In addition, a similar inhibitory effect on the concentrations of plasma nonesterified fatty acids was subsequently observed at 4 h. 5. Therefore, the present study suggested that α-lipoic acid alleviates acute heat stress if chickens are in a hypothyroid status.

Topics: Animal Feed; Animals; Body Weight; Chickens; Diet; Dietary Supplements; Fatty Acids, Nonesterified; Female; Hot Temperature; Hypothyroidism; Poultry Diseases; Propylthiouracil; Stress, Physiological; Thioctic Acid

Two experiments were conducted during mid-gestation to examine effects in ewes of propylthiouracil (PTU) treatment alone or with melatonin on serum thyroid hormones, postpartum reproduction, and lamb performance. In the first experiment, beginning on day 0 (first day of treatment when all animals were 72.2+/-0.9 days of gestation), ewes received daily treatments (gavage) consisting of either 0mg (n=6) or 40 mg (n=6) PTU/kg body weight/day for 15 days. After 15 days, the 40 mg dosage was decreased to 20mg/kg body weight for an additional 20 days (35 days of PTU). Serum thyroxine (T4) did not differ (P>0.10) between groups through day 4; but on day 5, control females had a serum value of 67 ng/ml compared with 46 (+/-5)ng/ml for PTU-treated ewes (P=0.02). On the last day that 40 mg of PTU was administered, serum T4 averaged 67 and 7 (+/-5)ng/ml (P<0.001) in the two respective groups. Serum T4 remained low and was 80 and 1 ng/ml (P<0.001) in control and treated ewes on day 34. Serum T4 rose gradually after PTU but remained different from that observed in control ewes through day 48. Lambs from control and treated ewes had similar (P=0.46) T4 values at birth but lambs from PTU-treated ewes had lower (P=0.03) birth weights than did those from control ewes. Serum progesterone (P4) after parturition indicated a lack of cyclicity in all ewes. In the second experiment, beginning on day 0 (76.8+/-4.7 days of gestation), ewes received PTU as in Experiment 1. In addition, after 15 days of PTU, melatonin was given (i.m. injections at 5mg/day) for 30 days. Propylthiouracil decreased (P0.60) for lambs born to control and treated ewes. Female offspring of PTU+melatonin-treated dams reached puberty, became anestrus, and returned to cyclicity at similar (P>0.10) times to contemporary ewe lambs. Results indicate that 40/20mg PTU alone or with melatonin does not induce cyclicity after lambing in spring lambing ewes and has little effect on offspring performance.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Estrous Cycle; Female; Hypothyroidism; Melatonin; Pregnancy; Progesterone; Propylthiouracil; Reproduction; Seasons; Sheep; Thyroxine; Time Factors; Triiodothyronine

This study examined links between taste responsiveness to 6-n-propylthiouracil (PROP), a heritable trait, and sensory responses to six common foods. Sixty-three young women subjects were divided into PROP tasters (n = 25) and nontasters (n = 25), based on their responses to PROP-impregnated filter paper and mean bitterness intensity ratings for seven PROP solutions. Thirteen subjects were excluded as unclassifiable. The 50 subjects sampled Brussels sprouts, broccoli, spinach, black coffee, soy milk, and soybean tofu. Sensory ratings for bitter intensity; pleasantness of taste, odor, and texture, and overall food acceptability scores were obtained using nine-point category scales. All subjects completed a food-preference checklist and a modified food-frequency questionnaire. PROP tasters rated Brussels sprouts as more bitter than did nontasters (p<0.05). Subjects who perceived the foods as more bitter also rated them as less pleasant and less acceptable. Taste preferences and food preferences were linked. Self-reported food preferences and self-reported frequencies of consumption for the same foods were also linked. Taste factors and food preferences may impact dietary choices and the frequency of food consumption.

Topics: Adult; Body Mass Index; Body Weight; Coffee; Dose-Response Relationship, Drug; Eating; Female; Food Preferences; Humans; Propylthiouracil; Stimulation, Chemical; Taste; Taste Disorders; Vegetables

Neonatal 6-N-propyl-2-thiouracil (PTU)-induced hypothyroidism reduces body weight but increases testicular size in adult male rodents. The objective of this study was to determine the effect of prepubertal PTU treatment on boars. For Experiment I, boars (n = 28) were randomly allotted to eight pens. Each pen received one of four PTU doses (0, 0.01, 0.03 and 0.1% in a basal diet) between 28 and 56 days of age (DOA). Due to a lack of difference among three PTU treatments, PTU-treated boars were pooled. Boars treated with PTU had lower (P < 0.05) ADG during treatment, lighter (P < 0.05) BW after 56 DOA and less (P < 0.05) developed epididymides at 154 DOA. For Experiment II, boars (n = 19) were randomly allotted to six pens. Each pen received one of three PTU treatments orally as: control (carrier), PTU-I (0.002% BW of PTU daily between 7 and 70 DOA), or PTU-II (0.002% BW of PTU daily between 28 and 91 DOA). During treatment, PTU-treated boars had lower (P < 0.05) serum T4 levels, rectal temperature, feed intake and ADG. Boars treated with PTU had lower (P < 0.05) BW between 63 and 154 DOA but higher (P < 0.05) gain/feed between 105 and 133 DOA. Boars treated with PTU had less (P < 0.05) developed epididymides and sperm count per gram testis at 238 DOA. These results suggest that prepubertal PTU-induced hypothyroidism had significant effects on growth, hormonal profiles, and reproductive traits of boars; however, it does not appear to be an effective method for increasing testis size and sperm production of commercial boars.

Topics: Aging; Animals; Body Composition; Body Temperature; Body Weight; Eating; Estradiol; Follicle Stimulating Hormone; Growth; Hormones; Male; Propylthiouracil; Reproduction; Sperm Count; Swine; Testosterone; Thyroxine

Bitterness and astringency (dryness) are characteristic sensory attributes of flavanol-rich foods. The degree of polymerization (DP) of flavanols influences their bitter and astringent sensations. Smaller DP compounds can enter the papillae on the tongue, eliciting a bitter response. Larger DP compounds are sterically inhibited from entering papillae and instead interact with oral proteins, cause precipitation, and elicit astringent sensations. Previous research has indicated that bitterness preference is related to health status, density of fungiform papillae on the tongue, and sensitivity to bitter compounds such as 6-n-propyl-thiouracil (PROP). The purpose of this study was to examine trends in liking, bitterness intensity, and astringency intensity of wine-like products with flavanols of different DP using a consumer sensory panel. Participants (n = 102) were segmented by phenotypes: body fat percentage (BF%), body mass index (BMI), PROP sensitivity, and stated bitter food preference. Differences in wine liking, perceived bitterness intensity, and astringency intensity were observed between three model wine samples of varying flavanol mean degrees of polymerization (mDP, i.e. the average size (polymer length) of flavanol compounds in a mixture). Specifically, with increased mDP, overall liking and bitterness liking decreased, with concurrent increased perception of bitterness and astringency intensity. Greater differences between phenotypes were observed when participants were segmented by BF% and BMI classification, than when segmented by PROP sensitivity classification. Reduced ability to detect differences in bitterness and astringency were noted in participants of higher weight status. Overall, these data suggest that weight status in adults is a greater predictor of liking of flavanol-rich foods than bitterness sensitivity (as determined by PROP classification), and that reduced perception of bitterness and astringency associated with weight gain may impact selection and preference for these foods.

Topics: Adipose Tissue; Adult; Body Composition; Body Mass Index; Body Weight; Female; Food Preferences; Humans; Male; Middle Aged; Polymerization; Polyphenols; Propylthiouracil; Taste; Taste Buds; Taste Threshold; Wine; Young Adult

To characterize the influence of hypothyroidism on the endocrine activity of mesenteric and omental adipose tissue (MOAT) and the peripheral regulation of energy balance (EB) in rats, we analyzed food intake (FI); basal metabolic rate (BMR); locomotor activity; body weight (BW); serum hormone concentrations and the expression of their receptors in MOAT. We evaluated the morphology and differentiation of adipocytes. Hypothyroidism decreased FI, BMR and BW. The percentage of visceral white adipose tissue (WAT) depots and the morphology of adipocytes were similar to euthyroid rats. Serum leptin and adiponectin expression in MOAT were altered by hypothyroidism. The expression of Perilipin 1, HSL, UCP1 and PRDM16 was significantly lower in MOAT of hypothyroid animals. Hypothyroidism in rats leads to a compensated EB by inducing a white adipocyte dysfunction and a decrease in BW, BMR, FI and adipokine secretions without changing the percentage of WAT depots and the morphology of the MOAT.

Topics: Adipocytes; Adipokines; Adipose Tissue; Adipose Tissue, White; Animals; Basal Metabolism; Biomarkers; Body Weight; Corticosterone; Eating; Fatty Acids; Female; Glucose; Hypothyroidism; Insulin; Mesentery; Motor Activity; Omentum; Ovary; Propylthiouracil; Rats, Sprague-Dawley; RNA, Messenger

We assessed orosensory detection of a long-chain fatty acid, linoleic acid (LA), and a bitter taste marker, 6-n-propylthiouracil (PROP), and correlated lipid-taster subjects with PROP detection and polymorphism in genes encoding bitter and lipid taste receptors, respectively, TAS2R38 and CD36, in normal weight and obese subjects.. The normal weight (n = 52, age = 35.3 ± 4.10 years, BMI = 23.22 ± 1.44 kg/m. The study included the participants who could detect LA, i.e., lipid-tasters. There was a positive correlation between BMI and detection thresholds for fat and bitter taste in normal weight and obese subjects. Obese participants showed a positive correlation between LA and PROP detection thresholds. PROP detection thresholds were higher for CD36 SNP (rs1761667) and TAS2R38 SNPs (rs1726866 and rs10246939) in obese participants compared to normal weight subjects. LA detection thresholds were not high for CD36 SNP (rs1761667) or TAS2R38 SNP (rs1726866 and rs10246939) in obese participants.. Orosensory detection thresholds for fat and bitter taste are associated with BMI, and CD36 and TAS2R38 genotypes are not always associated with taste phenotypes.

Topics: Adult; Body Weight; Case-Control Studies; CD36 Antigens; Humans; Male; Obesity; Polymorphism, Single Nucleotide; Propylthiouracil; Receptors, G-Protein-Coupled; Taste

Reduced taste sensitivity to 6-n-propylthiouracil (PROP), a genetic trait regarded as a general index for oral chemosensory perception, has been associated with a calorie-rich food preference and lower circulating endocannabinoid levels in participants with normal weight (NW), which suggests an adaptive mechanism to maintain a lean phenotype. In this study, we assessed whether participants with obesity (OB) show different patterns of plasma endocannabinoids and lipid metabolism biomarkers from those of NW, with further categorization based on their PROP sensitivity. NW and OB were classified by their PROP taster status as non-tasters (NT), medium-tasters (MT) and supertasters (ST). The blood samples were analysed for plasma endocannabinoids, nonesterified fatty acids (NEFA) and retinol, which have been associated to metabolic syndrome. In OB, we found a higher BMI and lower circulating endocannabinoids in ST vs. OB NT. However, OB ST showed lower circulating NEFA and retinol levels, which suggested a more favourable lipid metabolism and body fat distribution than those of OB NT. We confirmed lower plasma endocannabinoid levels in NW NT than in NW ST. These data suggest that PROP taste sensitivity determines metabolic changes and ultimately body mass composition differently in OB and NW.

Topics: Adult; Body Mass Index; Body Weight; Endocannabinoids; Erythrocytes; Female; Humans; Lipid Metabolism; Male; Middle Aged; Obesity; Propylthiouracil; Taste

This study aimed to examine the neuroprotective effects of Nigella sativa (N. sativa) in the hippocampus of propylthiouracil (PTU)-induced hypothyroid rats during neonatal and juvenile growth. Twenty- five pregnant rats from early gestation (GD 0) were divided into five groups: (1) control (received drinking water), (2) PTU (received 0.005% PTU in drinking water), (3-5) PTU + NS 0.05%, PTU + NS 0.1%, PTU + NS 0.2% (along with PTU, received 0.05%, 0.1% and 0.2% W/V of N. sativa respectively) and treatment continued until postnatal day 60 (PN 60). The brains of male pups were removed for histological and stereological assessments. N. sativa extract significantly reduced the production of dark neurons and apoptotic cells in different areas of the hippocampus compared to the PTU group. Moreover, it significantly attenuated the effect of hypothyroidism on the volume reduction of the hippocampus. The results of the present study suggested that N. sativa extract has a potential ability to prevent the hippocampal neural damage after inducing hypothyroidism during neonatal and juvenile growth in rats.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Apoptosis; Body Weight; Cell Count; Female; Hippocampus; Hypothyroidism; Male; Neurons; Neuroprotective Agents; Nigella sativa; Plant Extracts; Pregnancy; Propylthiouracil; Rats; Rats, Wistar

Thyroid hormones (THs) are important for growth and development of many tissues, and altered thyroid status affects various organs and systems. Testis also is considered as a thyroid hormone responsive organ. Though THs play an important role in regulation of testicular steroidogenesis and spermatogenesis, the exact mechanism of this regulation remains poorly understood. The present study, therefore, is designed to examine the effect of neonatal hypothyroidism on prepubertal Parkes (P) strain mice testis in relation to thyroid hormone receptor alpha 1 (THRα1). Hypothyroidism was induced by administration of 6-propyl-2-thiouracil (PTU) in mother's drinking water from birth to day 28; on postnatal day (PND) 21 only pups, and on PND 28, both pups and lactating dams were euthanized. Serum T

Topics: Animals; Animals, Newborn; Body Weight; Female; Hypothyroidism; Immunoblotting; Male; Mice; Organ Size; Propylthiouracil; Reproducibility of Results; RNA, Messenger; Sexual Maturation; Steroids; Testis; Thyroid Hormone Receptors alpha; Thyroid Hormones

Thyroid hormone deficiency during fetal life could affect the cardiac function in later life. The mechanism underlying this action in fetal hypothyroidism (FH) in rats has not been elucidated thus far.. The aim of this study is to evaluation the effect of FH on cardiac function in male rats and to determine the contribution of α-myosin heavy chain (MHC) and β-MHC isoforms.. Six pregnant female rats were randomly divided into two groups: The hypothyroid group received water containing 6-propyl-2-thiouracil during gestation and the controls consumed tap water. The offspring of the rats were tested in adulthood. Hearts from the FH and control rats were isolated and perfused with langendroff setup for measuring hemodynamic parameters; also, the heart mRNA expressions of α- MHC and β-MHC were measured by qPCR.. Baseline LVDP (74.0 ± 3.1 vs. 92.5 ± 3.2 mmHg, p < 0.05) and heart rate (217 ± 11 vs. 273 ± 6 beat/min, p < 0.05) were lower in the FH rats than controls. Also, these results showed the same significance in ±dp/dt. In the FH rats, β-MHC expression was higher (201%) and α- MHC expression was lower (47%) than control.. Thyroid hormone deficiency during fetal life could attenuate normal cardiac functions in adult rats, an effect at least in part due to the increased expression of β-MHC to α- MHC ratio in the heart.

Topics: Animals; Antithyroid Agents; Body Weight; Congenital Hypothyroidism; Disease Models, Animal; DNA, Complementary; Female; Heart Rate; Male; Myocardium; Myosin Heavy Chains; Pregnancy; Propylthiouracil; Random Allocation; Rats, Wistar; RNA, Messenger; Thyroxine; Triiodothyronine; Ventricular Pressure

Clotting abnormalities are discussed both in the context with thyroid dysfunctions and obesity caused by a high fat diet. This study aimed to investigate the impact of hypo-, or hyperthyroidism on the endogenous thrombin potential (ETP), a master indicator of clotting activation, on Sprague Dawley rats fed a normal or high fat diet. Female Sprague Dawley rats (n = 66) were grouped into normal diet (ND; n = 30) and high-fat diet (HFD; n = 36) groups and subdivided into controls, hypothyroid and hyperthyroid groups, induced through propylthiouracil or triiodothyronine (T3) treatment, respectively. After 12 weeks of treatment ETP, body weight and food intake were analyzed. Successfully induced thyroid dysfunction was shown by T3 levels, both under normal and high fat diet. Thyroid dysfunction was accompanied by changes in calorie intake and body weight. In detail, compared to euthyroid controls, hypothyroid rats showed significantly increased-and hyperthyroid animals significantly decreased-ETP levels. High fat diet potentiated these effects in both directions. In summary, we are the first to show that hypothyroidism and high fat diet potentiate the thrombotic capacity of the clotting system in Sprague Dawley rats. This effect may be relevant for cardiovascular disease where thyroid function is poorly understood as a pathological contributor in the context of clotting activity and obesogenic nutrition.

Topics: Animals; Body Weight; Diet, High-Fat; Eating; Female; Hyperthyroidism; Hypothyroidism; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thrombophilia; Triiodothyronine

Hypothyroidism affects cardiopulmonary regulation and function of dopaminergic receptors. Here we evaluated effects of 5 months of hypothyroidism on dopamine D1 receptor modulation of breathing in female hamsters using a D1 receptor antagonist SCH 23390. Euthyroid hamsters (EH) served as controls. Results indicated that hypothyroid female hamsters (HH) exhibited decreased body weights and minute ventilation (VE) following hypoxia due to decreased frequency of breathing (F). Moreover, SCH 23390 administration in HH increased VE by increasing tidal volume during exposure to air, hypoxia and following hypoxia. Relative to vehicle, SCH 23390 treatment decreased body temperature and hypoxic VE responsiveness in both groups. In EH, SCH 23390 decreased F in air, hypoxia and post hypoxia, and VE during hypoxia trended to decrease (P=0.053). Finally, expression of D1 receptor protein was not different between the two groups in any region evaluated. Thus, hypothyroidism in older female hamsters affected D1 receptor modulation of ventilation differently relative to euthyroid animals, but not expression of D1 receptors.

Topics: Animals; Benzazepines; Blotting, Western; Body Temperature; Body Weight; Carbon Dioxide; Disease Models, Animal; Dopamine Antagonists; Female; Hypothyroidism; Mesocricetus; Oxygen Consumption; Propylthiouracil; Receptors, Dopamine D1; Respiration; Tidal Volume

One of the most important thyroid hormone targets is the cardiovascular system. Hemodynamic changes, such as decreased resting heart rate (HR), myocardial contractility, and cardiac output, and increased diastolic pressure and systemic vascular resistance, have been observed in hypothyroid patients. Moreover, in these patients, ECG changes include sinus bradycardia and low voltage complexes (P waves or QRS complexes).. This study aimed at evaluating the prophylactic effect of apelin on HR changes and QRS voltage that occur in propylthiouracil (PTU)-induced hypothyroid rats.. In this study, 48 adult male Wistar rats weighing 170-235g were randomly divided into 6 groups: Control group (normal saline ip injection + tap water gavage); P group (PTU 0.05%, in drinking water); A group (apelin 200 µg.kg-1.day-1, ip); PA group [co-administration of PTU and apelin]; PT group [co-administration of PTU + T4 (0.2 mg/g per day, gavage)]; and PAT group (co-administration of PTU, apelin and T4). All experiments were performed for 28 consecutive days, and then the animals were anesthetized with an ip injection of ketamine (80 mg/kg) and xylazine (12 mg/kg). Lead II electrocardiogram was recorded to calculate HR and QRS voltage.. Heart rate and QRS voltage increased more significantly in the hypothyroid group that consumed both apelin and T4 (201 ± 4 beat/min, 0.71 ± 0.02 mv vs. hypothyroid 145 ± 9 beat/min, 0.563 ± 0.015 mv; respectively).. The co-administration of apelin and T4 showed a protective effect on QRS voltage and HR in PTU‑induced hypothyroid rats.

Topics: Animals; Antithyroid Agents; Apelin; Body Weight; Cardiotonic Agents; Drug Combinations; Electrocardiography; Heart Rate; Hypothyroidism; Intercellular Signaling Peptides and Proteins; Male; Myocardial Contraction; Propylthiouracil; Random Allocation; Rats, Wistar; Reproducibility of Results; Thyrotropin; Thyroxine

Previous studies show that children who are sensitive to the bitter taste of 6-n-propylthiouracil (PROP) report more frequent intake of sweets and less frequent intake of meats (savory fats) relative to children who are PROP insensitive. Laboratory studies are needed to confirm these findings. In this study, seventy-nine 4- to 6-year-olds from diverse ethnicities attended four laboratory sessions, the last of which included a palatable buffet consisting of savory-fats (e.g. pizza), sweet-fats (e.g. cookies, cakes), and sweets (e.g. juices, candies). PROP phenotype was classified by two methods: 1) a common screening procedure to divide children into tasters and nontasters, and 2) a three-concentration method used to approximate PROP thresholds. Height and weight were measured and saliva was collected for genotyping TAS2R38, a bitter taste receptor related to the PROP phenotype. Data were analyzed by General Linear Model ANOVA with intake from savory fats, sweet-fats, and sweets as dependent variables and PROP status as the independent variable. BMI z-score, sex, age, and ethnicity were included as covariates. Adjusted energy intake from the food group "sweets" at the test-meal was greater for tasters than for nontasters. PROP status did not influence children's adjusted intake of savory-fats, but BMI z-score did. The TAS2R38 genotype did not impact intake at the test-meal. At a palatable buffet, PROP taster children preferentially consumed more sweets than nontaster children, while heavier children consumed more savory fats. These findings may have implications for understanding differences in susceptibility to hyperphagia.

Topics: Body Weight; Child; Child, Preschool; Diet; Dietary Fats; Dietary Sucrose; Female; Food Preferences; Genotype; Humans; Male; Meals; Phenotype; Propylthiouracil; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Taste; Taste Buds; Taste Perception

Hypothyroidism leads to somatic, neuropsychological, and psychiatric changes that are similar to depression. The mechanisms underlying the behavioral abnormalities in adult onset hypothyroidism remain ambiguous. Hypothyroidism was induced in adult male Wistar rats by the maintenance of 0.05% propylthiouracil (PTU) in drinking water for 5 weeks (hypothyroid group; HP group); control rats (CON group) received an equivalent amount of water. The open field and sucrose preference tests were employed, and the link between behavioral changes and brain glucose metabolism was evaluated using micro positron emission tomography imaging. The open field test revealed slightly decreased locomotor activity and significantly reduced rearing and defecation in the hypothyroid group. Hypothyroid rats were also characterized by decreased body weight, sucrose preference, and relative sucrose intake compared to control rats. Hypothyroidism induced reduced brain glucose metabolism in the bilateral motor cortex, the caudate putamen, the cortex cingulate, the nucleus accumbens, and the frontal association cortex. A decreased sucrose preference was positively correlated with metabolic glucose changes in the caudate putamen and the nucleus accumbens. The results indicate that the activity pattern in adult onset hypothyroidism is different from the activity pattern when hypothyroidism is induced in the developmental period of the central nervous system. Decreased sucrose preference in hypothyroid rats may be attributed to anhedonia. Furthermore, these findings suggest there may be a common mechanism underlying adult onset hypothyroidism and depression.

Topics: Animals; Antithyroid Agents; Body Weight; Brain; Disease Models, Animal; Drinking Water; Food Preferences; Glucose; Hypothyroidism; Locomotion; Male; Motor Activity; Positron-Emission Tomography; Propylthiouracil; Rats; Rats, Wistar; Sucrose

The role of thyroid hormones in gonad development remains incompletely understood. We examined the dose-related effects of perinatal hypothyroidism induced by a reversible goitrogen, 6-propyl-2-thiouracil (PTU), on reproductive development in male rat offspring. Timed-pregnant Sprague-Dawley rats were orally administered PTU (0, 0.5, 1.0, or 2.0 mg/kg/day) by gavage from gestational day 15 through postnatal day 20. We observed a significant dose-dependent decrease in body weight in offspring with PTU exposure up to 13 weeks of age, but body weight became comparable among groups by 26 weeks of age. Testicular weight tended to be lower up to 7 weeks but was higher after 13 weeks of age. Epididymis weight was not different among the groups at any age. Plasma concentrations of thyroxine and triiodothyronine in the PTU groups were significantly lower at 3 weeks of age but recovered to normal levels by 26 weeks of age. No dose-related trend in plasma testosterone concentrations was found. Seminiferous tubules were larger at 13 and 26 weeks of age with PTU exposure. The number of Sertoli cells was significantly higher from 3 through 26 weeks of age. The number of Leydig cells was significantly lower up to 7 weeks of age but was comparable among groups from 13 weeks of age onwards. Thus, transient gestational and lactational thyroid hormone suppression induced small testes in early life but led to paradoxical dose-dependent testicular enlargement in adults as indicated partly by larger seminiferous tubules with numerous Sertoli cells in male rat offspring.

Topics: Administration, Oral; Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Dose-Response Relationship, Drug; Female; Gestational Age; Hypothyroidism; Leydig Cells; Male; Maternal-Fetal Exchange; Pregnancy; Propylthiouracil; Rats, Sprague-Dawley; Seminiferous Tubules; Sertoli Cells; Testis

One of the critical factors that determines individual differences in dietary behavior and nutritional status is the sensory-affecting quality of food, in particular its taste. Variation of one bitter taste receptor gene, TAS2R38, which is associated with the differential sensitivity to phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), has been demonstrated to affect the dietary intake pattern. A case study was performed to examine the association of the TAS2R38 genotypes/haplotypes with the body size (height, weight and BMI) and with the food and nutrient intake. Eighty-four college students, all females, with an age range of 18-21 y were recruited from the University of Shizuoka. The genotypes of two common single nucleotide polymorphisms in TAS2R38 (A49P and I296V) were determined by PCR-restriction fragment length polymorphism (RFLP) method. The height, weight and body mass index (BMI), and (in a subgroup of 47 subjects) food and nutrition intake estimated from 3 d of food recording, were compared between homozygotes for the PTC/PROP-nontaster haplotype (AI haplotype) and carriers with the PTC/PROP-taster haplotype (PV haplotype). The results show that the homozygotes with AI haplotype were taller and heavier than the carriers of PV haplotype, while BMI values were similar between them. The former group also had higher energy and carbohydrate intakes than the latter group. Neither vegetable nor dairy product intake was different between the homozygotes with AI haplotype and the carriers of PV haplotype. In conclusion, the PTC/PROP-nontaster TAS2R38 genotype/haplotype was associated with height and weight but not with BMI, which may in turn have influenced the energy and carbohydrate intakes.

Topics: Adolescent; Adult; Body Height; Body Mass Index; Body Weight; Diet; Dietary Carbohydrates; Dysgeusia; Eating; Energy Intake; Female; Genotype; Humans; Phenylthiourea; Polymorphism, Single Nucleotide; Propylthiouracil; Students; Taste; Universities; Young Adult

The PROP bitter-taste phenotype is a marker for food preferences and eating behavior, and may associate with differences in body weight in children. Previous work has shown that PROP status in combination with eating attitudes are better predictors of weight status in preadolescents, than either factor alone. However, no studies have examined the role of PROP phenotypes in body weight change in children over time. The primary objective of this study was to investigate current weight status and change in weight status in children from preschool (baseline) to preadolescence as a function of eating attitudes and PROP phenotype. Other measures included self-reported food intakes and physical activity by activity monitor. Seventy-three lean (BMI percentile=57.7±3.2%) children with mean age=10.3±0.5yrs, participated in the follow up. There were no group differences in energy intake, current BMI-percentile or change in BMI percentile from baseline by PROP phenotype in either boys or girls. However, there was a trend for non-taster girls to show a downward shift in BMI-percentile at follow up. Hierarchical regression analysis revealed that baseline BMI percentile and physical activity energy expenditure were the strongest predictors of current weight (28.5% variance),followed by child restraint, the taster×gender interaction, and the maternal BMI×maternal emotional eating interaction, accounting for 7.1%, 6.0% and 4.8% of variance in the model, respectively. These findings suggest that PROP status and eating attitudes are modest predictors of weight status in preadolescent children.

Topics: Adiposity; Adolescent; Attitude; Body Mass Index; Body Weight; Child; Child, Preschool; Cohort Studies; Diet; Energy Intake; Feeding Behavior; Female; Follow-Up Studies; Genotype; Humans; Male; Mothers; Motor Activity; Propylthiouracil; Receptors, G-Protein-Coupled; Taste

A serum metabonomic profiling method based on ultra-performance liquid chromatography/time-of-flight mass spectrometry (UHPLC/TOF-MS) was applied to investigate the metabolic changes in hypothyroid rats induced by propylthiouracil (PTU). With Significance Analysis of Microarray (SAM) for classification and selection of biomarkers, 13 potential biomarkers in rat serum were screened out. Furthermore, Ingenuity Pathway Analysis (IPA) was introduced to deeply analyze unique pathways of hypothyroidism that were primarily involved in sphingolipid metabolism, fatty acid transportation, phospholipid metabolism and phenylalanine metabolism. Our results demonstrated that the metabonomic approach integrating with IPA was a promising tool for providing a novel methodological clue to systemically dissect the underlying molecular mechanism of hypothyroidism.

Topics: Animals; Body Weight; Chromatography, High Pressure Liquid; Fatty Acids; Hypothyroidism; Male; Mass Spectrometry; Metabolomics; Phenylalanine; Phospholipids; Propylthiouracil; Rats; Rats, Wistar; Sphingolipids

Protein kinase Cα (PKCα) has been implicated in the regulation of a variety of cellular functions, such as proliferation, differentiation, and apoptosis, in response to a diverse range of stimuli. Activated PKCα mediates oxidative stress, apoptosis, and inflammatory reaction. Thyroid hormone (TH) is essential for the proper development of the mammalian central nervous system. TH deficiency during critical periods of brain development results in permanent cognitive and neurological impairments. In the present study, we attempted to explore whether PKCα is involved in impaired brain function in developing hypothyroid rat brain. Severe perinatal hypothyroidism was obtained by administration of 30 mg/day propylthiouracil to dams. Brain PKC activity in hypothyroid pups was increased significantly in cytosol and membrane fractions. The change of membrane PKC activity was more marked than that of cytosol, and hypothyroidism led to a higher ratio of membrane PKC activity to that in cytosol, which means abnormal activation of PKC in developing hypothyroid rat brain. Thyroxine replacement partially corrected these changes. After being treated with bisindolmaleimide XI, a mainly selective inhibitor for PKCα, the hypothyroid pups showed improved place navigation test results, and further Western blot analysis showed that PKCα expression in cytosol fractions was increased in hypothyroid rat brain with or without bisindolmaleimide XI treatment, but, after treatment with bisindolmaleimide XI, PKCα content in membrane fractions decreased almost to normal. Therefore, we conclude that PKCα appears to be involved in the impaired brain development observed in perinatal hypothyroid rat brain.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Brain; Enzyme Inhibitors; Female; Gene Expression Regulation, Developmental; Hypothyroidism; Indoles; Male; Maleimides; Maze Learning; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Protein Kinase C-alpha; Rats; Rats, Sprague-Dawley; Thyroxine; Time Factors

Eating behaviors and obesity are complex phenotypes influenced by genes and the environment, but few studies have investigated the interaction of these two variables. The purpose of this study was to use a gene-environment interaction model to test for differences in children's food acceptance and body weights.. Inherited ability to taste 6-n-propylthiouracil (PROP) was assessed as a marker of oral taste responsiveness. Food environment was classified as "healthy" or "unhealthy" based on proximity to outlets that sell fruits/vegetables and fast foods using Geographic Information Systems (GIS). The cohort consisted of 120 children, ages 4-6 years, recruited from New York City over 2005-2010. Home address and other demographic variables were reported by parents and PROP status, food acceptance, and anthropometrics were assessed in the laboratory. Based on a screening test, children were classified as PROP tasters or non-tasters. Hierarchical linear models analysis of variance was performed to examine differences in food acceptance and body mass index (BMI) z-scores as a function of PROP status, the food environment ("healthy" vs. "unhealthy"), and their interaction.. Results showed an interaction between taster status and the food environment on BMI z-score and food acceptance. Non-taster children living in healthy food environments had greater acceptance of vegetables than taster children living in healthy food environments (P ≤ 0.005). Moreover, non-tasters from unhealthy food environments had higher BMI z-scores than all other groups (P ≤ 0.005). Incorporating genetic markers of taste into studies that assess the built environment may improve the ability of these measures to predict risk for obesity and eating behaviors.

Topics: Body Mass Index; Body Weight; Child; Child, Preschool; Cohort Studies; Consumer Behavior; Cross-Sectional Studies; Fast Foods; Female; Food Preferences; Food, Organic; Fruit; Gene-Environment Interaction; Genetic Markers; Geographic Information Systems; Humans; Male; New York City; Obesity; Phenotype; Propylthiouracil; Residence Characteristics; Socioeconomic Factors; Taste; Vegetables

Humans and wildlife are exposed to environmental pollutants that have been shown to interfere with the thyroid hormone system and thus may affect brain development. Our goal was to expose pregnant rats to propylthiouracil (PTU) to measure the effects of a goitrogen on white matter development in offspring using magnetic resonance imaging (MRI) and volumetric analysis. We exposed pregnant Sprague Dawley (SD) rats to 3 or 10 ppm PTU from gestation day 7 (GD7) until postnatal day 25 (P25) to determine the effects on white matter (WM), gray matter (GM), and hippocampus volumes in offspring. We sacrificed offspring at P25 but continued the life of some offspring to P90 to measure persistent effects in adult animals. P25 offspring exposed to 10 ppm PTU displayed lowered levels of triiodothyronine (T3) and thyroxine (T4); cerebral WM, GM, and total brain volumes were significantly lower than the volumes in control animals. P90 adults exposed to 10 ppm PTU displayed normal T3 levels but lowered T4 levels; WM, GM, total brain, and hippocampal volumes were significantly lower than the volumes in control adults. Both P25 and P90 rats exposed to 10 ppm PTU displayed significant reductions in percent WM as well as heterotopias in the corpus callosum. Exposure to 3 ppm PTU did not produce any significant effects. These results suggest that MRI coupled with volumetric analysis is a powerful tool in assessing the effects of thyroid hormone disruption on white matter development and brain structure. This approach holds great promise in assessing neurotoxicity of xenobiotics in humans and wildlife.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Nerve Fibers, Myelinated; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Diseases; Thyroid Hormones; Tyrosine 3-Monooxygenase

The plasticity and vulnerability of the rat spinal cord (SC) during postnatal development has been less investigated compared to other CNS structures. In this study, we determined the effects of thyroid hormonal (TH) deficiency and excess on postnatal growth and neurochemical development of the rat SC. The growth as well as the specific and total activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes of the SC were determined in hypo- and hyperthyroid rat pups at postnatal (P) days P1, P5, P10 and P21 (weaning), and were compared to age-matched untreated normal controls. AChE is a cholinergic synaptic enzyme while BuChE is a metabolic enzyme mainly found in glial cells and neurovascular cells. The SC is rich in somatic motor, autonomic cholinergic neurons and associated interneurons. Daily subcutaneous injection of pups with thyroxine (T4) and administration of antithyroid goitrogen propylthiouracil (PTU) in the litter's drinking water were used to induce hyper- and hypothyroidism, respectively. Enzyme assays were carried out spectrophotometrically at the above-mentioned ages, using SC homogenates with acetylthiocholine-chloride as the substrate, together with specific cholinesterase inhibitors, which specifically target AChE and BuChE. SC weights were significantly lower at P10 and P21 in hypothyroid pups but unchanged in the hyperthyroid ones. Hypothyroidism significantly reduced both specific and total AChE activity in SC of P10 and P21 rat pups, while having no effects on the BuChE activity, although total BuChE activity was decreased due to reduced total tissue weight. In contrast both specific and total AChE activities were markedly and significantly increased (>100%) in the P10 and P21 hyperthyroid pups. However, BuChE specific activity was unaffected by this treatment. The results indicate that hypothyroid condition significantly reduces, while hyperthyroidism increases, the postnatal development of cholinergic synapses, thereby influencing the functional development of this major sensory and motor structure. However, the neurochemical development of glia and other non-neuronal cells, where BuChE is mainly localized, is comparatively unaffected in these abnormal developmental conditions.

Topics: Acetylcholinesterase; Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Butyrylcholinesterase; Female; Hyperthyroidism; Hypothyroidism; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Spinal Cord; Thyroxine

Little information is available about changes in body weight and body mass index in children before, during, and after treatment for Graves' disease (GD).. Our objective was to examine changes in body weight after treatment for GD in children as related to clinical features.. The medical records of 43 pediatric patients with GD [35 girls and eight boys, aged 4.0-18.5 (mean 10.9) yr] were examined. Patients were included if clinical data were available for 1 yr before and after the diagnosis of GD.. Weight, height, body mass index (BMI) z-scores, and thyroid hormone levels were assessed.. Overall, patients presented with an average BMI z-score of -0.02 ± 1.05 that was not different from the normal population (P = 0.921) or their premorbid values (P = 0.07). However, in the subset of patients who were initially overweight or obese in the premorbid state, the BMI decreased significantly during the development of hyperthyroidism (P < 0.05). After initiation of treatment, patients gained significant amounts of weight over the first 6 months leading to elevated BMI z-scores (P < 0.0001), and elevations in BMI persisted in about 25% of the patients.. Excessive weight gain within 6 months of treatment is seen in children treated for GD, and the gain in weight can persist.

Topics: Adolescent; Aging; Antithyroid Agents; Body Mass Index; Body Weight; Child; Child, Preschool; Cohort Studies; Female; Graves Disease; Humans; Iodine Radioisotopes; Male; Methimazole; Propylthiouracil; Sex Characteristics; Thyroid Function Tests; Thyroid Hormones; Thyroidectomy; Weight Gain

Previous studies have shown that inherited taste blindness to bitter compounds like 6-n-propylthiouracil (PROP) may be a risk factor for obesity, but this literature has been highly controversial. The objectives of this study were (i) to confirm findings that show an interaction between PROP status and sex on BMI z-score, and (ii) to determine if sex also interacts with variations in TAS2R38 (phenylthiocarbamide (PTC) genotype) to influence weight status in 4-6 year olds. Also, we tested whether nontaster children consumed more fat and total energy at laboratory-based meals. Seventy-two ethnically diverse children who ranged in weight status were classified as tasters (N = 52) or nontasters (N = 20) using a standard PROP screening solution. Anthropometric measures were taken, and at the end of each visit, children ate ad libitum from test meals intended for exploratory purposes. Genomic DNA was extracted from saliva and alleles at TAS2R38 were genotyped for A49P polymorphisms. In 75.8% of children, PTC genotype predicted PROP phenotype, whereas in 24.4%, genotype did not predict phenotype. PROP nontaster males had higher BMI z-scores than taster-males and females in both groups (P < 0.05), but due to a three-way interaction between PROP phenotype, TAS2R38 genotype, and sex, this relationship was only true for children who were homozygous for the bitter-insensitive allele (P < 0.0005). There were no differences in test-meal intake as a function of PROP phenotype or TAS2R38 genotype. These results suggest that the TAS2R38 variation, PROP phenotype, and sex interact to impact obesity risk in children. Future studies should be done to determine how this trait influences energy balance.

Topics: Body Mass Index; Body Weight; Child; Child, Preschool; Female; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Male; Obesity; Propylthiouracil; Receptors, G-Protein-Coupled; Risk; Sex Characteristics; Taste; Taste Disorders; Thiourea

This study was performed to investigate the effects of L-thyroxine treatment on plasma vasopressin (AVP) levels in rats with hypothyroidism induced by propylthiouracil (PTU). Animals were separated into three groups each having 6 rats: control, PTU, PTU+L-thyroxine groups. Then, the groups were further divided into 3 sub-groups including 6 rats (a; basal, b; hypertonic stimulated and c; hypovolemic stimulated). At the end of the experiments all rats were decapitated in order to obtain plasma samples for analysis in terms of Hct, osmolality, TT 3 , TT 4 and vasopressin. Haematocrit (Hct) levels were the highest in hypovolemic stimulated sub-group (P < 0.001). Osmolality levels were higher in hypertonic stimulated sub-groups (P < 0.001). Total T 3 and T 4 values were the lowest in the PTU group and the highest in the L-thyroxine treated group (P < 0.001). Plasma AVP levels were reduced by hypothyroidism. However, L-thyroxine treatment after the hypothyroidism prevented this reduction (P < 0.001). Vasopressin responses to basal, hypovolemic and hypertonic stimulations were the lowest in the PTU group (P < 0.001). The results of the present study show that basal and stimulated plasma vasopressin levels are reduced in PTU-induced hypothyroidism. However, L-thyroxine treatment following hypothyroidism prevents this reduction.

Topics: Animals; Antithyroid Agents; Body Weight; Dietary Supplements; Hypertonic Solutions; Hypothyroidism; Hypovolemia; Male; Propylthiouracil; Rats; Rats, Wistar; Thyroxine; Vasopressins

Thyroid hormones play important roles in vertebrate brain development. However, there is little understanding of the direct effects of fetal thyroid dysfunction, i.e., not acquired through the mother, on learning ability. In the present study, we use a chick embryo as a fetal model to investigate the effects of prenatal exposure to antithyroid drugs on imprinting behavior in hatched chicks. Methimazole (MMI) at 20micromol/egg or 5micromol/egg of propylthiouracil (PTU) was administered to eggs on day 14 while the control was given only a vehicle. An imprinting test was conducted after the chicks hatched. Day-old chicks were exposed to a rotating training object for 150min. The next day, the trained chicks were exposed to the training object and a novel object. The imprinting preference was represented as a preference score (PS) calculated as the rate of following the training object to following the training and novel objects. In the MMI-treated chicks, the PS was 0.68+/-0.06 (range, 0.38-0.88), which was significantly lower than that in the control chicks (0.86+/-0.04, p<0.01). In the PTU-treated chicks, the PS was 0.69+/-0.04 (range, 0.52-0.89), which was also significantly lower than that in the control (0.88+/-0.02, p<0.001). The present findings suggested that fetal thyroid dysfunction inhibited brain development, leading to impaired learning and memory. Our chick model can be considered useful for investigating the direct effects of prenatal exposure to antithyroid drugs or substances in the environment on learning ability after birth.

Topics: Age Factors; Animals; Antithyroid Agents; Birth Rate; Body Weight; Chick Embryo; Chickens; Dose-Response Relationship, Drug; Female; Imprinting, Psychological; Methimazole; Organ Size; Propylthiouracil; Thyroid Gland; Time Factors

Human populations are simultaneously exposed to a variety of anthropogenic contaminants. However, despite extensive literature on animal exposure to single compounds, data on the toxicity of complex mixtures are scarce. The Northern Contaminant Mixture (NCM) was formulated to contain the 27 most abundant contaminants in the same relative proportions found in the blood of Canadian Arctic populations. Sprague-Dawley rat dams were dosed from the first day of gestation until weaning with methylmercury (MeHg), polychlorinated biphenyls (PCBs) or organochlorines pesticides (OCs) administered either separately or together in the NCM. An additional control group for hypothyroxinemia was included by dosing dams with the goitrogen 6-propyl-2-thiouracil (PTU). Offspring growth, survival, serum thyroxine and Thyroid Stimulating Hormone (TSH) levels, thyroid gland morphology, brain taurine content and cerebellum and hippocampus protein expression patterns resulting from such exposures were monitored. Pups' increased mortality rate and impaired growth observed in the NCM treatment group were attributed to MeHg, while decreased circulating thyroxine levels and perturbations of thyroid gland morphology were mostly attributable to PCBs. Interestingly, despite comparable reduction in serum thyroxine levels, PCBs and PTU exposures produced markedly different effects on pup's growth, serum TSH level and brain taurine content. Analysis of cerebellum and hippocampus protein expression patterns corroborated previous cerebellum gene expression data, as contaminant co-exposure in the NCM significantly masked the effects of individual components on protein two-dimensional electrophoresis patterns. Identification by MALDI-TOF/TOF MS of differentially expressed proteins involved notably in neuronal and mitochondrial functions provided clues on the cellular and molecular processes affected by these contaminant mixtures.

Topics: Age Factors; Animals; Arctic Regions; Body Weight; Brain; Canada; Cerebellum; Complex Mixtures; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Female; Gestational Age; Hippocampus; Hydrocarbons, Chlorinated; Hypothyroidism; Male; Methylmercury Compounds; Mitochondrial Proteins; Nerve Tissue Proteins; Pesticides; Polychlorinated Biphenyls; Propylthiouracil; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Taurine; Thyroid Gland; Thyroid Hormones; Water Pollutants, Chemical

C cells are primarily known for producing calcitonin, a hypocalcemic and hypophosphatemic hormone. Nevertheless, besides their role in calcium homeostasis, C cells may be involved in the intrathyroidal regulation of follicular cells, suggesting a possible interrelationship between the two endocrine populations. If this premise is true, massive changes induced by different agents in the activity of follicular cells may also affect calcitonin-producing cells. To investigate the behaviour of C cells in those circumstances, we have experimentally induced two opposite functional thyroid states. We hyperstimulated the follicular cells using a goitrogen (propylthiouracil), and we suppressed thyroid hormone synthesis by oral administration of thyroxine. In both scenarios, we measured T(4), TSH, calcitonin, and calcium serum levels. We also completely sectioned the thyroid gland, specifically immunostained the C cells, and rigorously quantified this endocrine population. In hypothyroid rats, not only follicular cells but also C cells displayed hyperplastic and hypertrophic changes as well as increased calcitonin levels. When exogenous thyroxine was administered to the rats, the opposite effect was noted as a decrease in the number and size of C cells, as well as decreased calcitonin levels. Additionally, we noted that the two cell types maintain the same numerical relation (10 +/- 2.5 follicular cells per C cell), independent of the functional activity of the thyroid gland. Considering that TSH serum levels are increased in hypothyroid rats and decreased in thyroxine-treated rats, we discuss the potential involvement of thyrotropin in the observed results.

Topics: Animals; Body Weight; Calcitonin; Calcium; Cell Size; Goiter; Hypothyroidism; Male; Paracrine Communication; Propylthiouracil; Rats; Rats, Wistar; Thyrotropin; Thyroxine

To clarify the developmental effects of hypothyroidism and to establish a detection system of resultant brain retardation, pregnant rats were administered 3 or 12 ppm of 6-propyl-2-thiouracil (PTU) or 200 ppm of methimazole (MMI) in the drinking water from gestation day 10 to postnatal day 20 and maintained after weaning until 11 weeks of age (adult stage). Offspring displayed evidence of growth retardation lasting into the adult stage, which was particularly prominent in males. Except for hypothyroidism-related thyroid follicular cell hypertrophy, most histopathological changes that appeared at the end of chemical exposure were related to growth retardation and reversed by the adult stage. A delayed onset of puberty and an adult stage gonadal enlargement occurred by exposure to anti-thyroid agents, both being especially evident in males, and this effect might be related to gonadal growth suppression during exposure. At the adult stage, the distribution variability of hippocampal CA1 pyramidal neurons reflecting mismigration could be detected in animals receiving both thyrotoxins, with a dose-dependent effect by PTU. Similarly, a reduction in the area of the corpus callosum and oligodendroglial cell numbers in the cerebral deep cortex, both reflecting impaired oligodendroglial development, were detected in rats administered both chemicals. Thus, all effects, except for impaired brain development, might be linked to systemic growth retardation, and the brain morphometric methods employed in this study may be useful to evaluate the potency of chemicals to induce hypothyroidism-related brain retardation.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Cell Movement; Disease Models, Animal; Embryo, Mammalian; Female; Fetal Growth Retardation; Genitalia; Hypothyroidism; Male; Oligodendroglia; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Pyramidal Cells; Rats; Thyroid Gland; Thyroid Hormones

Markedly lowered thyroid hormone levels during development may influence a child's behaviour, intellect, and auditory function. Recent studies, indicating that even small changes in the mother's thyroid hormone status early in pregnancy may cause adverse effects on her child, have lead to increased concern for thyroid hormone disrupting chemicals in the environment. The overall aim of the study was therefore to provide a detailed knowledge on the relationship between thyroid hormone levels during development and long-lasting effects on behaviour and hearing. Groups of 16-17 pregnant rats (HanTac:WH) were dosed with PTU (0, 0.8, 1.6 or 2.4 mg/kg/day) from gestation day (GD) 7 to postnatal day (PND) 17, and the physiological and behavioural development of rat offspring was assessed. Both dams and pups in the higher dose groups had markedly decreased thyroxine (T(4)) levels during the dosing period, and the weight and histology of the thyroid glands were severely affected. PTU exposure caused motor activity levels to decrease on PND 14, and to increase on PND 23 and in adulthood. In the adult offspring, learning and memory was impaired in the two highest dose groups when tested in the radial arm maze, and auditory function was impaired in the highest dose group. Generally, the results showed that PTU-induced hypothyroxinemia influenced the developing rat brain, and that all effects on behaviour and loss of hearing in the adult offspring were significantly correlated to reductions in T(4) during development. This supports the hypothesis that decreased T(4) may be a relevant predictor for long-lasting developmental neurotoxicity.

Topics: Age Factors; Animals; Animals, Newborn; Antithyroid Agents; Auditory Threshold; Behavior, Animal; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gestational Age; Hearing; Hypothyroidism; Male; Maze Learning; Motor Activity; Nervous System; Neurotoxicity Syndromes; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar; Thyroid Gland; Thyroxine

This study examined the deleterious effects of di(n-butyl) phthalate (DBP) on the male reproductive organs in hypothyroid rats. Hypothyroidism was induced in prepubertal male rats (28 days of age) by an intraperitonial (i.p.) injection of 10 mg/kg/day propylthiouracil (PTU) for 30 days. DBP (100 and 500 mg/kg/day) was administered by oral gavages to the intact or hypothyroid rats for 30 days. The body weight of the PTU-treated rats was significantly lower than the control group. The total triiodothyronine (T3) and thyroxine (T4) serum level was lower, and the thyroid-stimulating hormone (TSH) level was higher in the hypothyroid rats than in the control rats. The DBP treatment rats showed significantly lower testes, epididymides, seminal vesicles, and ventral prostate weights than the untreated rats. The hypothyroid rats had significantly higher thyroid weights and lower adrenal glands weights than the control rats. The histomorphological examination showed diffused Leydig cells hyperplasias and germ cells loss in the DBP (500 mg/kg)-treated rats, whereas these effects were mild in the DBP-treated hypothyroid rats. The serum levels of monobutyl phthalate (MBP) were significantly lower in PTU-induced hypothyroid rats than in the DBP-treated rats. This data suggests that the hypothyroid status might offer some protection from male reproductive organ toxicity caused by a disturbance in the metabolic activation of the parent compound, DBP.

Topics: Animals; Body Weight; Dibutyl Phthalate; Hypothyroidism; Male; Organ Size; Phthalic Acids; Propylthiouracil; Rats; Rats, Sprague-Dawley; Testis; Thyroid Hormones; Thyrotropin

Variation in the bitter-taste receptor gene, TAS2R38 confers the ability to taste 6-n-propylthiouracil (PROP). The objective of this study was to relate TAS2R38 haplotypes and PROP-tasting phenotypes to adiposity in a genetically isolated population. We hypothesized that the nontaster phenotype would be associated with higher BMI and waist circumference (WC) in females, and that dietary restraint would mediate this relationship.. Participants were 540 healthy inhabitants of the genetically isolated village of Carlantino in southern Italy who were 15-89 years of age at the time of the study. Haplotype analyses were performed and PROP tasting was assessed using a filter paper method. Height, weight, and WC were measured and restrained eating was assessed using a brief questionnaire.. Nontaster females had higher BMI and WC than females who were phenotypic tasters, and this relationship was specific to females with low dietary restraint. Regression analysis showed that BMI declined by 1.7 units across taster groups in females when the model included the PROP by restraint interaction. PROP phenotype was not significantly associated with WC in the regression models. Polymorphisms in TAS2R38 were not associated with BMI or WC in females. Neither TAS2R38 haplotype nor PROP phenotype was strongly related to BMI or WC in males.. These data support previous findings of a relation between the nontaster phenotype and higher BMI in females that is modified by dietary restraint. Assessment of PROP phenotypes might provide unique information about adiposity that is not captured by haplotype analysis alone.

Topics: Adiposity; Adolescent; Adult; Aged; Aged, 80 and over; Body Height; Body Mass Index; Body Weight; Caloric Restriction; Female; Haplotypes; Humans; Italy; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Propylthiouracil; Receptors, G-Protein-Coupled; Regression Analysis; Sex Factors; Surveys and Questionnaires; Taste

Hypothyroidism during pregnancy and the early postnatal period has severe neurological consequences for the developing offspring. The impact of milder degrees of perturbation of the thyroid axis as encompassed in conditions of subclinical hypothyroidism and hypothyroxinemia, however, has not been established. The present investigation examined the effects of graded levels of hypothyroidism, from subclinical to severe, on global gene expression in the developing rodent brain. Thyroid hormone insufficiency was induced by administration of propylthiouracil (PTU) to pregnant rats via drinking water from gestational day 6 until sacrifice of pups prior to weaning. In the first study a specialised microarray, the Affymetrix Rat Neurobiology array RN_U34, was used to contrast gene expression in the hippocampus of animals exposed to 0 or 10 ppm (10 mg/l) PTU, a treatment producing severe hypothyroidism. In the second study, a more complete genome array (Affymetrix Rat 230A) was used to compare gene expression in the neocortex and hippocampus of postnatal day (PN) 14 animals experiencing graded degrees of thyroid hormone insufficiency induced by delivery of 0, 1, 2 or 3 ppm PTU to the dam. Dose-dependent up- and down-regulation were observed for gene transcripts known to play critical roles in brain development and brain function. Expression levels of a subset of approximately 25 genes in each brain region were altered at a dose of PTU (1 ppm) that induced mild hypothyroxinemia in dams and pups. These data indicate that genes driving important developmental processes are sensitive to relatively modest perturbations of the thyroid axis, and that the level of gene expression is related to the degree of hormone reduction. Altered patterns of gene expression during critical windows of brain development indicate that thyroid disease must be viewed as a continuum and that conditions typically considered 'subclinical' may induce structural and functional abnormalities in the developing central nervous system.

Topics: Animals; Body Weight; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Hippocampus; Hypothyroidism; Molecular Sequence Data; Neocortex; Oligonucleotide Array Sequence Analysis; Pregnancy; Propylthiouracil; Rats; Rats, Long-Evans; Thyroid Hormones

Cardiac myosin heavy chain (MHC) gene expression undergoes a rapid transition from beta- to alpha-MHC during early rodent neonatal development (0-21 days of age). Thyroid hormone (3,5,3'-triiodothyronine, T(3)) is a major player in this developmental shift; however, the exact mechanism underlying this transition is poorly understood. The goal of this study was to conduct a more thorough analysis of transcriptional activity of the cardiac MHC gene locus during the early postnatal period in the rodent, in order to gain further insight on the regulation of cardiac MHC genes. We analyzed the expression of alpha- and beta-MHC at protein, mRNA, and pre-mRNA levels at birth and 7, 10, 15, and 21 days after birth in euthyroid and hypothyroid rodents. Using novel technology, we also analyzed RNA expression across the cardiac gene locus, and we discovered that the intergenic (IG) region between the two cardiac genes possesses bidirectional transcriptional activity. This IG transcription results in an antisense RNA product as described previously, which is thought to exert an inhibitory effect on beta-MHC gene transcription. On the second half of the IG region, sense transcription occurs, resulting in expression of a sense IG RNA that merges with the alpha-MHC pre-mRNA. This sense IG RNA transcription was detected in the alpha-MHC gene promoter, approximately -1.8 kb relative to the alpha-MHC transcription start site. Both sense and antisense IG RNAs were developmentally regulated and responsive to a hypothyroid state (11, 14). This novel observation provides more complexity to the cooperative regulation of the two genes, suggesting the involvement of epigenetic processes in the regulation of cardiac MHC gene locus.

Topics: Aging; Animals; Animals, Newborn; Base Sequence; Body Weight; Disease Models, Animal; DNA, Intergenic; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Gene Transfer Techniques; Genes, Reporter; Heart Ventricles; Hypothyroidism; Molecular Sequence Data; Myocardium; Myosin Heavy Chains; Promoter Regions, Genetic; Propylthiouracil; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Antisense; RNA, Messenger; Time Factors; Transcription Initiation Site; Transcription, Genetic; Triiodothyronine; Ventricular Myosins

In the present study, effects of transient hypothyroidism (from birth to 30 days) and persistent hypothyroidism (from birth to 90 days) on testicular antioxidant defence system of mature rats were compared in order to know the role of hypothyroidism induced oxidative stress in testicular development and maturation. Rats were made hypothyroid by feeding lactating mothers and adult rats with 0.05% 6-n-propyl thiouracil (PTU) in drinking water. PTU treatment for 30 days or for 90 days to rats from birth resulted in a decrease in body weight at the age of 90 days in comparison to the controls. The testicular germ cell counts were significantly decreased in persistent hypothyroid rats whereas they were increased in the transient hypothyroid rats. However, a significant reduction in the number of live sperms in epididymis of both 30 day and 90-day PTU treated rats was noticed on 90 days of age. Mitochondrial lipid peroxidation (LPx) levels were decreased in transient hypothyroidism whereas LPx and protein carbonylation were elevated during persistent hypothyroidism in the testis. Reduced testicular superoxide dismutase (SOD), catalase and glutathione reductase (GR) and glutathione peroxidase (GPx) activities were marked during transient hypothyroidism. In contrast, an elevation in SOD (PMF) and catalase activities with a significant decline in GPx and GR activities was found following persistent hypothyroidism. Marked histological changes were observed in the testis of both experimental groups. These results suggest a direct regulatory role of thyroid hormone on testicular physiology and antioxidant defence system during development and maturation.

Topics: Animals; Antimetabolites; Antioxidants; Body Weight; Catalase; Glutathione Peroxidase; Glutathione Reductase; Hypothyroidism; Lipid Peroxidation; Male; Oxidative Stress; Propylthiouracil; Rats; Rats, Wistar; Sexual Maturation; Spermatozoa; Superoxide Dismutase; Testis; Thyroid Hormones

Effects of postnatal hypothyroidism and recovery from this condition on regional growth of the rat hippocampus (HC) were studied using two-dimensional (2D) foldout, morphometric maps of HC and its constituent CA1-CA4 regions. The maps were derived from unfolding serial coronal sections of the rat forebrain, consisting of the entire rostrocaudal extent of HC pyramidal cell layer in the normal control and hypothyroid weanling (P25, postnatal day 25) and young adult (P90) male rats, as well as animals allowed to recover from hypothyroid-induced growth retardation at weaning. The maps revealed novel views of HC regions for assessment of topological relationships and measurement of surface areas of the HC cortical sheet (pyramidal cell layer). In normal control P90 rats, the unfolded HC on each side extended 4 times more laterally than rostrocaudally; total HC surface area was about 40 mm(2), compared to 30 mm(2) in the weanling, indicating 35% growth from P25 to P90; CA1 took up 52% of the total HC surface area, followed by CA3 (31%) and CA2 and CA4, 8% each. Hypothyroidism resulted in significant (p<0.01) 11% and 20% reductions in the HC surface area in P25 and P90 rats, respectively; CA1 and CA4 regions suffered the most reductions while CA3 and CA2 regions the least. Recovering rats examined at P90 exhibited remarkable growth plasticity and recovery in HC regions, as evident by their near normal HC cortical surface area values, compared to age-matched controls. The 2D maps also revealed growth deficits in all HC regions of the hypothyroid rats; recovery in these parameters occurred across all dimensions, although the anterior-posterior growth was more severely affected than the mediolateral one. These results are confirmed and extended by volumetric analysis of laminar volumes of HC regions presented in a companion paper [Farahvar, A., Darwish, N., Sladek, S., Meisami, E., in press. Marked recovery of functional metabolic activity and laminar volumes in the rat hippocampus and dentate gyrus following postnatal hypothyroid growth retardation: a quantitative cytochrome oxidase study. Exp. Neurol.]. These results imply that HC regions, in contrast to whole brain, possess exceptional growth plasticity, as shown by ability to dramatically recover from early hypothyroid retardation; also 2D morphometric maps are useful tools to visualize complex and convoluted regional sheet of HC cortex and depict quantitative aspects of growth in normal and experimental condit

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Body Weight; Brain Mapping; Computer-Aided Design; Disease Models, Animal; Female; Hippocampus; Hypothyroidism; Male; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Recovery of Function; Thyroxine; Triiodothyronine

Genetic taste blindness to the bitterness of 6-n-propylthiouracil (PROP) may be a marker for increased energy intake and body weight. This hypothesis has not been tested in pre-adolescent children. This study determined if non-taster children would report higher energy intakes and maintain higher body weights than taster children. Maternal variables which are known to influence food intake and body weight during childhood were also considered including maternal weight, maternal restraint and disinhibition and child feeding practices. Sixty-five children with a mean age of 9.0+/-0.2 years participated. They completed a 3-day diet recall for the estimation of daily energy and macronutrient intakes. BMI (mothers) and BMI%-for-age (children) were calculated from measured heights and weights. Non-taster children reported higher daily energy intakes than super-taster children (p < or = 0.05), but no differences in macronutrient selection were observed. Also, children of disinhibited mothers reported higher daily energy intakes than children of mothers who were not disinhibited (p < or = 0.05). However, these variables did not predict children's body weight. Rather, regression modeling (R2 = 0.59; p < or = 0.0001) revealed that restriction, concern for child weight and maternal BMI were positive predictors of children's BMI%-for-age and pressure to eat was a strong negative predictor (p-value range = 0.02-0.004). PROP status was not a predictor of body weight in these children. These results suggest that in pre-adolescent children, current energy intakes were negatively related to children's PROP status and positively related to maternal disinhibition. However, BMI%-for-age, a measure of long-term energy balance, was related to child feeding practices and maternal BMI.

Topics: Analysis of Variance; Arousal; Body Mass Index; Body Weight; Child; Cohort Studies; Eating; Energy Intake; Feeding Behavior; Female; Humans; Inhibition, Psychological; Male; Propylthiouracil; Quantitative Trait, Heritable; Statistics, Nonparametric; Taste

The BIO 14.6 hamster (dystrophic), animal model of limb girdle muscular dystrophy, exhibits low plasma triiodothyronine levels, muscle weakness, and decreased breathing. After exposure to acute intermittent bouts of hypoxia, dystrophic hamsters depress ventilation relative to baseline resulting in ventilatory long-term depression (LTD). Control hamsters may increase ventilation relative to baseline resulting in ventilatory long-term facilitation (LTF). Serotonin (5-HT) receptors, especially the 5-HT(2A) subtype, are involved in the development of LTF. The purpose of this study was to evaluate the role of 5-HT(2A) receptors in ventilatory and metabolic responses before, during, and following intermittent hypoxia in eleven euthyroid, nine dystrophic, and eleven propylthiouracil (PTU)-induced hypothyroid male hamsters. Animals received subcutaneous injections of vehicle or 0.5 mg/kg MDL (5-HT(2A) receptor antagonist). Plethysmography was used to evaluate ventilatory responses of the three groups to air, five bouts of 5 min of 10% oxygen, each interspersed with 5 min of air, followed by 60 min of exposure to air. CO(2) production was measured using the flow-through method. Vehicle-treated dystrophic and PTU-treated hamsters exhibited LTD. MDL decreased body temperature in all groups. After MDL treatment, the euthyroid group exhibited LTD. MDL treatment in the dystrophic, but not in the PTU-treated hamsters, maintained tidal volume, but did not reverse LTD. CO(2) production was increased in the euthyroid group with MDL treatment. Thus, 5-HT(2A) receptors affect body temperature, ventilation, and metabolism in hamsters. The differential responses noted in this study may be in part dependent on thyroid hormone status.

Topics: Animals; Antithyroid Agents; Atmosphere Exposure Chambers; Body Temperature; Body Weight; Carbon Dioxide; Cricetinae; Hypoxia; Male; Mesocricetus; Muscular Dystrophies, Limb-Girdle; Propylthiouracil; Receptor, Serotonin, 5-HT2A; Respiratory Mechanics; Thyroid Gland

Thyroid hormone is known to play a critical role in growth and development of rat testes with a specific effect on the differentiation of Sertoli cells leading to a normal evolution of germ cells. In the present study, we aimed to compare the effect of induced hypothyroidism during fetal and post-natal life on the structure and function of the testis in adult. Pregnant or lactating mothers were treated with 6-propyl-2-thiouracil (PTU) during 21 days and weight gain of pups was steady until adult age. Plasma hormonal levels were determined by RIA and morphology of testis was studied on sections stained with Masson's trichrome. Pre and early post natal hypothyroidism resulted in an impairment of body development and a diminution of thyroid hormone levels of treated rats. No significant effect on testicular development has been observed when hypothyroidism is induced in fetal life while it was associated with reduction in testis weight, diameter of seminiferous tubules and hormonal levels and delay in maturation of germ cells, when induced during early post natal life.

Topics: Administration, Oral; Age Factors; Analysis of Variance; Animals; Animals, Newborn; Body Weight; Female; Male; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar; Seminiferous Tubules; Spermatozoa; Testis; Thyroid Hormones; Time

Some ubiquitous pollutants of the aquatic environment, such as PCBs or other polyhalogenated aromatic hydrocarbons, may disrupt the thyroid hormone system. In a partial life cycle assay with zebrafish (Danio rerio), we studied the effects of the reference compound propylthiouracil (PTU) on reproduction, growth and development, histopathology of some target tissues, and plasma thyroid hormone levels. PTU induced a concentration-dependent increase of egg production with a concomitant decrease of mature oocyte size but had no effect on fertilization rate or hatching. In F1, serious dysmorphogenesis was found in 4 dph larvae at the highest PTU level tested (100 mg/L), and there was a dose-dependent decrease in body length and weight at 42 dph (significant at 100 mg/L PTU). At this time, there was also a decreased scale thickness, suggesting inhibited metamorphosis, detectable at 1 mg/L PTU and higher. PTU also induced activation of the thyroid follicles in a concentration-dependent way, in juveniles associated with hyperemia in the thyroid area, and depletion of liver glycogen. Effects in adults were associated with decreased circulating levels of the thyroid hormones T3 and T4. These observations indicate that disruption of the thyroid hormone system may affect the fitness of these aquatic organisms. The zebrafish model may contribute to the identification of thyroid hormone disrupting activity in water samples and also in the interpretation of histological observations in free-ranging fish species.

Topics: Animals; Antithyroid Agents; Biological Assay; Body Size; Body Weight; Growth; Larva; Life Cycle Stages; Liver; Liver Glycogen; Propylthiouracil; Reproduction; Thyroid Gland; Thyroid Hormones; Water Pollutants, Chemical; Zebrafish

Thyroid hormones are critical for the maturation and function of the central nervous system. Insufficiency of thyroid hormones in the adulthood causes a wide range of cognitive dysfunctions, including deficits in learning and memory. The present study investigated whether adult-onset hypothyroidism would alter synaptic functions in the dorsal hippocampo-medial prefrontal cortex (mPFC) pathway, a neural pathway important for learning and memory. Adult hypothyroidism was induced by oral administration of 1% (g/l) antithyroid acting drug 6-n-propyl-2-thiouracil (PTU) to adult male Sprague-Dawley rats for 4 weeks. Postsynaptic potentials (PSP) were recorded in the mPFC by stimulating the dorsal hippocampal CA1 region in vivo. Basal synaptic transmission was evaluated by comparing input-output relationships. Paired-pulse facilitation and long-term potentiation were recorded to examine short- and long-term synaptic plasticity. Adult-onset hypothyroidism did not change the basal synaptic transmission, but significantly reduced paired-pulse facilitation and long-term potentiation of PSP. These inhibitions can be restored by thyroid hormone replacement. The results suggest that such alterations in synaptic plasticity of the dorsal hippocampo-mPFC pathway might contribute to understanding basic mechanisms underlying learning and memory deficits associated with adult-onset hypothyroidism.

Topics: Animals; Antithyroid Agents; Body Weight; Electric Stimulation; Electrophysiology; Excitatory Postsynaptic Potentials; Hippocampus; Hypothyroidism; Long-Term Potentiation; Male; Neural Pathways; Prefrontal Cortex; Propylthiouracil; Rats; Rats, Sprague-Dawley; Synapses; Synaptic Transmission; Thyroid Hormones

Terminalia arjuna bark extract is believed to exhibit cardio-protective effects. In the present study we investigated the possible involvement of thyroid hormones in the amelioration of cardiac and hepatic lipid peroxidation (LPO) by a bark extract of the plant in albino rats. While L-thyroxine (L-T4) treatment increased the level of thyroid hormones, heart/body weight ratio as well as cardiac and hepatic lipid peroxidation, simultaneous administration of 21.42 and 42.84 mg/kg of the plant extract decreased the level of thyroid hormones and also the cardiac LPO, suggesting the possible mediation of the drug action through an inhibition in thyroid function. These effects were comparable to a standard antithyroid drug, propyl thiouracil (PTU). When the drug was administered to euthyroid animals, serum concentrations of thyroid hormones were decreased, whereas the hepatic LPO increased indicating a drug induced toxicity in euthyroid subjects. Although a suboptimal dose of the drug was found to be non-toxic to the liver, it appeared to be of no use, as it could neither affect the thyroid functions nor the cardiac lipid peroxidation. Since in euthyroid animals, thyroid hormones were decreased and hepatic LPO was increased, it is suggested that high amounts of this plant extract should not be consumed, as hepatotoxicity as well as hypothyroidism may be caused.

Topics: Animals; Antithyroid Agents; Body Weight; Cardiotonic Agents; Female; Hyperthyroidism; Lipid Peroxidation; Liver; Malondialdehyde; Organ Size; Plant Bark; Propylthiouracil; Radioimmunoassay; Rats; Rats, Wistar; Terminalia; Thiobarbituric Acid Reactive Substances; Thyroid Hormones; Thyroxine; Triiodothyronine

In this preliminary study, the potential of an in utero-lactation assay to detect thyroid effectors was evaluated by treating three dams/group with 6-n-propyl-2-thiouracil (PTU), a known thyroid antagonist, by oral gavage at doses of 0, 0.0032, 0.016, 0.08 and 0.4 mg/kg/day during fetal organogenesis and lactation. Hearing disturbances and an elevated relative thyroid weight were observed in offspring of both sexes in the 0.4 mg/kg/day group. The Biel-type water T-maze test showed an increase in the number of errors made by females in the 0.4 mg/kg/day group. Histopathologically, flattening of follicular epithelium, a decrease in resorptive colloid droplets, degeneration of follicular epithelium, and hyperplasia of follicular epithelium were observed in males belonging to the 0.4 mg/kg/day group. Histopathological abnormalities were also observed in some offspring belonging to the 0.08 mg/kg/day group. In the dams, hypertrophy of the follicular epithelium of the thyroid was observed in the 0.4 mg/kg/day group. Although we could not explain the mechanism for the difference in the effects seen in the offspring and the dams, the effect of PTU in utero through lactational exposure is apparently different from that resulting from exposure in homeostatically mature rats. Most reports studying PTU have involved administration in water or in food, and reports on the oral gavage of PTU during the fetal organogenesis and lactation period are very rare. This assumes that dosages >0.4 mg/kg/day would also produce clear anti-thyroid effects by oral gavage and, possibly, emphasizes that dosages <0.4 mg/kg/day did not have a noticeable effect. Based on the present results, a study to determine the reproducibility of the data in a much larger number of dams will be performed to confirm the findings in the present study, and to evaluate other endpoints, such as hormonal evaluation of dams and their offspring, sexual developmental landmarks, and fertility of the offspring.

Topics: Animals; Antithyroid Agents; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Female; Fetal Development; Lactation; Maze Learning; Motor Activity; Organ Size; Postural Balance; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Reflex; Reflex, Startle; Thyroid Gland

Taste blindness to the bitterness of 6-n-propylthiouracil (PROP) may be a genetic marker for food preferences and dietary choices that ultimately influence body weight. A previous study in middle-aged women showed that those who were taste blind to PROP (i.e., nontasters) had higher BMIs than those with the greatest sensitivity to PROP (i.e., supertasters). This study tested the hypothesis that the nontaster phenotype was associated with greater adiposity in middle-aged women.. Forty women with a mean BMI of 26.6+/-1.3 kg/m2 and a mean age of 41.8+/-1.8 years were recruited from the local community. They were classified as nontasters (n=8), medium tasters (n=18), or supertasters (n=14) of PROP using a filter paper screening procedure. Anthropometric measures included height, weight, body fatness, triceps skinfold thickness, and waist circumference. Dietary restraint and disinhibition were also measured to assess cognitions associated with body weight.. BMI was 6.2 units higher in nontaster women compared with supertaster women (29.7+/-0.9 vs. 23.5+/-0.9, respectively; p<0.05). Body fatness (p<0.01) and triceps skinfold thickness (p<0.05) were also higher in these women. Waist circumference showed a trend in the appropriate direction. Although disinhibition was associated with greater adiposity, the relation between PROP status and adiposity was not altered after controlling for disinhibition.. The PROP nontaster phenotype was strongly associated with several measures of adiposity in middle-aged women. These data confirm our previous findings and suggest that the PROP polymorphism may be a reliable indicator of weight gain susceptibility.

Topics: Adipose Tissue; Adult; Ageusia; Body Composition; Body Mass Index; Body Weight; Female; Humans; Middle Aged; Propylthiouracil; Skinfold Thickness; Statistics, Nonparametric

To determine if thyroid function affects faecal shedding of Escherichia coli O157:H7.. Eight yearling cattle (n = 4 per treatment group), previously identified as shedding E. coli O157:H7, received either 0 or 10 mg 6-N-propyl-2-thiouracil (PTU) kg(-1) BW day(-1) for 14 days to reduce serum concentrations of the thyroid hormones, T(3) and T(4). Animals were monitored daily for changes in faecal shedding of E. coli O157:H7 and E. coli (EC) for the 14-day treatment period and an additional 7 days post-treatment. Body weight was measured weekly and serum concentrations of T(3) and T(4) were determined every 3 days. No differences in faecal shedding of E. coli O157:H7 were observed during the 14-day treatment period. However, compared with control animals, a greater percentage of PTU-treated cattle ejected E. coli O157:H7 on day 16 (100 vs 25%) and 18 (75 vs 0%) of the post-treatment period. Serum T(3) was lower in PTU-treated cattle during the 14-day treatment period and greater on day 18 of the post-treatment period.. Cattle with chemically altered thyroid hormones had similar shedding patterns of faecal E. coli O157:H7 and EC during the 14-day treatment period. However, faecal shedding of E. coli O157:H7 tended to be greater, and serum concentrations of T(3), were greater for PTU-treated cattle immediately following the termination of PTU treatment.. Short-term chemical inhibition of thyroid hormones had minimal effects on faecal shedding of E. coli O157:H7 in naturally infected cattle. However, a hyperthyroid state as observed postdosing might play a role in the seasonal shedding of E. coli O157:H7 in cattle.

Topics: Animals; Antithyroid Agents; Body Weight; Cattle; Cattle Diseases; Colony Count, Microbial; Escherichia coli; Escherichia coli Infections; Escherichia coli O157; Feces; Food Microbiology; Propylthiouracil; Thyroid Gland; Thyroxine; Triiodothyronine

It is known that there is abnormal osteopontin (OPN) expression at the sites of atherosclerotic lesions. In the Apolipoprotein E gene knockout (ApoE-KO) mouse, a model of the atherosclerotic process, altered cholesterol metabolism with associated increase in OPN expression is evident at 12-22 weeks in the aorta and at 22 weeks in the heart. In this study, we analyzed another animal model of hypothyroid mice created by ingestion of propylthiouracil (PTU). After 2 weeks of PTU ingestion, the animals had significant decreases in thyroid hormones (T3 and T4) and immediate increases in blood lipids/cholesterol. Hypothyroid mice showed 1.3-, 1.5-, 2-fold increases in blood levels of total cholesterol, triglycerides, and low density lipoprotein-cholesterol respectively. Semi-quantitative RT-PCR analysis showed that hypothyroid mice had 1.4- to 2-fold increases of OPN mRNA expression in the aorta and 1.5-fold increases in the heart. Hypothyroid animals treated with T3 (5 microg/day for 6 days) or statin (0.2 mg/30 g for 2 weeks) reduce blood lipids and aortic OPN mRNA expression. Data obtained with ELISA analyses showed 1.5- and 1.7-fold increases in OPN protein in the aorta (10 weeks) and the heart (22 weeks), respectively. This increase is close to the mRNA expression in both tissues of hypothyroid mice. In addition, western blots showed several variants of OPN protein expressed in the aorta and the heart. The decrease in the 70 kDa OPN is accompanied by an increase in 45 kDa OPN in the aorta of hypothyroid mice. In contrast, only 45 kDa OPN is found in the heart of control and hypothyroid mice. These data indicate that the increase of OPN mRNA and protein expression occurs in cardiovascular tissues of hypothyroid mice.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Blood Pressure; Blotting, Western; Body Weight; Cardiovascular System; Cholesterol; Cholesterol, LDL; Disease Models, Animal; Electrophoresis, Agar Gel; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Heart; Heart Rate; Hypothyroidism; Lipids; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Models, Statistical; Myocardium; Osteopontin; Propylthiouracil; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sialoglycoproteins; Thyroxine; Time Factors; Triglycerides; Triiodothyronine

Effects of transient neonatal hypothyroidism (HPOT) on adult testis size and serum hormone profiles were evaluated in the Charles foster strain of rats, maintained under the temperature of 21 degrees C (HPOTL) or of 34 degrees C (HPOTH).. Hypothyroidism was induced in suckling pups in preweanling period (1-21 days), by administering 0.1% 6-propyl-2-thiouracil in drinking water to mothers. Body mass and testis characteristics, the steroidogenic potential [measured by histochemical localization of 3alpha-, 3beta- and 17beta-hydroxysteroid dehydrogenases (HSDHs)] and serum concentrations of thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), luteinizing hormone (LH), testosterone (T) and corticosterone (Cort) were evaluated on the 35th, 45th, 60th and 90th day of age.. The HPOTH rats showed lower testis masses, while the HPOTL rats showed higher testis masses and lower body masses after 90 days. Histologically, the testes of the HPOTH rats demonstrated increased germ cell degeneration after 35 and 45 days and reduced tubular size, germ cell numbers and sperm density after 90 days. In contrast, the testes of the HPOTL rats showed reduced tubular diameters after 35 and 45 days, and increased tubular diameters, germ cell numbers and sperm density after 90 days. Serum TSH, T3, T4, LH and T concentrations and 3beta- and 17beta-HSDH activities were reduced in both groups of the HPOT rats after 35 and 45 days. Intratubular steroidogenesis and a prominent triangle up5 pathway were also found in the HPOT animals.. The temperature has a definite influence on the thyroid hormone action, postnatal growth and function of rat testes.

Topics: Age Factors; Animals; Animals, Newborn; Body Weight; Corticosterone; Female; Germ Cells; Hydroxysteroid Dehydrogenases; Hypothyroidism; Luteinizing Hormone; Male; Organ Size; Pregnancy; Propylthiouracil; Rats; Temperature; Testis; Thyroid Hormones; Thyrotropin

Several cardiac genes possess thyroid hormone (TH) response elements regulated by TH receptors. Mutation in TR-beta gene causes the human syndrome of resistance to TH, which is characterized by elevated serum concentration of T(4) and T(3) and variable degrees of insensitivity to TH. It is unclear, however, whether a mutant TR-beta could function as a dominant negative in the heart when expressed from the endogenous locus. A well-described resistance to TH (Delta337T) was either introduced into germline of mice (KI-mut) or expressed as a transgene in the heart using a cardiac-specific promoter (KS-mut). Mice were studied at baseline, after 5-propyl-2-thiouracil (PTU) or after PTU and T(3) treatment (PTU + T(3)). PTU + T(3) treatment significantly increased left ventricular mass in all groups compared with baseline measurements, although the increase in left ventricular mass was significantly less in KI-mut animals. Baseline heart rates (HRs) were similar in wild-type (WT) and KI-mut but were lower in KS-mut animals. After TH deprivation (PTU), HR decreased in WT and KI-mut animals; similarly, HR increased in WT and KI-mut after PTU + T(3). In contrast, HR in KS-mut animals did not change after either treatment. Except for cardiac hypertrophy, the presence of a germline TR-beta mutation had surprisingly little effect on cardiac function.

Topics: Animals; Body Weight; Echocardiography; Gene Expression; Germ-Line Mutation; Heart; Hemodynamics; Humans; Mice; Mice, Inbred Strains; Mice, Transgenic; Propylthiouracil; Thyroid Hormone Receptors beta; Thyroid Hormone Resistance Syndrome; Thyroid Hormones; Triiodothyronine

Transient reductions in thyroid hormone during critical periods of brain development can have devastating and irreversible effects on neurological function. The hippocampus is a brain region sensitive to thyroid hormones and is a necessary substrate for some forms of learning and memory. Subregions within the hippocampus display distinct ontogenetic profiles and have shown differential vulnerability to some indices of thyrotoxic insult. Synaptic function can be readily assessed in the hippocampus, yet little information exists on the consequences of early thyroid hormone insufficiency on the neurophysiological integrity of this structure. Previous work has examined the long-term consequences of perinatal hypothyroidism on neurophysiology of the dentate gyrus of the hippocampal formation. The current study reveals that alterations in synaptic function also exist in area CA1, and some differences in the pattern of effects are evident between the two hippocampal subfields. Developing rats were transiently exposed to the thyrotoxicant, propylthiouracil (PTU; 0 or 15 ppm), through the drinking water of pregnant dams beginning on gestational day 18. This regimen markedly reduced circulating levels of thyroid hormones and stunted pup growth. PTU exposure was terminated on postnatal day (PN) 21 and electrophysiological assessments were conducted by recording field potentials in area CA1 of hippocampal slices derived from adult male offspring. Synaptic transmission, short-term, and long-term synaptic plasticity were assessed. Consistent with observations in the dentate gyrus, somatic population spike amplitudes were reduced in assessments of baseline synaptic transmission of slices from PTU-exposed animals. No differences were identified in excitatory postsynaptic potentials (EPSP). Short-term plasticity of the EPSP as indexed by paired pulse facilitation was markedly impaired by PTU exposure. Long-term potentiation (LTP) of the population spike was enhanced, consistent with findings in dentate gyrus, but no change in EPSP LTP was detected. Perturbations in synaptic function in the hippocampus of adult rats transiently exposed to a period of hormone insufficiency during the perinatal period are likely to contribute to cognitive deficits associated with developmental hypothyroidism.

Topics: Aging; Animals; Animals, Newborn; Body Weight; Electric Stimulation; Electrophysiology; Excitatory Postsynaptic Potentials; Female; Hippocampus; Hypothyroidism; In Vitro Techniques; Long-Term Potentiation; Male; Neuronal Plasticity; Pregnancy; Propylthiouracil; Radioimmunoassay; Rats; Rats, Long-Evans; Synaptic Transmission; Thyroid Hormones; Time Factors

Development of an internationally recognized standard for the Hershberger assay as a screening tool to detect potential (anti-)androgenic chemicals is in progress. In the present preliminary study, we evaluated the reliability of the enhanced Hershberger assay to detect thyroid hormone modulating activity, while concentrating attention on possible confounding influence on evaluation of (anti-)androgenic activity. Castrated or testosterone propionate (TP; 0.2 or 0.25 mg/kg/day)-injected castrated male Crj:CD(SD) IGS rats (seven weeks of age) were dosed for 10 days by oral gavage with vehicle (corn oil) or the following chemicals: propylthiouracil (PTU; 2.5 mg/kg/day), a potent inhibitor of thyroid hormone synthesis, phenobarbital (PB; 125 mg/kg/day) and 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE; 100 mg/kg/day), two hepatic enzyme inducers that enhance the clearance of thyroid hormones. PTU markedly increased thyroid weights, and decreased serum T3 and T4, and increased serum TSH, also causing marked microscopic alteration of the thyroid gland. In comparison, PB and p,p'-DDE only significantly affect serum T4 and revealed some histopathological findings. The alterations appeared to be more robust in the presence of TP. Furthermore, data for p,p'-DDE demonstrated its anti-androgenic effects, whereas PTU and PB had little or no effects on the weights of androgen-related accessory glands/tissues: the ventral prostate, dorso-lateral prostate, seminal vesicles with coagulating glands, glans penis, Cowper's glands, and levator ani plus bulbocavernosus (LABC) muscles. Weight of the LABC muscles was decreased by PB treatment in TP-treated castrated rats. These findings in the present study suggests that the enhanced Hershberger assay, with evaluation of thyroid histopathology and weights, and hormone levels, appears to be reliable for screening for not only (anti-)androgenic chemicals but also thyroid hormone modulators. In order to evaluate whether the sensitivity and specificity of such a thyroid assay is great enough for routine screening purposes, future experiments including dose-response studies using lower dose levels have to be performed.

Topics: Administration, Oral; Androgen Antagonists; Animals; Antithyroid Agents; Body Weight; Castration; Dichlorodiphenyl Dichloroethylene; Drug Evaluation, Preclinical; Eating; Injections, Subcutaneous; Male; Organ Size; Phenobarbital; Propylthiouracil; Rats; Rats, Inbred Strains; Reproducibility of Results; Testosterone Propionate; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Negative associations between the inherited ability to taste the bitter compound 6-n-propylthiouracil (PROP) and preference for fat and body weight have been observed in adults. This study tested the relationships among the ability to taste PROP, reported food intake, and body weight in young children.. Fifty-three 4- to 5-year-old children were classified as tasters (N = 35) or nontasters (N = 18) of PROP using a standard screening solution. Anthropometric measures were taken in the laboratory. Mothers completed questionnaires to assess their child's food intake and their own dieting behaviors.. Nontaster boys had higher weight-for-height percentiles than taster boys (77th vs. 56th percentile, respectively), but the relationship was opposite for girls (p < or = 0.05). Nontasters reportedly consumed a higher percentage of their daily energy from protein (p < or = 0.01), mainly as high-fat meat products. Tasters reportedly consumed a higher percentage of their daily energy from sugars (p < or = 0.05), mainly in the form of brownies, doughnuts, cookies, soft drinks, and juice drinks. There were no differences between tasters and nontasters for reported intake of grains, fruits, vegetables, dairy products, or discretionary fats.. This study is the first, to our knowledge, to report weight differences in children as a function of their PROP status. Genetic taste factors seem to play a role in the development of dietary patterns and weight differences in young children, but the nature of these relationships may vary with gender.

Topics: Body Weight; Child, Preschool; Eating; Female; Food Preferences; Humans; Male; Propylthiouracil; Statistics, Nonparametric; Surveys and Questionnaires; Taste

To develop a method to reliably induce congenital hypothyroidism in guinea pigs (Cavia porcellus) and assess similarities between the resultant developmental abnormalities and those described in horses with congenital hypothyroidism.. 35 female guinea pigs and their offspring.. Guinea pigs were allocated to control groups or groups treated with a low-iodine diet before and throughout gestation; an s.c. injection of 100 or 200 microCi of radioactive iodine 131 (131I) on day 40 of gestation; or 0.1% propylthiouracil (PTU) continuously in the drinking water, beginning day 3 or 40 of gestation. In all groups, assessments included gestation duration, litter size, proportion of stillborn pups, and laboratory analyses in live pups and dams; postmortem examinations were performed on all pups and dams and selected tissues were examined histologically.. Compared with control animals, pups from dams receiving a low-iodine diet or 131I s.c. had mild changes in their thyroid glands but no grossly or radiographically detectable lesions of hypothyroidism. Pups from dams receiving PTU were often stillborn (24/27 pups) and had enlarged thyroid glands (characterized by large, variably sized follicles of tall columnar epithelium and little or no colloid), an incomplete coat, and radiographically detectable skeletal dysgenesis.. Many of the lesions detected in guinea pig pups from the experimentally treated dams were similar to those described in foals with congenital hypothyroidism. Experimental induction of congenital hypothyroidism in guinea pigs may be useful for the study of naturally occurring congenital hypothyroidism in horses.

Topics: Animals; Body Weight; Bone and Bones; Congenital Hypothyroidism; Female; Guinea Pigs; Histological Techniques; Horse Diseases; Horses; Hypothyroidism; Iodine; Iodine Radioisotopes; Litter Size; Models, Animal; Propylthiouracil; Radiography; Thyroxine; Triiodothyronine

Twenty-four Rambouillet ewe lambs (average weight=43.7+/-1.2 kg, approximately 6 months of age) were used to examine the effect of thyroid suppression before the onset of puberty on serum thyroid hormones, body weights (BW), and reproductive performance. Beginning in early September, ewe lambs were randomly assigned to three treatments (n=8 lambs/treatment). All animals remained in a single pen (4 x 12 m) with access to salt, water, shade and alfalfa hay (2.5 kg per animal per day) throughout the experiment. Beginning on Day 0 (first day of treatment), all ewe lambs received daily treatments (gavage) for 15 days consisting of 0, 20, or 40 mg 6-N-propyl-2-thiouracil(PTU)/kg BW per day. Beginning on Day 15, the 20 and 40 mg treatments were lowered to 10 and 20 mg PTU/kg BW, respectively. All animals were treated for 28 days. Ovarian cyclicity was determined by twice weekly progesterone (P(4)) analysis. Thyroxine (T(4)) concentrations were similar on Day 0 (61.6, 54.8 and 56.9+/-2.5 ng/ml, P=0.17) in ewe lambs receiving 0, 20 and 40 mg PTU/kg BW, respectively. By Day 7, both PTU-treated groups had T(4) values less than 20 ng/ml (9.0 and 15.4+/-2.5 ng/ml) compared with 78.5 ng/ml in controls (P<0.01). By 7 days after termination of PTU treatment, serum T(4) had risen to 29.1 and 26.9 (+/-2.9)ng/ml in the 20/10 and 40/20 PTU groups, respectively. On Day 66, control ewes had 55.0 ng T(4)/ml compared with 43.1 and 39.0 (+/-2.6 ng/ml) for ewes in the 20/10 and 40/20 groups, respectively (linear, P<0.01). Serum triiodothyronine (T(3)) followed a similar pattern to that observed for T(4). Ewe lamb BW were similar (P>0.50) among groups throughout the treatment period. However, following the treatment, PTU-treated ewes tended (P<0.10) to weigh less than controls. Average Julian day of puberty was also similar (P>0.50) among treatments (286, 288 and 288+/-5 days; control, 20/10 and 40/20, respectively). Control ewes had a pregnancy rate of 75%, while both PTU-treated groups had pregnancy rates of 88% (P>0.20). The administration of PTU resulted in a rapid decline in serum T(4) and T(3) but neither time of puberty nor pregnancy rates were affected by lowered thyroid hormones.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Birth Weight; Body Weight; Female; Male; Pregnancy; Progesterone; Propylthiouracil; Random Allocation; Reproduction; Sexual Maturation; Sheep; Thyroxine; Triiodothyronine

Two experiments were conducted to determine if propylthiouracil (PTU)-induced thyroid suppression immediately before onset of anestrus would extend the breeding season in mature ewes. In Exp. 1, twice-weekly serum concentrations of progesterone indicated that all ewes were cyclic before initiation of treatment. Beginning on d 0 (January 17), ewes received 0 (n = 4), 20 (n = 5), or 40 (n = 5) mg of PTU x kg(-1) of body weight (BW) x (-1) for 35 d. Blood samples were collected regularly throughout the trial and serum thyroxine and progesterone were quantified. Ewe BW were similar (P > 0.90) among treatments before the experiment began (mean = 78.2 +/- 4.5 kg). Likewise, serum concentrations of thyroxine averaged 86.5 +/- 8.0 ng/mL on d 0. After 11 d of PTU treatment, serum thyroxine was 90.2,75.2, and 44.2 +/- 14.0 ng/mL in ewes receiving 0, 20, and 40 mg of PTU/kg BW, respectively (linear effect, P = 0.04). On d 20, thyroxine values in the three respective groups were 73.0, 51.1, and 16.1 +/- 12.9 ng/mL (linear effect, P < 0.01). Fourteen days after PTU treatment ended, serum thyroxine did not differ (P = 0.53) among the three respective groups (71.4,73.3, and 57.5 +/- 11.8 ng/mL). Ewes receiving PTU tended to weigh less on d 42 (84.2, 78.2, and 71.8 +/- 5.1 kg for ewes treated with 0, 20, and 40 mg PTU/kg, respectively; linear effect, P = 0.10). Day of onset of anestrus was designated as the day on which serum progesterone decreased and remained below 1 ng/mL. Ewes treated with 0, 20, or 40 mg of PTU/kg BW became anestrous on d 16,40, and 81 (+/- 12) of the experiment, respectively (linear effect, P < 0.01). At the time the 35-d treatment period ended, 25, 60, and 100% of ewes receiving 0, 20, or 40 mg of PTU/kg exhibited normal estrous cycles. In Exp. 2, ewes received 0, 20, or 40 mg of PTU/kg BW for 14 d. The dose was then decreased to 0, 10, and 20 mg of PTU/kg BW for the remaining 21 d. Serum thyroxine decreased to concentrations below 20 ng/mL by d 9 after initiation of PTU treatment. Ewe weights did not differ throughout the trial and no BW loss was observed. The average day that each group entered anestrus was similar to those in Exp 1. Large doses of PTU dramatically lower serum thyroxine and this effect appears to inhibit onset of anestrus in ewes.

Topics: Analysis of Variance; Anestrus; Animals; Antithyroid Agents; Body Weight; Dose-Response Relationship, Drug; Female; Ovary; Progesterone; Propylthiouracil; Random Allocation; Reproduction; Seasons; Sheep; Thyroxine; Time Factors

To develop and pre-validate an enhanced protocol for OECD Test Guideline 407, we performed a 28-day repeated-dose toxicity study using the administration of propylthiouracil (PTU) and tamoxifen (TAM) in Sprague-Dawley (SD) rats. Six male and female SD rats were treated orally with PTU in corn oil at the dose of 0, 0.1, 1, or 10 mg/kg per day and TAM at dose of 0, 5, 30 or 200 microg/kg per day for 4 weeks. In the study using PTU, the body weights were reduced from the third week of the study in 10 mg/kg per day group. In clinical biochemistry, the levels of 3,5,3'-triiodothyronine (T3) and thyroxine (T4, 3,5,3',5'-tetraiodothyrosine) were also significantly decreased in 10 mg/kg per day group. Also, thyroid glands in 10 mg/kg per day group were bigger than those in the control group. In the histopathological examination, diffuse hyperplasia and hypertrophy of thyroid follicular cells were observed in all treatment groups, leading to the reduction of lumen size and papillary enfolding of lining epithelium. In the study using TAM, the body weights were reduced from the first week of the study in 200 microg/kg per day group. Relative testes and epididymes weights were increased and relative right ovary and uterus weights were reduced in 200 microg/kg per day group. Also, in the histopathological finding severe endometrial squamous metaplasia and endometrial gland atrophy and severe follicular cystic change were observed in TAM 200 microg/kg per day-treated group. On the basis of the results, the thyroid hormone levels, gross findings, and histopathological findings may be useful parameters for the detection of the endocrine-related effect of PTU and also reproductive organ weight and histopathological findings may be good parameters to detect the effect of TAM. Therefore, it is concluded that enhanced OECD TG407 might be useful for screening and detecting endocrine disrupters.

Topics: Animals; Antimetabolites; Antineoplastic Agents, Hormonal; Blood Cell Count; Body Weight; Dose-Response Relationship, Drug; Eating; Estrous Cycle; Female; Guidelines as Topic; Intubation, Gastrointestinal; Male; Organ Size; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sperm Count; Sperm Motility; Tamoxifen; Testis

Each year, 75 million pounds of the broadleaf herbicide atrazine (ATR) are applied to crops in the United States. Despite limited solubility, ATR is common in ground and surface water, making it of regulatory concern. ATR suppresses the immunomodulatory hormones prolactin (PRL) and the thyroid hormones (THs), with developmental exposure to ATR permanently disrupting PRL regulation. We hypothesized that ATR may cause developmental immunotoxicity through its disruption of PRL or THs. To test this hypothesis, pregnant Sprague-Dawley (SD) rats were exposed to 35-mg ATR/kg/d from gestational day (GD) 10 through postnatal day (PND) 23. Separate groups were exposed to bromocryptine (BCR) at 0.2 mg/kg/2x/day to induce hypoprolactinemia or to propylthiouracil (PTU) at 2 mg/kg/day to induce hypothyroidism. After the offspring reached immunologic maturity (at least 7 weeks old), the following immune functions were evaluated: natural killer (NK) cell function; delayed-type hypersensitivity (DTH) responses; phagocytic activity of peritoneal macrophages; and antibody response to sheep erythrocytes (SRBC). ATR decreased the primary antibody and DTH responses in male offspring only. Neither PTU nor BCR caused immunosuppression in any measured variable, although PTU increased phagocytosis by peritoneal macrophages. These results demonstrate that developmental exposure to ATR produced gender-specific changes in immune function in adult rats and suggest that immune changes associated with ATR are not mediated through the suppression of PRL or THs.

Topics: Abnormalities, Drug-Induced; Adjuvants, Immunologic; Administration, Oral; Animals; Animals, Suckling; Atrazine; Body Weight; Bromocriptine; Congenital Hypothyroidism; Female; Herbicides; Hypoproteinemia; Hypothyroidism; Immune System; Immunity; Lactation; Longevity; Organ Size; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sex Factors

Reductions in thyroid hormone during critical periods of brain development can have devastating effects on neurological function that are permanent. Neurochemical, molecular and structural alterations in a variety of brain regions have been well documented, but little information is available on the consequences of developmental hypothyroidism on synaptic function. Developing rats were exposed to the thyrotoxicant, propylthiouracil (PTU: 0 or 15 ppm), through the drinking water of pregnant dams beginning on GD18 and extending throughout the lactational period. Male offspring were allowed to mature after termination of PTU exposure at weaning on PND21 and electrophyiological assessments of field potentials in the dentate gyrus were conducted under urethane anesthesia between 2 and 5 months of age. PTU dramatically reduced thyroid hormones on PND21 and produced deficits in body weight that persisted to adulthood. Synaptic transmission was impaired as evidenced by reductions in excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitudes at a range of stimulus intensities. Long-term potentiation of the EPSP slope was impaired at both modest and strong intensity trains, whereas a paradoxical increase in PS amplitude was observed in PTU-treated animals in response to high intensity trains. These data are the first to describe functional impairments in synaptic transmission and plasticity in situ as a result of PTU treatment and suggest that perturbations in synaptic function may contribute to learning deficits associated with developmental hypothyroidism.

Topics: Aging; Analysis of Variance; Animals; Animals, Newborn; Antimetabolites; Body Weight; Dentate Gyrus; Disease Models, Animal; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Electric Stimulation; Electrophysiology; Excitatory Postsynaptic Potentials; Female; Hippocampus; Hypothyroidism; Male; Neuronal Plasticity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Radioimmunoassay; Rats; Rats, Long-Evans; Synaptic Transmission; Thyroid Hormones

The antithyroid acting drug propylthiouracil (PTU) was administered to male and female Wistar rats at 0, 0.1, 1, or 10mg/kg body weight for 4 weeks according to the draft protocol of the "Enhanced OECD Test Guideline 407" (enhanced TG 407) in order to investigate its suitability to detect endocrine-mediated effects. The study was conducted with two identical subsets of five animals per sex and dose each to provide data on sensitivity. The modified protocol includes the investigation of additional organ weights, pathology, and histopathology, of thyroid hormones, of spermatozoa, and of estrus cycle. At time of sacrifice, all females were in the diestrus stage as prescribed. Adverse effects were observed in the thyroid gland (hypertrophy/ hyperplasia) and the pituitary gland (hyperplasia of basophilic cells, hypoplasia of acidophilic cells) together with dose-related decreased serum triiodothyronine (T3) and thyroxine (T4) levels and increased thyroid stimulating hormone (TSH) levels. Other effects of PTU included decrease of organ weights, anaemia, impaired blood coagulation, and reduced activity of enzymes. Hence, some of the additional examined endpoints of the enhanced TG 407, e.g., examination of pituitary gland and thyroid hormones, were suitable to detect endocrine-modulating effects of propylthiouracil. Treatment of five animals provides sufficient sensitivity to detect the described adverse effects of propylthiouracil. The enhanced TG is currently under investigation in several laboratories, evaluation of all the results will allow determining its practicability as well as the most suitable additional endpoints.

Topics: Administration, Oral; Animals; Antithyroid Agents; Body Weight; Drug Evaluation, Preclinical; Eating; Female; Gonads; International Cooperation; Intubation, Gastrointestinal; Male; Organ Size; Propylthiouracil; Rats; Rats, Wistar; Reproducibility of Results; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

An in vivo screening assay using intact adult male rats has been evaluated for its ability to detect four endocrine-active compounds (EACs) via oral (gavage) administration. The test compounds included the aromatase inhibitor fadrozole (FAD), the testosterone biosynthesis inhibitor ketoconazole (KETO), and the thyroid modulators phenobarbital (PB) and propylthiouracil (PTU). Three of the test compounds (KETO, PB, and PTU) have been previously evaluated in the 15-day intact male assay with compound administration via intraperitoneal injection (ip). For the current studies, male rats were dosed for 15 days via oral gavage and euthanized on the morning of test day 15. The endpoints evaluated included final body and organ weights (liver, thyroid gland, testes, epididymides, prostate, seminal vesicles with fluid, accessory sex gland unit [ASG]), serum hormone concentrations (testosterone [T], estradiol [E2], dihydrotestosterone [DHT], luteinizing hormone [LH,] follicle stimulating hormone [FSH], prolactin [PRL], T(3), T(4), thyroid stimulating hormone [TSH]), and histopathology of the testis, epididymis, and thyroid gland; positive results for each endpoint are described below. In addition, an evaluation of immune system endpoints (humoral immune function, spleen and thymus weights, and spleen cell number) was conducted on a subset of animals dosed with either KETO or PB. FAD and KETO decreased the weights for the androgen-dependent tissues and caused similar patterns of hormonal alterations (decreased serum T and DHT; increased serum FSH and/or LH). In addition, KETO caused spermatid retention. For FAD and KETO, effects on thyroid parameters were not indicative of thyroid toxicity. PB and PTU caused thyroid effects consistent with thyroid modulators (increased thyroid weight, decreased serum T(3) and T(4), increased serum TSH, thyroid follicular cell hypertrophy/hyperplasia, and colloid depletion). In addition, PB increased relative liver weight and altered reproductive hormone concentrations (decreased serum DHT, PRL, LH; increased serum E2). Orally administered KETO and PB did not alter the primary humoral immune response to sheep red blood cells (SRBC), although spleen weights were increased at the highest doses for both compounds. In the current study, all four test substances were identified as endocrine-active. The effects that were observed in the current study via oral (gavage) compound administration were similar to the responses that were observed b

Topics: Androgens; Animals; Antibody Formation; Antithyroid Agents; Aromatase Inhibitors; Body Weight; Drug Evaluation, Preclinical; Enzyme Inhibitors; Female; Hormones; Injections, Intraperitoneal; Ketoconazole; Male; Organ Size; Phenobarbital; Propylthiouracil; Rats; Rats, Sprague-Dawley; Spleen; Steroids; Thyroid Gland

Two repeated-dose studies of 6-n-propyl-2-thiouracil (PTU) in male rats based on the research protocol 'Pubertal Development and Thyroid Function in Immature Male Rats' (pubertal assay) proposed by the Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) and the draft protocol of the 'Enhanced OECD Test Guideline 407' (enhanced TG 407) were performed to investigate the suitability of both assays as screening methods for the detection of endocrine-mediated effects and to compare their sensitivity for the endocrine-mediated effects. In the pubertal assay, PTU at doses of 0, 0.01, or 1 mg/kg per day was orally administered to male Sprague-Dawley rats for 30 days, starting at 23 days of age. In the enhanced TG 407 the same doses of PTU were orally administered to male Sprague-Dawley rats for 28 days, starting at 7 weeks of age. In the pubertal assay, decreased serum thyroxine (T4) and triiodothyronine (T3), increased thyroid and pituitary weights, hypertrophy of follicular epithelial cells in the thyroid, and increased basophilic cells in the pituitary were detected as endocrine-mediated effects of PTU in the 1 mg/kg group. In the enhanced TG 407, decreased T4 and T3 were detected in both the 0.01 and 1 mg/kg groups, together with increased thyroid-stimulating hormone in the 1 mg/kg group, increased thyroid and pituitary weights in the 1 mg/kg group, and hypertrophy of follicular epithelial cells in the thyroid and increased basophilic cells in the pituitary of the 1 mg/kg group. Thus, among the parameters tested, the thyroid hormone levels, organ weight changes, and the histopathological assessment allowed detection of the endocrine-related effects of PTU in both the pubertal assay and the enhanced TG 407, but the sensitivity of the hormone analysis was higher in the latter.

Topics: Animals; Antithyroid Agents; Blood Cell Count; Blood Chemical Analysis; Body Weight; Dose-Response Relationship, Drug; Eating; Enzymes; Guidelines as Topic; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sexual Maturation; Sperm Motility; Thyroid Gland; Thyroid Hormones

AMP-activated protein kinase (AMPK) consists of three subunits: alpha, beta, and gamma. Two isoforms exist for the alpha-subunit (alpha(1) and alpha(2)), two for the beta-subunit (beta(1) and beta(2)), and three for the gamma-subunit (gamma(1), gamma(2), and gamma(3)). Although the specific roles of the beta- and gamma-subunits are not well understood, the alpha-subunit isoforms contain the catalytic site and also the phosphorylation/activation site for the upstream kinase. This study was designed to determine the role of thyroid hormones in controlling expression levels of these AMPK subunits and of one downstream target, acetyl-CoA carboxylase (ACC), in muscle. AMPK subunit and ACC levels were determined by Western blots in control rats, in rats given 0.01% propylthiouracil (PTU) in drinking water for 3 wk, and in rats given 3 mg of thyroxine and 1 mg of triiodothyronine per kilogram chow for 1 or 3 wk. In gastrocnemius muscle, all isoforms of AMPK subunits were significantly increased in rats given thyroid hormones for 3 wk vs. those treated with PTU. Similar patterns were seen in individual muscle types. Expression of muscle ACC was also significantly increased in response to 3 wk of treatment with excess thyroid hormones. Muscle content of malonyl-CoA was elevated in PTU-treated rats and depressed in thyroid hormone-treated rats. These data provide evidence that skeletal muscle AMPK subunit and ACC expression is partially under the control of thyroid hormones.

Topics: Acetyl-CoA Carboxylase; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Antithyroid Agents; Blotting, Western; Body Weight; Eating; Glycogen; Male; Malonyl Coenzyme A; Multienzyme Complexes; Muscle, Skeletal; Phosphorylation; Propylthiouracil; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Thyroid Gland; Thyroxine; Triiodothyronine

The main objectives of the present study were to investigate the effects of 6-n-propyl-2-thiouracil (PTU) on Sertoli cell proliferation, germ cell number, and testis size in Nile tilapias (Oreochromis niloticus). In this regard, young fish (approximately 1 g BW and approximately 3.5 cm total in length) were treated for a period of 40 d with different concentrations (100 and 150 ppm) of PTU. The animals were killed and analyzed on d 1, 30, 40, 98, and 208 after the beginning of the treatment. On d 30 and 40 the spermatogenic process was delayed in fish treated with PTU compared with the control group. Also at these periods, treated tilapia had decreased (P < 0.05) body weight and total length. On d 98 body weight and total length had recovered in PTU-treated fish and were similar (P > 0.05) to those of the controls. However, testis weight and gonadosomatic index (testis mass/body weight) were approximately 100% higher (P < 0.05) in treated tilapia. Similarly, the area occupied by seminiferous tubules, the number of Sertoli cells and germ cells per cyst, and the number of Leydig cells per testis were significantly (P < 0.05) greater in treated fish. Nevertheless, nuclear volume and individual Leydig cell volume were significantly lower (P < 0.05) in tilapia receiving PTU treatment. Compared with controls, at 208 d all parameters analyzed presented the same trend as that observed at 98 d. In general, at 98 d the different PTU concentrations used during the treatment period induced similar effects. However, at 208 d the mean values observed for several parameters were significantly higher (P < 0.05) in fish exposed to 150 ppm. Probably due to the higher density of Sertoli cells per cyst in treated tilapia, these cells presented a smaller (P < 0.05) nucleolus and a trend to decrease its support capacity (efficiency). However, the meiotic index (germ cell loss during the two meiotic divisions) was similar (P > 0.05) in the three groups of fish investigated. Remarkably, the results found in tilapia were similar to those found for rats treated with PTU. This suggests strongly that the mechanisms of control of Sertoli cell and Leydig cell proliferation seem to be preserved during vertebrate evolution.

Topics: Animals; Antithyroid Agents; Body Weight; Cell Count; Cell Division; Cell Nucleus; Germ Cells; Leydig Cells; Male; Meiosis; Organ Size; Propylthiouracil; Sertoli Cells; Spermatids; Spermatocytes; Stimulation, Chemical; Testis; Tilapia

Adult tasters of 6-n-propylthiouracil (PROP) are more sensitive to bitter taste and fattiness in foods, and often show lower acceptance of foods that are high in these taste qualities. This study hypothesized that PROP taster children would show lower acceptance of these same foods. Sixty-seven preschool children were classified as PROP tasters (N = 43) or nontasters (N = 24) using a suprathreshold screening solution. Children rated acceptance of 10 bitter and/or fat-containing foods using a 5-pt. facial scale. Parents completed a food frequency questionnaire to estimate their child's intake. Taster children showed lower acceptance of raw broccoli and American cheese (p < or = 0 x 05). Taster-girls showed lower acceptance of full-fat milk than nontaster-girls (p < or = 0 x 05). This effect was not seen in boys. Nontasters reported more daily intake of discretionary fats than tasters (p < or = 0 x 05), an effect largely due to nontaster-girls, in whom reported intake was 2--3 more servings per day than taster-girls, and boys of both groups. These data suggest that PROP taste sensitivity plays a role in acceptance of certain bitter cruciferous vegetables and cheese by young children. In addition, taster group differences in acceptance of full-fat milk and intake of discretionary fats seen in girls, suggest that gender-specific environmental factors might interact with genetics to influence fat preferences.

Topics: Analysis of Variance; Body Height; Body Weight; Child, Preschool; Diet Records; Eating; Feeding Behavior; Female; Food Preferences; Humans; Male; Propylthiouracil; Surveys and Questionnaires; Taste

The male pubertal onset assay is under consideration as an alternate Tier I screening assay to detect potential endocrine active chemicals (EACs) acting through a variety of steroid hormone and thyroid hormone receptor-mediated and non-receptor-mediated mechanisms. This study focused on the assay's ability to detect several non-receptor-mediated EACs. Weanling male CD rats (21 days old) were dosed for 30 d by gavage with vehicle (0.5% METHOCEL) or the following EAC classes (mg/kg/d): a potent thyroid agent (6-propylthiouracil, PTU, 240), a weak thyroid agent (phenobarbital, PB, 50 or 100), a dopamine antagonist (haloperidol, HALO, 2 or 4), or a dopamine agonist (bromocryptine, BRC, 10 or 50). In vehicle-treated males, preputial separation (PPS) occurred at 44.4 +/- 2.0 days of age. Age at PPS was delayed with PTU and 50 BRC, treatments that also delayed growth. Absolute testes and/or epididymal weights were decreased by PTU and 100 PB. BRC (50) and PB (100) decreased absolute prostate and seminal vesicle weights. Relative thyroid weights were altered by HALO, PTU, and PB, agents that significantly decreased serum T(4) levels. PTU increased serum thyroid-stimulating hormone (TSH) by 8.5 times and markedly altered thyroid histology, whereas HALO and PB did not significantly increase TSH and had marginal effects on thyroid histology. Thus, this assay detected both strong (PTU) and weak (PB) thyroid agents as well as the dopamine agonist BRC; however, its ability to detect dopamine antagonists remains unproven. These results confirm that thyroid weight measurements, although not required in the current male pubertal assay protocol, may add valuable information for interpretation of thyroid effects. Due to the apical nature of the male pubertal assay end points, additional work will be required to establish definitive criteria for a positive result in this assay.

Topics: Animals; Antithyroid Agents; Body Weight; Bromocriptine; Dopamine Agonists; Dopamine Antagonists; Genitalia, Male; Haloperidol; Liver; Male; Organ Size; Phenobarbital; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sexual Maturation; Thyroid Gland; Thyrotropin; Thyroxine

To investigate the possibility that TRH (pGlu-His-Pro-NH(2)) and EEP (pGlu-Glu-Pro-NH(2)) contribute to the behavioral and mood changes attending hypothyroidism, hyperthyroidism and hypogonadism, we have treated young, adult, male Sprague-Dawley rats (5/group, 250 g bw at time of sacrifice) for one week with either daily ip injections of saline, 5 microg T(4), 3 mg PTU or castration. Immunoreactivity for TRH (TRH-IR), TRH-Gly (pGlu-His-Pro-Gly, a TRH precursor), EEP and Ps4 (prepro-TRH-derived TRH-enhancing peptide) was measured in 8 brain regions by RIA. Castration reduced the Ps4-IR levels in hippocampus by 80%. High pressure liquid chromatography revealed that in many brain regions EEP-IR and TRH-IR consisted of a mixture of TRH and other TRH-like peptides including EEP, Val(2)-TRH, Tyr(2)-TRH, Leu(2)-TRH and Phe(2)-TRH. Transition from the hyperthyroid to the hypothyroid state increased the Val(2)-TRH and Tyr(2)-TRH levels in the accumbens by 10-fold and 15-fold, respectively, and the corresponding ratios for the pyriform cortex increased 9-fold and 12-fold, respectively. Hypothyroidism and castration reduced the levels of TRH and the majority of other TRH-like peptides in the entorhinal cortex. This is the first report that thyroid and steroid hormones alter the levels of TRH, prepro-TRH-derived peptides, and a newly discovered array of TRH-like neuropeptides in limbic brain regions.

Topics: Animals; Body Weight; Brain; Castration; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Male; Organ Size; Peptides; Propylthiouracil; Prostate; Rats; Rats, Sprague-Dawley; Steroids; Thyroid Hormones; Thyrotropin-Releasing Hormone; Time Factors

In the present study the effect of thyroid hormone (T(3)) on oxidative stress parameters of mitochondria of rat liver is reported. Hypothyroidism is induced in male adult rats by giving 0.05% propylthiouracil (PTU) in drinking water for 30 days and in order to know the effect of thyroid hormone, PTU-treated rats were injected with 20 microg T(3)/100 g body weight/day for 3 days. The results of the present study indicate that administration of T(3) to hypothyroid (PTU-treated) rats resulted in significant augmentation of oxidative stress parameters such as thiobarbituric acid reactive substances and protein carbonyl content of mitochondria in comparison to its control and euthyroid rats. The hydrogen peroxide content of the mitochondria of liver increased in hypothyroid rats and was brought to a normal level by T(3) treatment. Induction of hypothyroidism by PTU treatment to rats also resulted in the augmentation of total and CN-sensitive superoxide dismutase (SOD) activities of the mitochondria, which was reduced when hypothyroid rats were challenged with T(3). Although CN-resistant SOD activity of the mitochondria remained unaltered in response to hypothyroidism induced by PTU treatment, its activity decreased when hypothyroid rats were injected with T(3). The catalase activity of the mitochondria decreased significantly by PTU treatment and was restored to normal when PTU-treated rats were given T(3). Total, Se-independent and Se-dependent glutathione peroxidase activities of the mitochondria were increased following PTU treatment and reduced when T(3) was administered to PTU-treated rats. The reduced and oxidised glutathione contents of the mitochondria of liver increased significantly in hypothyroid rats and their level was restored to normal when hypothyroid rats were injected with T(3). The results of the present study suggest that the mitochondrial antioxidant defence system is considerably influenced by the thyroid states of the body.

Topics: Animals; Body Weight; Glutathione; Glutathione Disulfide; Glutathione Peroxidase; Hydrogen Peroxide; Hypothyroidism; Lipid Peroxidation; Male; Mitochondria, Liver; Propylthiouracil; Proteins; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxide Dismutase; Triiodothyronine

The objective of the present study was to examine whether hypothyroidism affects the reproductive system of adult female rats by evaluating ovarian morphology, uterus weight and the changes in serum and pituitary concentrations of prolactin and gonadotropins. Three-month-old female rats were divided into three groups: control (N = 10), hypothyroid (N = 10), treated with 0.05% 6-propyl-2-thiouracil (PTU) in drinking water for 60 days, and T4-treated group (N = 10), receiving daily sc injections of L-thyroxine (0.8 microg/100 g body weight) during the last 10 days of the experiment. At the end of 50 days of hypothyroidism no hypothyroid animal showed a regular cycle, while 71% of controls as well as the T4-treated rats showed regular cycles. Corpora lutea, growing follicles and mature Graafian follicles were found in all ovaries studied. The corpora lutea were smaller in both the hypothyroid and T4-replaced rats. Graafian follicles were found in 72% of controls and only in 34% of hypothyroid and 43% of T4-treated animals. Serum LH, FSH, progesterone and estradiol concentrations did not differ among the three groups. Serum prolactin concentration and the pituitary content of the three hormones studied were higher in the hypothyroid animals compared to control. T4 treatment restored serum prolactin concentration to the level found in controls, but only partially normalized the pituitary content of gonadotropins and prolactin. In conclusion, the morphological changes caused by hypothyroidism can be a consequence of higher prolactin production that can block the secretion and action of gonadotropins, being the main cause of the changes observed.

Topics: Animals; Antithyroid Agents; Body Weight; Estradiol; Female; Gonadotropins; Hypothyroidism; Infertility, Female; Ovary; Pituitary Gland; Progesterone; Prolactin; Propylthiouracil; Rats; Rats, Wistar; Thyrotropin; Thyroxine; Uterus

Propylthiouracil (PTU) or low-iodine diet (LID) treatment increases thyroid-follicular-cell proliferation, possibly by disrupting the movement of small molecules (< 1.2 kD) through membrane channels called gap junctions. Numerous tumor promoters and proliferative disease states exhibit inhibited gap-junctional-intercellular communication (GJIC) prior to the induction of cell proliferation, yet the association between GJIC and apoptosis is unclear. In the present study, we used an ex vivo method to examine whether GJIC is inhibited in the thyroid of PTU- or LID-treated rats. In addition, the effect of these models of hypothyroidism on thyroid-follicular-cell proliferation and apoptosis was examined to determine the association between GJIC and cell homeostasis. After 14 days of treatment of either PTU or LID (plus 1% KClO4 in the drinking water), serum tri-iodothyronine (T3) and thyroxine, (T4) was decreased to nearly undetectable levels and serum TSH was increased in PTU- and LID-treated rats. At the same time point, GJIC was decreased 30-35% in PTU- and LID-treated rats while thyroid-follicular-cell proliferation increased nearly threefold in both treatment groups. Interestingly, apoptosis increased twofold in both hypothyroid treatment groups. These data suggest that PTU or LID treatment inhibit thyroid GJIC during a state of increased thyroid-follicular-cell proliferation and apoptosis. While the increase in proliferation was anticipated, the paradoxical increase in apoptosis during decreased GJIC in thyroid-follicular cells warrants further examination.

Topics: Animals; Antithyroid Agents; Apoptosis; Body Weight; Cell Communication; Cell Division; Diet; Gap Junctions; Hypothyroidism; Immunohistochemistry; Iodine; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

To determine if individuals who taste 6-n-propylthiouracil (PROP), one marker of genetic variation in taste, as exceptionally bitter can also perceive sugars as sweeter, other bitters as more intense, and dietary fats as more creamy and/or viscous than do individuals who taste PROP as weakly bitter. This study examined the association between genetic variation in taste and acceptance for sweet, high-fat, and bitter foods and beverages.. Genetic variation was measured by perceived bitterness of PROP (influenced by genetic, hormonal, and pathologic factors) and density of fungiform papillae on the anterior portion of the tongue (influenced primarily by genetic factors). Four sweet, 3 fat, and 3 bitter groups were derived from principal components analyses of questionnaire items.. Convenience sample of healthy adults (24 women, 22 men; mean age +/- standard deviation = 21 +/- 6 years) who did not report high dietary restraint.. Pearson product moment correlations between genetic taste measures and food and beverage groups.. The sample showed diversity in genetic taste measures: perceived bitterness of 0.0032 mol/L PROP ranged from "weak" to well above "very strong"; fungiform papillae densities ranged from 33 to 156 papillae per square centimeter. Distribution of perceived bitterness of PROP and fungiform papillae density differed in women and men. The association between genetic taste measures and acceptance of sweet and high-fat groups differed in women and men. In women, liking of sweet and high-fat food and beverage groups decreased with increasing perceived bitterness of PROP. In men, liking of these foods and beverages increased but with increasing papillae densities. Genetic taste measures were not associated with a dislike of bitter food and beverage groups.. The influence of genetic variation in taste on food intake depends on how perceptible sweet, fat, or bitter components are in foods and beverages, as well as the value of sensory factors vs other factors (e.g., health, convenience) on personal dietary choices. Female supertasters of PROP bitterness may avoid high-fat or sweet foods because these oral sensations are too intense and thus less pleasant. Supertasters may taste more bitterness in vegetables but still enjoy eating them because of their healthfulness and because condiments (especially those that are salt based) can block bitterness.

Topics: Adolescent; Adult; Body Height; Body Weight; Feeding Behavior; Female; Food; Genetic Variation; Humans; Male; Methylene Blue; Propylthiouracil; Sex Factors; Sodium Chloride; Statistics, Nonparametric; Surveys and Questionnaires; Taste; Tongue

We tested the effects of thyroid hormone on Leydig cell (LC) regeneration in the adult rat testis after ethane dimethyl sulphonate (EDS) treatment. Ninety-day-old, thyroid-intact (n = 96) and thyroidectomized (n = 5) male Sprague-Dawley rats were injected intraperitoneally (single injection) with EDS (75 mg/kg) to destroy LC. Thyroid-intact, EDS-treated rats were equally divided into three groups (n = 32 per group) and treated as follows: control (saline-injected), hypothyroid (provided 0.1% propyl thiouracil in drinking water), and hyperthyroid (received daily subcutaneous injections of tri-iodothyronine, 100 microg/kg). Testing was done at Days 2, 7, 14, and 21 for thyroid-intact rats and at Day 21 for thyroidectomized rats after the EDS treatment. Leydig cells were absent in control and hyperthyroid rats at Days 2, 7, and 14; in hypothyroid rats at all ages; and in thyroidectomized rats at Day 21. The LC number per testis in hyperthyroid rats was twice as those of controls at Day 21. 3beta-Hydroxysteroid dehydrogenase (LC marker) immunocytochemistry results agreed with these findings. Mesenchymal cell number per testis was similar in the three treatment groups of thyroid-intact rats on Days 2 and 7, but it was different on Days 14 and 21. The highest number was in the hypothyroid rats, and the lowest was in the hyperthyroid rats. Serum testosterone levels could be measured in control rats only on Day 21, were undetectable in hypothyroid rats at all stages, and were detected in hyperthyroid rats on Days 14 and 21. These levels in hyperthyroid rats were twofold greater than those of controls on Day 21. Serum androstenedione levels could be measured only in the hyperthyroid rats on Day 21. Testosterone and androstenedione levels in the incubation media showed similar patterns to those in serum, but with larger values. These findings indicate that hypothyroidism inhibits LC regeneration and hyperthyroidism results in accelerated differentiation of more mesenchymal cells into LC following the EDS treatment. The observations of the EDS-treated, thyroidectomized rats confirmed that the findings in hypothyroid rats were, indeed, due to the deficiency of thyroid hormone.

Topics: Androstenedione; Animals; Antithyroid Agents; Body Weight; Cell Differentiation; Hydroxysteroid Dehydrogenases; Hyperthyroidism; Hypothyroidism; Leydig Cells; Luteinizing Hormone; Male; Mesoderm; Mesylates; Organ Size; Propylthiouracil; Rats; Rats, Sprague-Dawley; Regeneration; Testis; Testosterone; Thyroid Hormones; Thyroidectomy

Thyroid hormone plays an important role during central nervous system (CNS) development. Experimentally-induced perinatal hypothyroid rats show abnormal cerebellar cytoarchitecture, but the underlying mechanism is not fully understood. Altered cell-cell interactions may contribute to such abnormalities, since the expression of NCAM is increased in hypothyroid animals. In the present study, we examined the expression of carbohydrate epitope 3-fucosyl-N-acetyl-lactosamine (CD15 antigen), that can be localized on both astrocytes and neurons in the developing brain, and is considered to play an important role in glial-neuronal interaction and cell migration. Newborn rats were treated with an antithyroid drug, propylthiouracil (PTU) and the CD15 glycolipid levels in the cerebellum were examined by enzyme-linked immunosolvent assay (ELISA) using 7A monoclonal antibody raised against rat forebrain antigen. A transient elevation of CD15 level was observed on postnatal day 10 in PTU-treated animals. Analysis of neutral glycolipids on high performance thin layer chromatography (HPTLC), revealed two distinct immunoreactive bands, corresponding to Fuc-nLc6 and Fuc-nLc4. The Fuc-nLc4 is preferentially increased in the PTU-treated group. These results suggest that a transient increase in CD15 glycoconjugates with isoform-specific manner induced by PTU may contribute to morphological abnormalities in hypothyroid rat cerebellum affecting granule cell migration.

Topics: Animals; Antithyroid Agents; Body Weight; Cerebellum; Female; Lewis X Antigen; Male; Organ Size; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley

Adults rats with hypothyroidism were prepared by administration of 6-propyl-2-thiouracil (PTU) or methimazole, and the tissues were examined for their gangliosides through methods including glycolipid-overlay techniques. Normal thyroid tissue contained GM3, GD3, and GD1a as the major gangliosides, with GM1, GD1b, GT1b, and GQ1b in lesser amounts. The goitrous tissue of PTU-induced hypothyroid rats had higher concentrations of GM1 and GD1a with a concomitant decrease of GM3. The amount of GT3 in thyroid tissue was increased in hypothyroid animals. While normal liver tissue had a complex ganglioside pattern with a- and b-series gangliosides, the PTU-induced hypothyroid tissue showed a simpler ganglioside profile that consisted mainly of a-series gangliosides with almost undetectable amounts of b-series gangliosides. The expression of c-series gangliosides was suppressed in the hypothyroid liver tissue. Heart tissue had higher contents of GM3 and GT3 than control. No apparent change was observed in the compositions of major and c-series gangliosides in other extraneural tissues (i.e., kidney, lung, spleen, thymus, pancreas, testis, skeletal muscle, and eye lenses), and neural tissues (i.e., cerebrum and cerebellum) from PTU-induced hypothyroid rats. The ganglioside changes of thyroid, liver, and heart tissues were reproduced in corresponding tissues of methimazole-induced hypothyroid rats. These results suggest that hypothyroid conditions affect the biosynthesis and expression of gangliosides in specific tissue and cell types.

Topics: Animals; Body Weight; Gangliosides; Heart; Hypothyroidism; Liver; Male; Methimazole; Myocardium; Propylthiouracil; Rats; Rats, Sprague-Dawley; Reference Values; Thyroid Gland; Thyroxine

Many millions of people throughout the world are at risk of developing iodine deficiency-associated disorders. The underlying effects of iodine deficiency on neuroendocrine function are poorly defined. We have studied stress-induced and diurnal variation in corticosterone secretion in female rats rendered chronically hypothyroid by feeding them an iodine-free diet for 6 months. Corticosterone secretory responses in iodine deficient animals were compared to those seen in animals rendered hypothyroid with propylthiouracil and untreated controls. By using a well-validated, automated blood sampling system to collect small samples of blood over the complete daily cycle in unrestrained animals, we have demonstrated for the first time that the normal diurnal rhythm of corticosterone secretion is lost in chronic iodine deficiency and that the corticosterone secretory response to the psychological stress of 10 min exposure to white noise is attenuated. Despite restoration of circulating triiodothyronine and thyrotropin releasing hormone- and thyroid stimulating hormone beta-transcript prevalence in the hypothalamus and pituitary, respectively, 1 month after restoration of normal iodine-containing diet both the diurnal variation in corticosterone levels and the corticosterone secretory response to the noise stress remained reduced in amplitude compared to control animals. Thus, chronic hypothyroidism induced by iodine deficiency significantly attenuates hypothalamo-pituitary-adrenal axis activity, an effect that persists after functional recovery of the thyroid axis.

Topics: Acoustic Stimulation; Animals; Antithyroid Agents; Body Weight; Circadian Rhythm; Corticosterone; Diet; Feedback; Female; Gene Expression; Hypothalamo-Hypophyseal System; Hypothyroidism; In Situ Hybridization; Iodine; Pituitary-Adrenal System; Propylthiouracil; Rats; Rats, Wistar; Receptors, Thyroid Hormone; RNA, Messenger; Stress, Psychological; Transcription, Genetic; Triiodothyronine

Topics: Antimetabolites; Body Weight; Child, Preschool; Eating; Food Preferences; Humans; Propylthiouracil; Taste; Taste Threshold

Phenobarbital (PB), a thyroid hormone excretion enhancer, and propylthiouracil (PTU), a thyroid hormone-synthesis inhibitor, have been examined in a Tier I screening battery for detecting endocrine-active compounds (EACs). The Tier I battery incorporates two short-term in vivo tests (5-day ovariectomized female battery and 15-day intact male battery using Sprague-Dawley rats) and an in vitro yeast transactivation system (YTS). In addition to the Tier I battery, thyroid endpoints (serum hormone concentrations, liver and thyroid weights, thyroid histology, and UDP-glucuronyltransferase [UDP-GT] and 5'-deiodinase activities) have been evaluated in a 15-day dietary restriction experiment. The purpose was to assess possible confounding of results due to treatment-related decreases in body weight. Finally, several thyroid-related endpoints (serum hormone concentrations, hepatic UDP-GT activity, thyroid weights, thyroid follicular cell proliferation, and histopathology of the thyroid gland) have been evaluated for their utility in detecting thyroid-modulating effects after 1, 2, or 4 weeks of treatment with PB or PTU. In the female battery, changes in thyroid endpoints following PB administration, were limited to decreased serum tri-iodothyronine (T3) and thyroxine (T4) concentrations. There were no changes in thyroid stimulating hormone (TSH) concentrations or in thyroid gland histology. In the male battery, PB administration increased serum TSH and decreased T3 and T4 concentrations. The most sensitive indicator of PB-induced thyroid effects in the male battery was thyroid histology (pale staining and/or depleted colloid). In the female battery, PTU administration produced increases in TSH concentrations, decreases in T3 and T4 concentrations, and microscopic changes (hypertrophy/hyperplasia, colloid depletion) in the thyroid gland. In the male battery, PTU administration caused thyroid gland hypertrophy/hyperplasia and colloid depletion, and the expected thyroid hormonal alterations (increased TSH, and decreased serum T3 and T4 concentrations). The dietary restriction study demonstrated that possible confounding of the data can occur with the thyroid endpoints when body weight decrements are 15% or greater. In the thyroid time course experiment, PB produced increased UDP-GT activity (at all time points), increased serum TSH (4-week time point), decreased serum T3 (1-and 2-week time points) and T4 (all time points), increased relative thyroid weight (2- and 4-

Topics: Animals; Antithyroid Agents; Body Fluids; Body Weight; Cell Division; Epithelial Cells; Estrus; Female; Glucuronosyltransferase; Gonadotropins, Pituitary; Iodide Peroxidase; Liver; Male; Microsomes, Liver; Ovariectomy; Phenobarbital; Propylthiouracil; Rats; Rats, Sprague-Dawley; Saccharomyces cerevisiae; Thyroid Gland; Thyroid Hormones; Toxicity Tests; Uterus

To evaluate the effects of hypothyroidism on ovarian function, multiparous, nonlactating Brahman cows (n = 18) were assigned randomly to dietary treatments containing either 0 (C; n = 9) or 4 mg x kg BW(-1) x d(-1) 6-n-propyl-2-thiouracil (PTU; n = 9), to suppress thyroid function, in the feed concentrate. Weekly changes in BW and body condition score (BCS) were recorded. Dietary treatments began on d 10 of the estrous cycle. Ten days after the first treatment estrus, all cows received daily i.m. injections of 25 IU of porcine FSH over a 3-d period. Seven days after AI, embryos were collected nonsurgically, and the ovaries were removed via midflank laparotomy. Based on thyroxine (T4) concentrations after 49 d of treatment, five cows were hypothyroid (H-PTU) and four were partially suppressed (P-PTU). Cows in the PTU group had greater (P<.01) ADG, (P<.05) ovarian weights, and numbers of large (> or =8 mm) (P<.05) follicles. Cows in the PTU group had lower embryo recovery rate (P<.001), fertilization rate (P<.001), and percentage of blastocysts (P<.1) than C cows. The H-PTU cows had greater numbers of luteinized follicles (P<.06), greater concentrations of progesterone (P4) in the follicular fluid at all size categories (P<.1), and greater numbers of corpora lutea (P<.05) than C cows. The ratio of luteal to serum P4 on d 7 was greater (P<.05) in hypothyroid cows. Induced hypothyroidism improved weight gain and BCS, increased ovarian response to FSH, and affected ovulation, fertility, and P4 secretion in superovulated Brahman cows.

Topics: Animals; Body Composition; Body Weight; Cattle; Corpus Luteum; Female; Hypothyroidism; Ovary; Progesterone; Propylthiouracil; Superovulation; Thyroxine; Tissue and Organ Harvesting; Triiodothyronine

Intestinal fructose transport rates or GLUT5 mRNA levels typically show a two- to threefold increase after weaning in rats allowed to wean normally but can be enhanced precociously by high-fructose diets during early weaning. Developmental increases in serum thyroxine levels coincide with the onset of weaning and have been linked to changes in intestinal sucrase and lactase activities.. Rat pups were made hypothyroid by giving the dam 0.01% propylthiouracil as drinking water from day 18 of gestation. The hypothyroid pups and age-matched euthyroid control pups were then fed high-fructose or high-glucose solutions by gavage, twice a day starting at 17 days of age for 3 days, and then killed at 20 days of age.. Serum thyroxine levels were five times lower in the hypothyroid pups. Rates of intestinal fructose uptake in the proximal and middle small intestine were 2.0 to 2.5 times higher in the hypothyroid and euthyroid pups fed high-fructose solution than in littermates fed high-glucose solution or those allowed to wean normally with the dam. Intestinal glucose uptake also increased in hypothyroid but not in euthyroid pups fed high-fructose or high-glucose solutions. GLUT5 mRNA levels increased in euthyroid and hypothyroid pups fed high fructose and paralleled the increase in fructose uptake.. During weaning, dietary fructose can precociously enhance intestinal fructose uptake and GLUT5 mRNA expression, independent of developmental increases in serum thyroxine levels. Modest changes in glucose transport rates indicate that nonspecific mechanisms may provide a minor contribution to diet-induced changes in nutrient absorption in hypothyroid pups.

Topics: Animals; Biological Transport; Blotting, Northern; Body Weight; Diet; Female; Fructose; Glucose; Glucose Transporter Type 5; Hypothyroidism; Intestinal Mucosa; Intestines; Monosaccharide Transport Proteins; Organ Size; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Solutions; Thyroxine

Effects of thyroid hormones on cardiac function or rhythm have been known; however, the mechanism is still unclear. In the present study examined were effects of triiodethyronine (T3) on voltage-gated potassium channel gene expression in rat heart since the potassium channels were presumed to modulate cardiac functions. The mRNA expression of five voltage-gated potassium channel gene alpha subunits (Kv1.2, Kv1.4, Kv1.5, Kv2.1, and Kv4.2) in heart was examined by ribonuclease protection assay in rats which were treated with T3 or propylthyouracil (PTU). All these genes except Kv1.4 mRNA were apparently expressed in the normal rat heart ventricle. Kv1.2 mRNA expression in ventricle was markedly suppressed by T3-treatment and enhanced by PTU-treatment. Interestingly, upregulation of Kv1.4 mRNA expression and downregulation of Kv1.5 mRNA expression were concomitantly induced in the ventricle by the PTU-treatment. In addition, the downregulation of the ventricular Kv1.5 mRNA expression induced by PTU was restored by T3 replacement. No changes of Kv2.1 and Kv4.2 mRNA expression were observed in the ventricles by the T3- or PTU-treatment. In heart atrium the same findings were observed. Kv1.4 mRNA expression, which was detectable in control rat atrium, also decreased significantly by T3-treatment. In contrast, no changes of Kv1.2, Kv1.4, and Kv1.5 mRNA expression in rat brains were induced by T3-treatment. These findings suggest that thyroid hormone specifically influences mRNA expression of Shaker-related potassium channel genes in rat hearts through a common T3 receptor-mediated regulation at a transcriptional level.

Topics: Animals; Body Weight; Female; Gene Expression Regulation; Heart Atria; Heart Ventricles; Myocardium; Organ Size; Potassium Channels; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Shaker Superfamily of Potassium Channels; Thyroid Hormones; Thyroxine; Triiodothyronine

To characterize developmental changes in the extracellular matrix of the postnatal rat testis in relationship to the timing of germ cell maturation, we immunolocalized fibulin-1, fibulin-2, and other matrix components in the testes of normal and propyl-thiouracil (PTU)-induced hypothyroid animals. Unlike laminin, nidogen, and perlecan, which were present in the seminiferous tubule basement membrane (BM) throughout postnatal development, fibulins were found to disappear from the postnatal tubule BM. Fibulin-1 was no longer detected after Day 5 whereas fibulin-2 became localized in a segmental manner within the BM of each seminiferous tubule on Days 10 and 15 and disappeared by Day 20. Fibronectin showed a segmental pattern in the level of immunostaining of the tubule BM on Days 10 and 15, with a more uniform staining seen at earlier and later ages. Collagen VI was initially confined to the interstitial matrix in the Day 5 testis and became progressively more closely associated with the seminiferous tubule BM at later stages. The disappearance of fibulin-2 and the BM-association of collagen VI were both delayed in the PTU-treated testes. The developmental changes in the staining patterns for fibulin-2 and fibronectin coincide with the adhesion and alignment of peritubular cells on the inner seminiferous tubule BM. The delay in maturation of the seminiferous tubule BM in the testes of PTU-treated rats demonstrates a correlation between changes in the composition of the tubule BM and cellular development of the testis.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Basement Membrane; Body Weight; Calcium-Binding Proteins; Extracellular Matrix Proteins; Fibronectins; Fluorescent Antibody Technique, Direct; Hypothyroidism; Male; Organ Size; Propylthiouracil; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Testis

1. Duchenne and Becker muscular dystrophies are X-linked disorders caused by defects in muscle dystrophin. The mdx mouse is an animal model for Duchenne muscular dystrophy which has a point mutation in the dystrophin gene, resulting in little (<3%) or no expression of dystrophin in muscle. Mdx mice show a characteristic pattern of muscle necrosis and regeneration. Muscles are normal until the third postnatal week when widespread necrosis commences. This is followed by muscle regeneration, with the persistence of centrally nucleated fibres. 2. This work has examined the hypothesis that the onset of this muscle necrosis is associated with postnatal maturation of the thyroid endocrine system and that pharmacological inhibition of thyroid hormone synthesis delays the onset of muscle necrosis. 3. Serum T4 and T3 concentrations of mice were found to rise immediately before the onset of muscle necrosis in the mdx mouse, and induction of hypothyroidism by treatment of animals with propylthiouracil was found to delay the onset of muscle necrosis. 4. The results provide the first demonstration of experimental delay of muscle necrosis by manipulation of the endocrine system in muscle lacking dystrophin, and provide a novel insight into the way in which a lack of dystrophin interacts with postnatal development to precipitate muscle necrosis in the mdx mouse.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Disease Models, Animal; Dystrophin; Hypothyroidism; Mice; Mice, Inbred mdx; Muscle, Skeletal; Muscular Dystrophy, Animal; Propylthiouracil; Thyroxine; Triiodothyronine

The effects of propyl thiouracil (PTU)-induced hypothyroidism on testicular interstitial cells and androgen secretion in vitro in the neonatal rat were investigated using Sprague Dawley rats of 1, 7, 14, and 21 days. The results revealed that the fetal Leydig cell (FLC) number per testis was unchanged between and within treatment groups at all ages tested. FLC size was 50% smaller in 21-day controls than in all other groups. Adult Leydig cells (ALCs) were present at Days 14 and 21 in controls but were absent in PTU rats. ALCs approximated FLCs of 21-day controls in size. ALC number per testis showed a sharp increase at Day 21. 11ss-HSD1-positive cells were absent in 21-day PTU testes, but a few were present in 21-day control testes. Testosterone secretion per testis was unchanged in 1- to 21-day controls and 7- to 21-day PTU rats. However, at Day 21, a significantly lower value was seen in controls compared to PTU rats. Testicular androstenedione secretion was not significantly different between control and PTU rats up to 14 days, but a sharp rise was observed in controls at Day 21. At this age, androstenedione levels in PTU rats were similar to those at younger ages. In summary, histological studies showed that hypothyroidism prevented the hypotrophy of FLC and the emergence of ALC in the neonatal rat testis, and agreed favorably with results concerning testicular androgen secretion in vitro. These findings suggest that thyroid hormones have a regulatory role in precursor cell differentiation into Leydig cells in the neonatal rat testis to establish the ALC population.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Aging; Androstenedione; Animals; Animals, Newborn; Body Weight; Cell Differentiation; Female; Hydroxysteroid Dehydrogenases; Hypothyroidism; Immunohistochemistry; Leydig Cells; Male; Organ Size; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Testis

Hypothyroidism in the human female is often associated with ovarian follicular cysts and hyperandrogenism, two cardinal signs of polycystic ovary syndrome. To explore the intraovarian changes that lead to follicular cyst formation in hypothyroidism, we have created a prepubertal hypothyroid rat model. These hypothyroid rats are hyperandrogenic and develop transient ovarian follicular cysts. Hypothyroidism in newborn rats was induced by providing the lactating dams with 0.04% propylthiouracil (PTU)-containing water. Subsequently, female rats were weaned and kept on PTU-containing water. On Day 25 of age, the rats were primed with 15 international units of pregnant mare's serum gonadotropin (PMSG) in 100 microl of phosphate buffered saline. Two days later, to initiate pseudopregnancy, they were injected with five international units of human chorionic gonadotropin (hCG). The animals were sacrificed at appropriate times, and blood and ovaries were collected for analyses. Control experiments were done with euthyroid rats. Two days after PMSG injection, well-developed antral follicles were observed in both the hypothyroid and euthyroid rats. Two days after hCG injection, while the euthyroid rat ovaries, as expected, contained numerous corpora lutea (CL), the hypothyroid rat ovaries still retained antral follicles. Some of these follicles with degenerating oocytes showed signs of luteinization. By 3-4 days post-hCG injection, the hypothyroid rat ovaries developed cystic follicles. By Day 6, however, the hypothyroid rat ovaries were indistinguishable from those of the euthyroid rats. Although serum testosterone concentrations were significantly elevated in the hypothyroid rats on Days 1-3, progesterone concentrations were not significantly different from the euthyroid animals. However, by Days 8-14, the hypothyroid rats had significantly higher serum progesterone concentrations. This model will be useful for investigating the intraovarian biochemical changes that lead to follicular cyst development in response to acute gonadotropin treatment.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Disease Models, Animal; Female; Follicular Cyst; Hypothyroidism; Lactation; Male; Organ Size; Ovary; Polycystic Ovary Syndrome; Progesterone; Propylthiouracil; Pseudopregnancy; Rats; Testosterone

The influence of thyroid status on glucagon receptor mRNA levels was investigated in rats using a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Glucagon receptor mRNA was detected in liver, brown and white adipose tissues (BAT and WAT) and brain. In BAT and WAT, pharmacologically-induced moderate hypothyroidism resulted in a marked reduction in the relative abundance of glucagon receptor mRNA. Short-term treatment of hypothyroid rats with exogenous 3,3',5'-triiodo-L-thyronine (T3), resulting in a marked hyperthyroidism, reversed the phenomenon in BAT while the reversal was only partial in WAT. In the liver, there was no significant effect of mild hypothyroidism while there was a positive effect of hyperthyroidism. In brain, the relative tissue abundance of glucagon receptor mRNA was not affected by the large changes in plasma T3. The present results therefore indicate that thyroid status may modulate the relative abundance of glucagon receptor mRNA in a tissue-specific manner.

Topics: Adipose Tissue; Animals; Body Weight; Brain; Gene Expression; Iopanoic Acid; Liver; Male; Organ Specificity; Propylthiouracil; Rats; Rats, Wistar; Receptors, Glucagon; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroid Diseases; Thyroid Gland; Triiodothyronine

A study was conducted to determine the effects of transient hypothyroidism induced by propylthiouracil (PTU) on termination of photorefractoriness and reinitiation of lay in turkey breeder hens. The PTU was given for 6- or 8-wk periods via the feed and at various doses to yearling hens that had been continuously exposed to long photoperiods [16 h light (L):8 h dark (D)] for at least 25 wk. There was a dose-dependent cessation of lay as well as deletion of thyroxine (T4) and triiodothyronine (T3) during the treatment period. Hens receiving 0.1% PTU or more had little or no circulating thyroid hormones after 2 wk of treatment. Furthermore, resumption of a normal rate and duration of egg laying occurred following withdrawal of the PTU, without any changes in photoperiod. However, this effect only occurred in those hens that had received PTU doses of 0.1% or more and only when the treatment had been given for greater than 6 wk. The resumption of normal levels of egg laying occurred in the absence of a typical preceding molt. Body weights, livability, and fertility and hatchability of eggs from these hens were similar to those of controls. Clearly, turkey hens can be effectively recycled by pharmacological manipulation of the thyroid gland and the results are supportive of thyroid hormone(s) involvement in maintaining photorefractoriness in turkey hens.

Topics: Animals; Antithyroid Agents; Body Weight; Dose-Response Relationship, Drug; Eating; Female; Fertility; Hypothyroidism; Oviposition; Photoperiod; Poultry Diseases; Propylthiouracil; Thyroid Gland; Thyroxine; Time Factors; Triiodothyronine; Turkeys

Selenium deficiency and propylthiouracil (PTU) treatment both decrease hepatic type I T4 5'-deiodinase activity (5'D-I), which is considered to be an important regulator of the serum T3 derived from peripheral T4 to T3 conversion (T3 neogenesis). The effects of PTU treatment or a selenium-deficient diet on T4 and T3 kinetics were compared in thyroid-ablated rats infused with stable T4 to determine whether PTU treatment is a more potent inhibitor of T3 neogenesis than selenium deficiency and to compare the degree of inhibition of T3 production with the degree of inhibition of 5'D-I. PTU treatment and selenium deficiency (Se-) did not affect the T3 MCR (control, 46.0 +/- 2.5; PTU, 41.7 +/- 2.8; Se-, 41.1 +/- 4.0 ml/h.100 g BW), but did reduce serum T3 concentrations by 29% and 25%, respectively (control, 58.7 +/- 2.6; PTU, 41.5 +/- 1.0; Se-, 43.9 +/- 2.7 ng/dl; P < 0.01 for PTU or Se- vs. control) and the T3 production rate by 35% and 32%, respectively (control, 26.6 +/- 1.0; PTU, 17.3 +/- 2.0; Se-, 18.0 +/- 1.9 ng/h.100 g BW; P < 0.01 for PTU or Se- vs. Control). PTU treatment and selenium deficiency significantly increased serum T4 concentrations by 36% and 32%, respectively, due to a decrease in T4 MCR (control, 1.4 +/- 0.1; PTU, 1.1 +/- 0.1; Se-, 1.1 +/- 0.04 ml/h.100 g BW; P < 0.05 for PTU or Se- vs. control). Assuming that the concentration of T4 available for T3 neogenesis is proportional to the serum T4 concentration, the increase in serum T4 concentrations caused by PTU treatment or Se- would probably have proportionally increased the rate of T3 neogenesis. Based on these considerations, the apparent decrease in T3 neogenesis in the PTU-treated animals was 52%. This is less than the 79% and 67% inhibition of 5'D-I noted, respectively, in the liver and kidneys of these rats. Similarly, the apparent decrease in T3 neogenesis in the Se- rats was 48%, again less than the 85% and 64% inhibition of 5'D-I in their liver and kidneys, respectively. These studies suggest that PTU and Se- have similar effects on T3 neogenesis. The more potent effects of these treatments on liver and kidney 5'D-I activities than on T3 neogenesis suggest that the activities of these enzymes in these tissues are not the only important determinants of the serum T3 that is derived from nonthyroidal sources.

Topics: Animals; Body Weight; Enzyme Inhibitors; Iodide Peroxidase; Kidney; Kinetics; Liver; Male; Metabolic Clearance Rate; Propylthiouracil; Rats; Rats, Sprague-Dawley; Selenium; Thyroidectomy; Thyrotropin; Thyroxine; Triiodothyronine

Gonadal differentiation, the onset of androgen-stimulated laryngeal growth and the genesis of a sex difference in laryngeal innervation, all temporally coincide with thyroid hormone (TH)-induced metamorphosis in Xenopus laevis. To explore the role TH plays in the ontogeny of the Xenopus androgen-sensitive vocal neuromuscular system, we examined gonadal and laryngeal development in tadpoles in which metamorphosis had been blocked by treatment with the thyroxine synthesis inhibitor propylthiouracil (PTU). PTU treatment did not arrest gonadal differentiation. Testes from PTU-treated male tadpoles had seminiferous tubules and advanced stage male germ cells, while in females stage 1 oocytes were present. In contrast to the gonads, PTU did block morphological development of the larynx. Tadpoles treated with PTU for 50 or 100 days had larynges which structurally resembled those of stage 54 control tadpoles. PTU-treated animals did not exhibit the extensive development of the laryngeal cartilage seen in untreated animals. Laryngeal cartilages of hypothyroid tadpoles exhibited low density and minimal patterning of chondrocytes; the complex lumen and marked expansion of the dilator muscles characteristic of 50- and 100-day untreated animals were absent. Laryngeal growth evoked by exposure to exogenous androgen (dihydrotestosterone) was entirely prevented by PTU treatment. Hypothyroid tadpoles did not exhibit the decline in laryngeal nerve axon number characteristic of age-matched controls, nor were laryngeal nerve axon numbers sexually dimorphic. PTU treatment also interfered with the myelination of laryngeal axons. We conclude that while gonadal differentiation is independent of TH, androgen sensitive laryngeal development and sexually dimorphic laryngeal innervation require exposure to secreted TH.

Topics: Animals; Axons; Body Weight; Cell Differentiation; Dihydrotestosterone; Female; Larva; Laryngeal Nerves; Larynx; Male; Metamorphosis, Biological; Microscopy, Electron; Ovary; Propylthiouracil; Sex Characteristics; Testis; Thyroid Hormones; Xenopus laevis

The aim of this study was to examine the effects of prepubertal hypothyroidism on ovarian development in rats. Therefore, from birth up to day 40 postpartum, rats were given 6-propyl-2-thiouracil (PTU) via the drinking water of mothers and pups. At ages ranging from 12 to 40 days, ovarian weights were measured and serum was collected to estimate thyrotrophin (TSH), follicle-stimulating hormone (FSH) and inhibin levels. Two hours before sacrifice the animals received an injection of bromodeoxyuridine (BrdU) to estimate the proliferative activity of the follicular granulosa cells. Ovaries were fixed in Carnoy's fluid and follicle counts were performed on sections stained with anti-BrdU and with haematoxylin and eosin. The PTU treatment resulted in increased serum TSH levels, indicative of hypothyroidism, and markedly lower body and ovarian weights, whereas serum FSH and inhibin levels were hardly affected. At day 40, ovaries of PTU-treated animals contained relatively more secondary and less antral follicles, smaller non-atretic antral follicles and more atretic follicles when compared with untreated rats, while corpora lutea were absent. It is concluded that this disturbed folliculogenesis is due to inadequate thyroid hormone supply, which hampers the differentiation and not the proliferation of granulosa cells because diameters of antral follicles were significantly smaller whereas the BrdU-labelling index had not changed.

Topics: Animals; Body Weight; Cell Division; Female; Follicle Stimulating Hormone; Follicular Atresia; Granulosa Cells; Hypothyroidism; Inhibins; Organ Size; Ovarian Follicle; Ovary; Pregnancy; Propylthiouracil; Rats; Rats, Wistar; Thyrotropin

Thyrotoxicosis rarely precipitates heart failure. Older patients and those with underlying cardiac disease are at greater risk of experiencing this complication of thyrotoxicosis. A 43 year old male who presented with subclinical thyrotoxicosis, atrial fibrillation, and a dilated cardiomyopathy is discussed. There was no evidence of clinically significant underlying cardiac disease. At admission, the patient had an ejection fraction of 25%. Thyrotoxicosis was treated with propylthiouracil. At 14 weeks after hospitalization, the patient had an ejection fraction of 50% with significant reduction in cardiac chamber sizes and left ventricular mass index. He was biochemically euthyroid at that time. After ten months of propylthiouracil therapy, he had progressive improvement in cardiac function and decrease in left ventricular mass index. Thyrotoxicosis-associated cardiomyopathy may reverse significantly with treatment of thyrotoxicosis alone; this complication of thyrotoxicosis should be considered in any young individual with a dilated cardiomyopathy of unknown etiology.

Topics: Adult; Antithyroid Agents; Body Weight; Cardiomyopathy, Dilated; Disease Progression; Echocardiography; Heart Ventricles; Humans; Male; Propylthiouracil; Thyrotoxicosis; Thyroxine

Deafness is a common result of severe hypothyroidism during development in humans and laboratory animals; however, little is known regarding the sensitivity of the auditory system to more moderate changes in thyroid hormone homeostasis. The current investigation compared the relative sensitivity of auditory function, motor function, and growth to the effects of moderate to severe perinatal hypothyroidism in the rat. Rats received propylthiouracil (PTU) in drinking water at concentrations of 0, 1, 5, and 25 ppm from Gestation Day 18 until postnatal day (PND) 21, and the effects on their offspring were evaluated. At 1 ppm, PTU did not affect any of the measured endpoints. Serum thyroxin concentrations were sharply reduced in the 5 and 25 ppm PTU groups at all ages sampled (PND 1, 7, 14, and 21). Marked reductions in serum triiodothyronine (T3) concentrations were also detected for all ages > or = 7 at 25 ppm PTU, whereas no effects of 5 ppm PTU on serum T3 were apparent until PND 21. Compared to the controls, pups exposed to the highest dose of PTU demonstrated a delay in eye opening, reduced body weights, decreased and/or delayed preweaning motor activity, and persistent, postweaning hyperactivity. Only slight and transient effects on eye opening and ontogeny of motor activity were seen at the intermediate dose of PTU (5 ppm). Reflex modification audiometry revealed that, compared to controls, adult offspring from the 5 and 25 ppm treatment groups showed dose-dependent auditory threshold deficits (35 to > 50 dB) at all frequencies tested (1, 4, 16, 32, and 40 kHz). Such dose-dependent effects indicate that the developing auditory system may be sensitive to mild hypothyroidism, suggesting the possible need for routine audiometric screening for infants and children at risk for iodine deficiency, myxedema, and/or exposure to thyrotoxic environmental agents.

Topics: Acoustic Stimulation; Animals; Animals, Newborn; Audiometry; Behavior, Animal; Body Weight; Drinking; Female; Habituation, Psychophysiologic; Hypothyroidism; Male; Motor Activity; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Reflex, Startle; Thyroxine; Triiodothyronine

Biochemical indices of selenium (Se) deficiency (liver Se content and glutathione peroxidase (GSHPx) activity, and urinary ketone bodies during fasting) were measured in Se-deficient or Se-sufficient control rats with or without ingestion of 6-propyl-2-thiouracil (PTU). Male weanling Wistar rats (50 to 60 g) were fed on a Torula yeast-based Se-deficient diet (Se content, < 0.01 microgram/g), or on the same diet supplemented with sodium selenite (0.1 microgram Se/g). The rats were given 0.05% PTU solution or deionized water as drinking water. After feeding for 6 weeks, the rats given PTU showed severe inhibition of growth and marked decreases in serum thyroxine (T4) and 3,5,3'-triiodothyronine (T3) levels. Animals fed the Se-deficient diet showed remarkably low hepatic Se content and GSHPx activity compared to the Se-sufficient control rats, irrespective of PTU-ingestion. In the rats without PTU, the Se deficiency was accompanied by significantly elevated serum T4 and lower T3 levels. Urinary ketone body excretion during fasting was significantly higher in the Se-deficient rats than in controls, irrespective of serum thyroid hormone levels. These results suggest that the increase in urinary ketone body excretion in Se deficiency may be independent of serum thyroid hormone.

Topics: Animals; Body Weight; Diet; Glutathione Peroxidase; Ketone Bodies; Liver; Male; Propylthiouracil; Rats; Rats, Wistar; Selenium; Thyroxine; Triiodothyronine

Clinical studies in thyrotoxicosis reveal a state of high bone turnover leading, eventually, to osteoporosis. Recently there has been concern that thyroxine (T4) treatment may have a similar effect on bone. Rat models have been used to study the effects of T4 on bone, but the majority of studies have looked at the effects of T4 after only 3 weeks of treatment. The aim of this study was to evaluate histomorphometric changes in rats after 12 weeks of thyroxine overtreatment or 12 weeks of hypothyroidism compared with untreated control animals. Animals received either T4 200 micrograms/kg per day, 0.1% propylthiouracil, or vehicle for 12 weeks. Tetracycline was administered 1 week and 3 weeks prior to killing. Iliac crest bone was used for histomorphometry. Serum T4 measurements (taken at killing) confirmed hyper- and hypothyroidism in the appropriate animal groups (between group difference p < 0.001 by ANOVA). In hyperthyroid animals there was an increase in mineral apposition rate (MAR; 0.94 vs. 0.59 microns/day, p < 0.001) and mineral formation rate (MFR/BS; 0.24 vs. 0.12 x 10(-2) micron3/micron2 per day, p < 0.001) and a slight increase in eroded surfaces (ES/BS%; 1.54 vs. 1.36, p < 0.05) compared with controls, consistent with previous in vitro and in vivo observations. In hypothyroid rats there was a marked reduction in osteoid surfaces (OS/BS%; 1.7 vs. 24.8, p < 0.001) and MAR (0.3 vs. 0.59 micrograms/day, p < 0.001), a reduction in ES/BS% (0.51 vs. 1.36, p < 0.05), and an increase in cancellous bone volume (BV/TV%; 30.29 vs. 19.6, p < 0.05), suggesting that thyroid hormones are a requirement for normal bone turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Animals; Body Weight; Calcinosis; Disease Models, Animal; Drug Overdose; Hyperthyroidism; Hypothyroidism; Ilium; Male; Propylthiouracil; Radioimmunoassay; Rats; Rats, Wistar; Tetracycline; Thyroid Function Tests; Thyroxine

Ketone bodies represent preferred energy substrates in the adult rat proximal tubule. They are abundant in the plasma of suckling rats and might represent an important oxidative substrate for the immature proximal tubule. The postnatal development of two enzymes involved in ketone body oxidation pathway, 3-ketoacid-CoA transferase and acetoacetyl-CoA thiolase, and of citrate synthase and carnitine acetyltransferase was studied in microdissected rat proximal convoluted tubule (PCT) at 1, 8, 16, and 21 days after birth. The enzyme levels in PCT of juxtamedullary and subcapsular nephrons were compared at 8, 16, and 21 days. A role of thyroid hormones in regulating the development of these enzymes was investigated by studying 8- and 21-day-old pups made hypothyroid by propylthiouracyl (PTU) treatment, as well as 21-day hyperthyroid rats. PTU treatment had no effect on enzyme activities on day 8. In contrast, the activity of all mitochondrial enzymes, except acetoacetyl-CoA thiolase, was significantly decreased in 21-day-old hypothyroid pups. In hypothyroid animals, the normal development of 3-ketoacid-CoA transferase, citrate synthase, and carnitine acetyltransferase could be restored after treatment by triiodothyronine (T3). In addition, one single injection of T3 to 8-day-old control pups induced a precocious rise in the activity of 3-ketoacid-CoA transferase, citrate synthase, and carnitine acetyltransferase in juxtamedullary PCT and in the activity of citrate synthase and carnitine acetyltransferase in subcapsular PCT. Altogether, these results point out the importance of the postnatal physiological rise in T3 in triggering the development of some mitochondrial oxidative enzymes in the PCT.

Topics: Aging; Animals; Animals, Newborn; Body Weight; Coenzyme A-Transferases; Energy Metabolism; Hypothyroidism; Kidney Tubules, Proximal; Mitochondria; Nephrons; Organ Size; Oxidation-Reduction; Propylthiouracil; Rats; Rats, Wistar; Reference Values; Thyroid Hormones; Triiodothyronine

The antithyroid drug propylthiouracil (PTU) has been shown previously to reduce hepatic oxygen utilization and to protect the liver from ethanol-induced injury. The present study examined the effect of PTU on hepatic microsomal oxygen consumption and on the activities of NADPH-cytochrome P450 reductase (CYP-reductase) and cytochrome P4502E1 (CYP2E1) in rats receiving ethanol or acetone chronically. Liver microsomes from rats treated with ethanol for 29 days displayed increases in (i) O2 consumption (70%), (ii) hydroxyl radical (.OH) production (49%) and (iii) ethanol oxidation (50%). Microsomal CYP2E1 levels were increased markedly by chronic ethanol administration, while CYP-reductase was affected marginally, but not significantly (P = 0.06). Chronic treatment with acetone for 14 days, produced similar effects, except that .OH production was not enhanced. Administration of PTU (25 mg/kg/day) to ethanol- or acetone-fed rats, for 10 and 14 days, respectively, led to a marked reduction in the levels and activity of CYP-reductase, and to a decrease in the rates of microsomal O2 consumption, .OH production and ethanol oxidation, but did not lower the levels of CYP2E1 or the metabolism of the CYP2E1 substrate N,N-nitrosodimethylamine. These data suggest that the ability of PTU to protect the liver from ethanol-induced injury may be due to a reduction in the levels of CYP-reductase, thereby minimizing the enhancement of microsomal oxygen consumption and free radical generation associated with ethanol-induced CYP2E1 activity.

Topics: Acetone; Animals; Body Weight; Cytochrome P-450 CYP2E1; Cytochrome P-450 Enzyme System; Enzyme Induction; Ethanol; Female; Hydroxyl Radical; Microsomes, Liver; NADPH-Ferrihemoprotein Reductase; Oxidoreductases; Oxidoreductases, N-Demethylating; Oxygen Consumption; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormones

Topics: Adolescent; Appetite; Behavior Therapy; Body Weight; Bulimia; Combined Modality Therapy; Female; Graves Disease; Humans; Propylthiouracil

In propylthiouracil (PTU)-fed (g/kg feed) hypothyroid cockerels, serum levels of growth hormone (GH), but not insulin-like growth factor (IGF)-1, tended to rise and those of IGF-binding activity to fall. Thyroxine (T4) supplement (200 micrograms/kg/day) to PTU-fed cockerels for 8 days produced a hyperthyroid state and reversed these serum parameters. A chromatographic analysis of serum proteins revealed that T4 supplement markedly enhanced the IGF-binding activity of a 30 kDa protein and slightly lowered that of a 150 kDa protein, suggesting that T4 increases unsaturated IGF-binding proteins by reducing circulating IGF-1 concentrations.

Topics: Animals; Animals, Newborn; Blood Proteins; Body Weight; Carrier Proteins; Chickens; Hyperthyroidism; Hypothyroidism; Insulin-Like Growth Factor Binding Proteins; Iodine Radioisotopes; Male; Organ Size; Propylthiouracil; Protein Binding; Somatomedins; Thyroid Gland; Thyroxine; Triiodothyronine

Rat lingual lipase undergoes maturational increases during postnatal development. The role of thyroxine (T4) in the control of lingual lipase during development was evaluated. T4 given at an early suckling stage (starting day 4 or 5) moderately increased lingual lipase (20-30%) compared to age-matched controls. A similar dose of T4 given later (age > 2 weeks) was ineffective. The T4-sensitive period coincides with a time of low circulating T4, suggesting a role of T4 in modulating the development of lingual lipase in rat pups. Since simultaneous treatment with U486, a type II glucocorticoid receptor antagonist only partially blocked the T4 induction of lingual lipase, T4 appeared to have a direct action on the lingual gland. Pups of propylthiouracil (PTU)-treated dams (previously found to be hypothyroid) showed a delay in the maturation of lingual lipase compared to age-matched pups whose dam was not given PTU. Pups were most sensitive to PTU in the early suckling stage. PTU-induced delayed maturation of lingual lipase was a result of hypothyroidism, since T4 replacement when given early (at the age of 5 days) abolished most of the effect of PTU. When T4 was given later (at the age of 10 days), recovery was much less. This suggests the presence of an early period that is critically dependent on T4 for the full expression of lingual lipase in the rat tongue serous glands.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Suckling; Body Weight; Dose-Response Relationship, Drug; Hypothyroidism; Lipase; Mifepristone; Pancreas; Propylthiouracil; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Thyroid Gland; Thyroxine; Tongue

The effect of treatment with propylthiouracil early in life (PTU; 8 mg k-1 day-1, ip, from day 17 of gestation to postnatal day 42) on the susceptibility of the cerebral cortex to spreading depression (SD) was studied in 13 adult Wistar rats (90-100 days of age). Ten animals injected with Ringer solution served as control. Adult PTU-treated rats displayed a significant (P < 0.05) reduction in body weight (mean +/- SD: 139.9 +/- 28.9 g vs 304.9 +/- 42.8 g) as well as wet brain weight (1.39 +/- 0.12 g vs 1.86 +/- 0.13 g) and dry brain weight (247.3 +/- 24.2 mg vs 359.4 +/- 30.1 mg). Their thyroid glands presented histological changes indicative of hypofunction and SD velocity of propagation was significantly reduced all along the 6 h of the recording session (mean +/- SD ranges: 1.90 +/- 0.46 to 2.52 +/- 0.68 mm/min vs 3.49 +/- 0.57 to 3.71 +/- 0.55 mm/min). The results indicate that PTU early in life was effective in producing hypothyroidism and that in this situation cortical susceptibility to SD is impaired.

Topics: Animals; Body Weight; Brain; Cortical Spreading Depression; Female; Organ Size; Pregnancy; Propylthiouracil; Rats; Rats, Wistar; Thyroid Gland

Epidermal growth factor (EGF) in mouse submandibular gland (SMG) is synthesized in the granular convoluted tubular (GCT) cells. The synthesis of EGF in SMG has been shown to be increased by thyroid hormone. This increase was attributed to the increase in EGF mRNA. Not known is how thyroid hormone increases the mRNA level. In the present study the effect of thyroid hormone administration on EGF gene expression in SMG was studied in hypothyroid mice. Hypothyroidism was induced by treating the mice with propylthiouracil. The amount of SMG EGF mRNA was markedly decreased in hypothyroid mice. Administration of T3 increased the mRNA in a dose-dependent manner. The increase in EGF mRNA by T3 was evident as early as 6 h after T3 administration. A nuclear run-off assay indicated that the induction of EGF gene expression by T3 is at a transcriptional level. Bromodeoxyuridine incorporation into GCT cells was not affected by T3 administration, suggesting that T3 does not cause the proliferation of these cells. In situ hybridization revealed that T3 increases EGF mRNA in GCT cells at a single cell level. These results suggest that thyroid hormone increases EGF gene transcription without affecting cellular proliferation.

Topics: Animals; Body Weight; Bromodeoxyuridine; Epidermal Growth Factor; Gene Expression; Hypothyroidism; In Situ Hybridization; Male; Mice; Organ Size; Propylthiouracil; RNA, Messenger; Submandibular Gland; Thyroxine; Transcription, Genetic; Triiodothyronine

In the central nervous system, type II 5' deiodinase (5'D-II) is highly regulated, as judged by the dramatic changes in enzyme levels observed after abrupt alterations in thyroid status. In this work, the 5'-DII activity has been studied in different situations of experimental hypothyroidism (propylthiouracil, methimazole, thyroidectomy, and low iodine diet), in various brain regions (pituitary, cerebellum, brain stem, hypothalamus, cortex, and whole brain) in adult rats. Propylthiouracil and methimazole significantly increase the activity in all brain regions. These increases are higher in rats treated with methimazole. Thyroidectomy significantly increases the activity in cortex and pituitary. A low iodine diet significantly increases in all brain regions except in the hypothalamus. The concentration of triiodothyronine (T3) studied in the major brain regions remained unchanged. The results obtained show a compensatory mechanism in pituitary and other brain regions in order to maintain the T3 levels in brain tissue.

Topics: Animals; Body Weight; Brain; Cytosol; Diet; Dithiothreitol; Glycerolphosphate Dehydrogenase; Hypothyroidism; Iodide Peroxidase; Liver; Malate Dehydrogenase; Male; Methimazole; Mitochondria, Liver; Propylthiouracil; Rats; Rats, Wistar; Thyroxine; Triiodothyronine

The effect of a wide range of doses of propylthiouracil (PTU, 0.01-5%) on the immune responses of young male chickens was examined. One-day-old chickens were rendered hypothyroid by PTU supplemented in the feed for 4 weeks. At all doses PTU treatment caused a significant dose-related reduction in body weight (except at 0.01%) and in relative lymphoid organ weights. Skin response to phytohemagglutinin (PHA) was significantly greater in the chickens treated with low doses of PTU (0.01-0.1%) and significantly less in the chickens treated with high doses of PTU (1.5-5%) than that in control chickens. Number of splenic plaque forming cells (PFC) to sheep red blood cells (SRBC) was significantly increased in the chickens treated with low doses of PTU. Concentrations of serum 3,3',5-triiodothyronine (T3) and thyroxin (T4) were significantly lower in the chickens treated with all doses of PTU. Addition of T3 to the feed supplemented with 0.01% PTU replaced the serum T3 concentration and reduced the skin response to PHA and the number of the splenic PFC. These data confirm our previous observations that a low dose of PTU enhances and a high dose suppresses the immune responses of young male chickens.

Topics: Adrenal Glands; Animals; Antibody Formation; Bird Diseases; Body Weight; Chickens; Dose-Response Relationship, Drug; Hemolytic Plaque Technique; Hypothyroidism; Immunity, Cellular; Liver; Lymphoid Tissue; Male; Organ Size; Propylthiouracil; Skin Tests; Thyroid Gland; Thyroxine; Triiodothyronine

Treatment of male rat pups with the reversible goitrogen 6-propyl-2-thiouracil (PTU), administered by adding 0.1% PTU to the mother's drinking water from birth to day 25, increases their testis size and daily sperm production (DSP) at 160 days of age by up to 80% and 140%, respectively. The purpose of this study was to examine the effectiveness of various concentrations of PTU and determine the PTU dose that would maximize testis growth while minimizing side effects such as decreased maternal water consumption and decreased pup growth. Whether this effect was specific to PTU was determined by evaluating the effects of another commonly used goitrogen, methimazole (MMI), in increasing adult testis size and sperm production. Dams were given PTU (0.1-0.0004% w/v) or 0.025% MMI (w/v) in their water from birth to day 25 post partum, then given no further treatment. Thyroxine concentrations were measured in all groups of pups at 25, 35 and 45 days, and testis weight and DSP were determined at 90 days of age. At 25 days of age, thyroxine concentrations were maximally decreased by PTU treatments of 0.0015% or greater; less severe decreases were produced by 0.0004% PTU or 0.025% MMI. Thyroxine concentrations increased in all treated groups at day 35 compared with day 25, and returned to normal by day 45. At 90 days of age, testis weight was increased by about 40% in rats whose mothers had been treated with doses of 0.006% PTU or greater, whereas testis weights in groups given 0.0015 and 0.0004% PTU or 0.025% MMI were increased 31, 15 and 18%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Body Weight; Dose-Response Relationship, Drug; Drinking; Drug Administration Schedule; Embryonic and Fetal Development; Male; Methimazole; Organ Size; Propylthiouracil; Rats; Rats, Sprague-Dawley; Spermatogenesis; Testis; Thyroxine

The effects of testosterone (TP) and thyroxine (T4) on the level of epidermal growth factor (mEGF) in the thyroid were compared in a hypothyroid mouse model. Groups of five adult female BALB/c mice were given a "severe" hypothyroid regimen consisting of an iodine deficient diet together with oral and s.c propylthiouracil (PTU). Sialoadenectomy or sham operation was performed after 18 days on the hypothyroid regimen. The mice convalesced on normal diet for 5 days and beginning from day 23 received either T4, 1 ug/g or 2 ug/g, s.c daily or TP, 0.3 mg or 0.75 mg, i.m. every third day until day 33, while continuing the hypothyroid regimen. Control mice received normal diet and vehicles for the various injections. The mice were killed on day 33 and thyroidal EGF levels determined by radioimmunoassay. The mean+S.E. levels of mEGF in the thyroid were 10.12 +/- 1.75 ng/mg protein (control), 3.82 +/- 0.67 ng/mg (hypothyroid; p < 0.01), 3.07 +/- 1.52 (T4, 1 ug/g; p < 0.02), 2.59 +/- 0.46 ng/mg (T4, 2 ug/g; p < 0.01), 8.58 +/- 2.48 (TP, 0.3 mg), and 9.65 +/- 1.86 (TP, 0.75 mg). Thus thyroidal mEGF levels decreased significantly in all groups except those subsequently treated with testosterone; T4 was ineffective in reversing the tissue depletion of mEGF in this model. These results show that mEGF levels in the thyroid could be depleted by hypothyroidism and may also be androgen responsive.

Topics: Animals; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Epidermal Growth Factor; Female; Hypothyroidism; Mice; Mice, Inbred BALB C; Organ Size; Propylthiouracil; Proteins; Radioimmunoassay; Salivary Glands; Testosterone; Thyroid Gland; Thyroxine

We have previously shown that treating rats with the reversible goitrogen 6-propyl-2-thiouracil (PTU) from birth to Day 25 increases testis size and sperm production in adulthood by up to 80% and 140%, respectively. The purpose of this study was to determine the critical period(s) during development when PTU treatment can increase adult testis size and sperm production. Rats were treated with PTU beginning on Days 0, 8, 16, or 24 for periods of 9, 17, or 25 days. To further define the critical period, additional rats were treated with PTU prenatally or on Days 4-24. PTU treatments of 9, 17, or 25 days beginning at birth increased testis weight 18%, 38%, and 69%, respectively, by 135 days of age, while daily sperm production (DSP) increased 35%, 65%, and 94%, respectively. Efficiency of sperm production (DSP/g testis) also increased by approximately 25% in these rats. There was an inverse relationship between testis and body weights: increasing lengths of PTU treatment increased testis weight but decreased body weight. PTU treatment starting on Day 8 or later did not increase testis weight or DSP regardless of duration. Treatment on Days 4-24 increased adult testis weight and DSP similarly to treatment from birth to Day 24, but prenatal PTU treatment was ineffective. Testosterone concentrations were not altered in treated rats, even those with increased testis weight. These results indicate that the later part of the first postnatal week (Days 4-8) is the crucial period during which PTU treatment must begin in order to increase adult testis size and sperm production.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Body Weight; DNA; Hypothyroidism; Male; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains; Spermatogenesis; Testis; Testosterone

This investigation was designed to morphologically evaluate the effects of hypothyroidism on the development of myelin and axons in the rat optic nerve. Four pups from each group of normal and propylthiouracil-induced hypothyroid rats were sacrificed at 14, 21, 28, and 35 postnatal days. Optic nerves were studied by both light and electron microscopes. The hypothyroid animals had significantly reduced body and brain weights compared to those of their age-matched controls. In the hypothyroid animals, the cross-sectional area of the optic nerve, the fiber density, and fiber occupancy were significantly diminished compared to those of the controls. The mean individual fiber size was unaffected. However, the relationship between the total axonal area to myelin thickness was similar in the control and experimental groups, implying that the feedback mechanism between myelinating cells and axons was not affected by hypothyroidism. Thus, this study indicates that the principal insult of neonatal hypothyroidism results in a delay in myelin acquisition of myelinated fibers, resulting in diminished cross-sectional area of the optic nerve, fiber density, and fiber occupancy.

Topics: Aging; Animals; Axons; Body Weight; Hypothyroidism; Myelin Sheath; Optic Nerve; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Regression Analysis

Undernutrition was induced in rats submitted to food restriction from the fetal stage, and malnutrition was continued after birth until 70 days of life. Body weight was decreased to less than 50%. Plasma T4 and T3 and pituitary TSH content were determined between 8-70 days of life. In control rats, plasma T4 and T3 reached a maximum at 14 and 35 days of life, respectively, and TSH pituitary content at 45 days of life. In undernourished rats, after 8 days of life, plasma T4 and T3 and pituitary TSH content were decreased to about 50% or less, and the pattern of sequential changes observed in control rats was absent or modified. T4 and T3 concentrations were measured in heart, liver, and brain in the fetus (22 days old) and 8, 14, and 23 days after birth, as well as liver and brain 5'-deiodinases (5'D). Hepatic 5'D type I was always decreased in undernourished rats from 8-70 days after birth. Liver and heart T4 and T3 concentrations were decreased in 14-day-old undernourished rats as well as brain T3. Brain 5'D type II was decreased at 8 and 14 days, and total brain 5'D activities at 8 days. These changes occurred during the critical period for brain development (7th to 20th day) during which most processes of myelination take place and T3 brain normal levels are required.

Topics: Aging; Animals; Body Weight; Brain; Embryonic and Fetal Development; Female; Heart; Iodide Peroxidase; Liver; Myocardium; Nutrition Disorders; Organ Size; Organ Specificity; Pituitary Gland; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The object of this experiment was to examine whether the administration of clenbuterol exerts clenbuterol's repartitioning effects in rats with hypothyroidism induced by the oral administration of propylthiouracil (PTU). Male Wistar rats aged 5 weeks were divided into 4 groups: control, PTU administrated (PTU), clenbuterol administrated (CL), and PTU plus clenbuterol administrated (PTU/CL) groups. Rats were raised for 7 weeks at 26 degrees C and given 13 g of diet every day. The PTU and PTU/CL groups were fed a basal diet containing PTU at the level of 30 mg/kg diet throughout the experimental period. Clenbuterol was added to the diet of the CL and PTU/CL groups at the dose of 0.1 ppm from the 3rd week. Serum thyroxine concentrations of rats were significantly lower in rats in the PTU and PTU/CL groups than those in the control and CL groups. Thus, the administration of PTU succeeded to induce hypothyroidism. The clenbuterol administration seemed to exert its repartitioning effects in euthyroid rats, while the administration neither increased body protein nor decreased body fat in hypothyroid rats. This result therefore suggests that the effects of clenbuterol on the alteration of body composition may vary with the level of thyroid activity in rats.

Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Cholesterol; Clenbuterol; Hypothyroidism; Liver; Male; Organ Size; Propylthiouracil; Proteins; Rats; Rats, Inbred Strains; Thyroxine; Triglycerides

We studied the effects of propylthiouracil (PTU), amiodarone (AMIO), diphenylhydantoin (DPH), phenobarbital (PB), and 3-methylcholanthrene (MC) on thyroid histomorphology, on the hepatic and renal enzymes involved in endogenous and exogenous metabolism, and on the plasma levels and pharmacokinetics of thyroid hormones after 7 and 14 days of treatment. PTU and PB, by decreasing both serum tetraiodothyronine (T4) and triiodothyronine (T3), induced a massive increase in serum thyrotropin (TSH) and thus induced thyroid hypertrophy. AMIO and MC, by decreasing respectively serum T3 and T4, also induced an increase of TSH, but to a lesser extent, not sufficient to induce thyroid hypertrophy. Hepatic 5'-deiodinase activity was decreased in all treated rats. Inhibition of this enzyme by PTU was demonstrated in vitro; AMIO also decreased the enzyme activity by a still unelucidated mechanism, which probably requires intact cell plasma membranes, whereas in PB- and MC-treated rats the decrease in enzyme activity certainly resulted from decreased serum concentrations of T4. In PTU-treated rats, and probably in MC-treated rats, decreases in circulating thyroid hormones were primarily due to impairment of synthesis and/or of secretion by the thyroid. In contrast, in PB-treated rats, the decrease in serum thyroid hormone levels seems to be due to increased excretion of these hormones, as T4 serum clearance was significantly increased. PB, a microsomal enzyme inducer, increased the cytochrome b5 and P450 content as well as the cytochrome P450-dependent O-depentylation of pentoxyresorufin. The other type of enzyme inducer, MC, did not affect cytochrome b5 and P450 levels, but did increase the cytochrome P450 dependent O-deethylation of ethoxyresorufin. PB increased the glucuronidation of morphine, whereas MC increased the glucuronidation of 1-naphthol. However, serum T4 clearance, mainly determined by its hepatic conjugation rate, was increased only in PB-treated rats. It appears from this study that the close metabolic relationship between the liver/kidney and the thyroid should be taken into consideration when the findings of chronic toxicology and carcinogenicity studies are interpreted.

Topics: Amiodarone; Animals; Body Weight; Cytochrome P-450 Enzyme System; Cytochromes b5; Glucuronosyltransferase; Kidney; Liver; Male; Methylcholanthrene; Microsomes, Liver; Organ Size; Oxygenases; Phenobarbital; Phenytoin; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

We showed previously that propylthiouracil (PTU), a thyroid inhibitor, could alleviate several major signs of hereditary muscular dystrophy in chickens. The goals of the present investigation were to: (1) determine whether a nearly athyroid condition (achieved within two days after hatching by surgical thyroidectomy plus PTU) during an 11-day period beneficially affects the dystrophic condition when followed by triiodothyronine (T3) replacement to 33 days of age; (2) determine the beneficial effects on the expression of avian dystrophy when the thyroidectomized-PTU-treated chickens received a wide range of moderate to low T3 replacement doses beginning by two days after thyroidectomy; and (3) examine the thyroid hormone receptor system in dystrophic muscle for a possible abnormality. Thyroid deprivation increased muscle function (righting ability) and reduced plasma creatine kinase activity in dystrophic chickens. The major thyroid-related abnormality in dystrophic pectoralis muscles was an increased maximum binding capacity of solubilized nuclear T3 receptors.

Topics: Animals; Body Weight; Chickens; Creatine Kinase; Dose-Response Relationship, Drug; Injections, Subcutaneous; Kinetics; Muscular Dystrophy, Animal; Pectoralis Muscles; Phenotype; Propylthiouracil; Receptors, Thyroid Hormone; Thyroid Gland; Thyroidectomy; Time Factors; Triiodothyronine

The purpose of the present study was to elucidate the mechanism by which thyroid hormone alters urea synthesis. The relative importance of urea cycle enzyme activities, substrate levels or the levels of urea cycle intermediates on urea production was investigated in a set of four experiments in which rats were fed a diet supplemented with 6-propyl-2-thiouracil (PTU, a thyroid inhibitor) and treated with triiodothyronine (T3). Compared with that of normal or control rats, the plasma level of T3 was significantly lower in rats fed a diet containing PTU only and elevated in rats given PTU + T3. Urinary excretion of urea and the liver content of ornithine in rats given PTU + T3 were significantly lower than in rats given PTU only. The liver level of ornithine was closely correlated to the excretion of urea in the present study. Fractional rates of protein synthesis in liver, kidney and small intestine were lower in the hypothyroid group. However, most free amino acid concentrations, except ornithine in liver and plasma and the activity of hepatic argininosuccinate synthetase (EC 6.3.4.5) of hypothyroid rats, were significantly reduced as compared with those of control or hyperthyroid rats. The results indicate that the increased hepatic ornithine content in the hypothyroid rats may be one of the regulatory factors causing changes in urea synthesis.

Topics: Administration, Oral; Amino Acids; Animals; Body Weight; Injections, Intravenous; Liver; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland; Triiodothyronine; Urea

Noxythiolin (Noxyflex-S) inhibited iodide organification (thyroid hormone synthesis) by cultured porcine thyrocytes in vitro after 5 hr (IC50 approx. 9.0 microM). The positive control, the anti-thyroid thiourea methimazole, was about 15 times more potent an inhibitor of iodide organification (IC50 approx. 0.6 microM) under the same incubation conditions. In an in vivo assessment of follicular organification capacity using the perchlorate discharge test, 14 days of ip treatment of male Charles River rats with noxythiolin (50 mg/kg body weight) produced no inhibition of iodide organification when tested 24 hr after the last administration of noxythiolin whereas the positive control, propylthiouracil, was a highly potent inhibitor.

Topics: Animals; Body Weight; Cells, Cultured; Injections, Intraperitoneal; Iodine; Male; Methimazole; Noxythiolin; Organ Size; Propylthiouracil; Rats; Swine; Thyroid Gland; Thyroid Hormones

1. Induction of hypothyroidism in rats by feeding propylthiouracil (PTU) significantly increased serum cholesterol concentrations, and the effect was more pronounced for cholesterol in low-density lipoproteins (LDL) rather than high-density lipoproteins (HDL). The concentrations of serum triacylglycerol were decreased in hypothyroidism. These effects on serum lipids were also seen when the normal rats were pair-fed with the PTU-treated group. 2. Feeding a diet rich in saturated fat and cholesterol further increased cholesterol concentrations in LDL and also elevated that in very-low-density lipoprotein (VLDL) of hypothyroid rats. In euthyroid rats such a diet resulted in a relatively small increase in VLDL cholesterol, whereas LDL cholesterol was decreased. 3. Steady-state concentrations of mRNA for the hepatic LDL receptor were significantly decreased in the livers of hypothyroid rats, but were not significantly changed by high-fat feeding in euthyroid or hypothyroid rats. 4. The expression of the LDL receptor in hepatocytes cultured from hypothyroid rats was decreased relative to the euthyroid controls. 5. Whereas the esterification of cholesterol with oleate in hepatocytes cultured from hypothyroid rats was decreased, the activity of acyl-CoA:cholesterol acyltransferase (ACAT) in the livers of these animals was not changed. 6. High-fat feeding increased the hepatic ACAT activity in normal and hypothyroid rats. 7. Incubation of rat hepatocytes with 10 nM-tri-iodothyronine for 4 h increased the relative concentration of the mRNA for the LDL receptor by 25%. 8. It is therefore concluded that thyroid hormones stimulate the synthesis and expression of the hepatic LDL receptor. Elevated cholesterol concentrations in LDL in hypothyroidism probably result from a primary defect in the expression of the hepatic receptor, rather than indirectly via changes in ACAT activity.

Topics: Animals; Body Weight; Cells, Cultured; Cholesterol, VLDL; Diet, Atherogenic; Esterification; Hypothyroidism; Lipoproteins, LDL; Liver; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, LDL; RNA, Messenger; Sterol O-Acyltransferase; Triiodothyronine

Male and female Long-Evans rat pups, exposed to an oral dose of 14 mg chlorine dioxide (CIO2)/kg/d (postnatal d 1-20), were examined for effects on brain development and for changes in thyroid activity. Body weight reductions were observed on postnatal (pn) d 11, 21, and 35. Forebrain weight and protein content were decreased on pnd 21 and 35, as were the DNA content on d 35 and the number of dendritic spines on cerebral cortical pyramidal cells, a marker for synapse formation. Otherwise, cell proliferation in the forebrain, cerebellum, and olfactory bulbs was normal, as were migration and aggregation of neuronal cells in three areas of the cerebral cortex. Histopathology of the forebrain, cerebellum, and brainstem showed no gross lesions, loss of myelin, or change in the cells staining positive for Nissl substance. Serum T3 and T4 levels, as well as hepatic mitochondrial alpha-glycerophosphate dehydrogenase activity, were unchanged by CIO2 treatment. The results indicated that CIO2 may have central neurotoxic potential. No underlying antithyroid activity was evident.

Topics: Animals; Animals, Newborn; Body Weight; Brain; Brain Stem; Cerebellum; Cerebral Cortex; Chlorine; Chlorine Compounds; Disinfectants; DNA; Female; Male; Olfactory Bulb; Organ Size; Oxides; Propylthiouracil; Proteins; Rats; Thyroid Hormones

Topics: Animals; Blood Pressure; Body Temperature Regulation; Body Weight; Electrophoresis, Polyacrylamide Gel; Heart; In Vitro Techniques; Myocardial Contraction; Myocardium; Myosins; Organ Size; Propylthiouracil; Rats; Rats, Inbred WKY

The effect of propylthiouracil oral treatment (400 mg/day per bird for 20 days) on body and thyroid weight, rectal temperature and plasma metabolic parameters of ducks (Cairina moschata) was determined. Propylthiouracil treatment produced a reduction (P less than .01) in body weight and an increase (P less than .01) in thyroid weight. The antithyroid drug also produced a decrease in rectal temperature starting from the 15th day of treatment, but did not significantly change blood glucose. Plasma free fatty acids and cholesterol concentrations progressively increased from the 5th and 10th day, respectively, in treated animals.

Topics: Animals; Blood Glucose; Body Temperature; Body Weight; Cholesterol; Ducks; Fatty Acids, Nonesterified; Female; Organ Size; Propylthiouracil; Thyroid Gland

Malic enzyme activity in the soluble fraction of neonate brains from mothers fed with propylthiouracil (0.015% w/v) in drinking water from day 12 of the gestation period was significantly lowered (P less than 0.01) as compared to the offspring of normal mothers. Supplementation of triiodothyronine to the neonates from experimental mothers restored the malic enzyme activity to normal levels. However, administration of triiodothyronine to adult control rats did not influence malic enzyme activity in the brains of these animals. Our data suggest that during the initial critical period of brain maturation, malic enzyme is under the control of thyroid hormones. The response of malic enzyme towards thyroid hormones is lost once the brain has matured.

Topics: Animals; Body Weight; Brain; Female; Liver; Malate Dehydrogenase; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Hormones; Triiodothyronine

After demonstrating that prenatal exogenous thyroid hormone administration to pregnant rats produces decreases in fetal lung antioxidant enzyme (AOE) development despite increases in surfactant development, we examined the role of endogenous thyroid hormones on the development of these two lung systems. We administered the antithyroid drug methimazole (or diluent) to pregnant rats for the final 3 days before premature or term delivery; in a second series of experiments, propylthiouracil was administered for the 10 days before delivery. Both antithyroid drugs, known to cross the placenta, produced significantly decreased thyroid hormone levels in the pregnant dams. Fetal offspring from methimazole-, and propylthiouracil-treated dams demonstrated significant increases in pulmonary superoxide dismutase activity at 20 and 21 days of gestation and in catalase and glutathione peroxidase activities at 21 days compared with control offspring. Surfactant, measured as lung tissue disaturated phosphatidylcholine, was not different between either experimental group and controls. These results suggest that thyroid blockade increases AOE because the influence of thyroid hormone on AOE development may be one of depression. The findings confirm that certain hormonal regulators may influence different developing fetal lung systems in different ways.

Topics: Animals; Body Weight; Catalase; Female; Fetus; Gestational Age; Glutathione Peroxidase; Lung; Methimazole; Organ Size; Pregnancy; Propylthiouracil; Pulmonary Surfactants; Rats; Rats, Inbred Strains; Reference Values; Thyroid Gland; Thyroxine; Triiodothyronine

Young, male ICR mice were given tap water or distilled water containing 200 mg/l propylthiouracil (PTU) and were then infected with 10 plerocercoids of Spirometra erinacei to investigate the effect of plerocercoid infection on thyroid hormone in their hosts. Plerocercoid infection stimulated growth in PTU-induced hypothyroid mice as if they had never received PTU treatment: there were increases in weight in the liver, skeletal muscle, and spleen, as well as enhancement of the head and body length, in spite of a greater decrease in serum T4 levels than was observed in PTU-treated controls. Furthermore, the intact mice infected with plerocercoids showed a decrease in serum T4 levels as well as in the concentration of T4-binding globulin. These observations suggest that the growth stimulation and the decrease in concentrations of serum T4 and T4-binding globulin associated with plerocercoid infection in mice probably resulted from secretion of a growth hormone-like substance produced by plerocercoids of S. erinacei.

Topics: Animals; Body Weight; Cestoda; Cholesterol; Diphyllobothriasis; Growth Substances; Hypothyroidism; Intercellular Signaling Peptides and Proteins; Liver; Male; Mice; Mice, Inbred ICR; Muscle Development; Organ Size; Propylthiouracil; Spirometra; Spleen; Thyroid Gland; Thyroxine; Thyroxine-Binding Proteins; Triglycerides

The reversibility of the effects of propylthiouracil induced neonatal hypothyroidism by daily subcutaneous injections of L-thyroxine (T4) was investigated in the rat. Four groups of rat pups were used in this experiment: Group I (control) received equivalent amounts of saline subcutaneously; Group II (hypothyroid) received propylthiouracil injections daily; Group III (T4-14) are hypothyroid rats who received daily T4 replacement therapy (2.5 micrograms/day) subcutaneously starting on Day 14; Group IV (T4-21) are also hypothyroid rats whose T4 replacement therapy (2.5 micrograms/day) was started on Day 21. The four parameters studied were body length, body weight, brain weight, and cerebellar weight in these four groups of animals at 4, 7, 10, 14, 21, 28, 35, and 42 postnatal days. A minimum of eight animals were studied for each time sequence. The present study clearly indicated the beneficial effect of T4 therapy on the length and body weight of the hypothyroid animals, whether therapy was started at Postnatal Day 14 or 21. In addition, a more important finding of this study was the significant increase in brain and cerebellar weights of T4-treated animals compared to the hypothyroid animals, this beneficial effect being more striking in the T4-14 group when compared to that in the T4-14 animals.

Topics: Animals; Animals, Newborn; Body Weight; Brain; Cerebellum; Hypothyroidism; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine

Hypothyroidism was induced in rats by treatment with propylthiouracil through the mother's milk throughout the suckling period followed by surgical thyroidectomy without use of radioiodine. The growth of these animals was considerably retarded and their light-dark discriminative operant learning ability was also significantly decreased. Replacement therapy with thyroxine to maintain its normal serum concentration was effective for continuing normal growth and development of learning ability. Therefore, these hypothyroid rats are a useful model of congenital hypothyroidism. Biochemical studies showed that the inhibition of cerebral Na,K-ATPase and succinic dehydrogenase activities detected in early postnatal life in these hypothyroid rats was transient and that normal activities of these enzymes were later regained in adult rats. However, the activity of 2',3'-cyclic nucleotide 3'-phosphohydrolase and the brain myelin remained low throughout life unless thyroxine was administered. Though a critical correlation between biochemical parameters and learning ability is still uncertain, these results suggest that the formation of myelin in the neonatal period is at least dependent on thyroid hormone and would play an important role in mental development.

Topics: Animals; Body Weight; Brain Chemistry; Conditioning, Psychological; Congenital Hypothyroidism; Disease Models, Animal; Hypothyroidism; Learning; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroidectomy; Thyroxine

The effect of 1000 ppm potassium perchlorate (KClO4), 1000 ppm potassium iodide (KI) or 1000 ppm propylthiouracil (PTU) in the diet on the development of thyroid tumors was studied histologically and biochemically in Wistar rats given a single ip injection of 280 mg of N-bis(2-hydroxypropyl)nitrosamine (DHPN) per 100 g body weight. Basal diet containing 100 ppm KClO4, 1000 ppm KI or 1000 ppm PTU was given for 19 weeks from week 2 to week 20. The incidence of thyroid adenomas at the end of week 20 of the experiment was 100% (20/20) in rats treated with DHPN followed by KClO4, 85% (17/20) in rats given DHPN followed by KI, 95% (19/20) in rats given DHPN followed by PTU, and 5% (1/20) in rats given DHPN alone. The incidence of thyroid cancers was 100% (20/20) in rats treated with DHPN followed by KClO4, 65% (13/20) in rats treated with DHPN followed by KI and 0% (0/20) in rats treated with DHPN followed by or not followed by PTU. Rats given KClO4, KI or PTU alone and untreated rats had no thyroid tumors. The mean values of TSH in serum were 2.94 +/- 0.79 ng/ml in rats treated with DHPN followed by KClO4, 9.40 +/- 16.0 ng/ml in rats treated with DHPN followed by KI and 60.94 +/- 20.60 ng/ml in rats treated with DHPN followed by PTU. It was confirmed that (1) KClO4, PTU and KI promote the development of thyroid tumor in rats treated with DHPN, (2) the promoting effect of KClO4 or KI is stronger than that of PTU and (3) the value of TSH in serum is not parallel to the promoting effect on the development of thyroid tumor.

Topics: Animals; Body Weight; Cocarcinogenesis; Male; Nitrosamines; Organ Size; Perchlorates; Potassium; Potassium Compounds; Potassium Iodide; Propylthiouracil; Radioimmunoassay; Rats; Rats, Inbred Strains; Thyroid Gland; Thyroid Neoplasms

The adrenal medulla of normal, hypothyroid and hyperthyroid young rats was stimulated by insulin-induced hypoglycaemia. In normal rats, insulin-induced adrenal epinephrine secretion increases during the first 10 days of post-natal life. Hypothyroidism retards the development of adrenal response; hyperthyroidism facilitates the development of this response. At 14 days, when insulin-induced adrenal epinephrine depletion is the same for all groups, the recovery of adrenal catecholamines stores after depletion is linear and takes less than 48 h. Recovery rate is slightly slower for hyperthyroid rats than for either hypothyroid or control rats at 14 days. Following epinephrine depletion, adrenal tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) activities are increased for a few days in the control rats, corresponding to a transsynaptic induction. Hypothyroidism impairs TH induction and completely suppresses DBH induction; hyperthyroidism impairs TH induction, but has no effect on DBH induction. These data show that the various processes related to CA synthesis, in the adrenal medulla of the developing rat, are controlled in different ways by the thyroid hormones.

Topics: Adrenal Medulla; Animals; Animals, Newborn; Body Weight; Catecholamines; Dopamine beta-Hydroxylase; Epinephrine; Hypoglycemia; Insulin; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Hormones; Time Factors; Tyrosine 3-Monooxygenase

The osmoregulatory responses to warmer temperatures and hormone treatment in cold-adapted (5 degrees C) Rana catesbeiana tadpoles and newly metamorphosed frogs were examined. Tadpoles transferred to 11 degrees C and 18 degrees C and left for 5 days lost 7% and 10% of their body weight. Plasma [Na+] was elevated 28% and 21%, respectively. Control (5 degrees C) animals maintained their body weight and plasma [Na+] constant. Daily treatment with either ovine prolactin (oPRL) or ovine growth hormone (oGH) prevented the weight loss and the increase in extracellular [Na+] that occurred when tadpoles were transferred to 18 degrees C. Neither propylthiouracil (PTU) nor arginine vasotocin (AVT) were effective in countering temperature-induced weight loss in tadpoles. Newly metamorphosed frogs transferred to 18 degrees C also lost weight; this was not prevented by daily treatment with saline, oPRL, oGH or PTU. However, in frogs treated daily with AVT, initial BW was regained by day 6. When warm-adapted (18 degrees C) tadpoles were treated daily for 18 days with saline, bPRL, bGH, thyroxine (T4), ergocornine, cortisol, or cortisol + T4, bPRL was most effective in retarding weight loss and maintaining body water content, whereas T4 + cortisol caused the greatest loss of weight and body water. By day 20, the correlations between weight loss and both body water content and hematocrit were highly significant. These data suggest that reported increases in plasma solute concentrations in larval amphibians may actually reflect decreases in extracellular fluid volume, rather than increased amounts of solutes, per se.

Topics: Animals; Body Water; Body Weight; Ergolines; Growth Hormone; Hormones; Hydrocortisone; Larva; Prolactin; Propylthiouracil; Rana catesbeiana; Sodium; Sodium Chloride; Temperature; Thyroxine; Vasotocin; Water-Electrolyte Balance

Experimental diabetes causes profound alterations in the metabolism of thyroxine (T4), including a decrease in hepatic triiodothyronine (T3) generation from T4 via 5'-deiodination (5'-D). Because 5'-D in brain differs markedly from that in liver, both in enzymatic mechanism and in the response to hypothyroidism, we studied iodothyronine deiodination, in particular T4 to T3 conversion (T4-T3), by incubating 125I T4 with particulate fractions of cerebral cortex (Cx) and cerebellum (Cm) from rats made diabetic by injection of streptozotocin. In nondiabetic thyroidectomized (Tx) rats Cx and Cm T4-T3 activity was increased approximately ten-fold and two-fold, respectively, compared with intact controls. Diabetic Tx rats did not differ from nondiabetic Tx rats in the rate of net T3 production from T4 but the formation of 3,3'-T2 was slightly reduced. Insulin-treated diabetic-Tx rats showed a pattern of T4 metabolism in Cx and Cm virtually identical to that of nondiabetic Tx rats. The rate of T3 degradation, determined in parallel incubations of Cx and Cm with 125I T3, did not differ significantly among the groups, indicating that the observed differences in net T3 production were due to changes in T4 5'-D activity. Intact diabetic rats compared to nondiabetic controls showed no significant changes in T4-T3 either in Cx or in Cm. Administration of T3, 0.8 microgram per 100 g bw per day for 6 days, by constant infusion to intact rats raised T4-T3 in Cx and Cm to levels found in Tx rats. Treatment of intact diabetics with T3 caused qualitatively similar changes, i.e., a hypothyroid response.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Cerebellum; Cerebral Cortex; Diabetes Mellitus, Experimental; Hypothyroidism; Insulin; Iodide Peroxidase; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Triiodothyronine

We studied the karyometric development of 4 subdivisions of the paraventricular nucleus (rostral, caudal, medial and lateral) and 3 subdivisions of the ventromedial nucleus of the hypothalamus (ventral, central and dorsal) in a hypothyroid group of male albino mice treated with propylthiouracil with or without interruption of the treatment at the 35th postnatal day. Hypothyroidism produces an increase of the nuclear-size values of the paraventricular and ventromedial nuclei, and the continued treatment increases this effect. The caudal and the rostral subdivisions of the paraventricular nucleus show more significant changes of their nuclear sizes compared to the medial and lateral subdivisions. The ventromedial nucleus responds similarly to hypothyroidism in all its subdivisions.

Topics: Animals; Body Weight; Cell Nucleus; Hypothyroidism; Karyometry; Male; Mice; Mice, Inbred Strains; Paraventricular Hypothalamic Nucleus; Propylthiouracil; Time Factors; Ventromedial Hypothalamic Nucleus

Topics: Aging; Animals; Birds; Body Weight; Hypothyroidism; Male; Propylthiouracil; Testis

Dietary administration of propylthiouracil (0.2%) to male Sprague-Dawley rats for a period of 8 weeks induced hypothyroidism and hypotension in these animals. Resting heart rate, body weight, colonic temperature and serum thyroxine (T4) were significantly lower in the treated hypothyroid rats than in the controls. Time-course study indicates that the maximal depression of these parameters occurred about the eighth week of PTU treatment; except T4 level which declined abruptly about the second week and remained steady thereafter. The mechanism(s) of hypotension is (are) unknown but there seems to be an interrelationship between hypothyroidism-induced hypotension and the parameters monitored, since discontinuation of PTU treatment reversed that trend of the response toward control levels.

Topics: Animals; Blood Pressure; Body Weight; Heart Rate; Hypotension; Hypothermia; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Time Factors

Newborn female Long-Evans rats were divided into groups of normal, hypothyroid [0.1% propylthiouracil (PTU) a reversible antithyroid goitrogen in the litter's drinking water], and hypothyroid rehabilitated (PTU water from birth to day 25, normal water thereafter). The rats were tested for several adaptive behavioral tasks between 40 and 90 days of age. At day 50, serum concentration of TSH and thyroid hormones revealed no detectable amounts of T4 and a 10-fold increase in TSH in the hypothyroid rats. At the same age in the rehabilitated animals, TSH levels were still below normal, a deficit fully normalized by day 90. Normal 50-day-old rats responded to pain stress (electric footshocks) by a significant depression of serum T4 and elevation of T3 levels within 10 min of treatment, whereas the rehabilitated animals exhibited an opposite pattern of response, i.e., an increase in the circulating T4 and a decrease in T3. At 50 days of age, both hypothyroid and rehabilitated rats showed decreased exploratory activity and no habituation in the hole-board test, whereas the locomotor activity of the rehabilitated females was significantly higher than that of the normals. No differences were found in the scores of passive avoidance learning (one trial step-through) among the three groups. Similarly, the rate of acquisition of the active one-way conditioned avoidance response (CAR) of the hypothyroid and rehabilitated rats did not differ significantly from that of the controls. However, the hypothyroid rats required significantly more unconditioned stimuli (footshocks) to acquire CAR and showed longer response latency and less intertrial responses. Although the hypothyroid rats showed no extinction of CAR, the rehabilitated rats were capable of extinction to an extent indistinguishable from normal rats. But compared with the normal animals, the rehabilitated rats showed significantly higher intertrial activity during both the acquisition and extinction phases of CAR.

Topics: Animals; Avoidance Learning; Body Weight; Conditioning, Classical; Exploratory Behavior; Extinction, Psychological; Female; Habituation, Psychophysiologic; Hypothyroidism; Learning; Propylthiouracil; Rats; Rats, Inbred Strains; Stress, Physiological; Thyrotropin; Thyroxine; Triiodothyronine

The thyroid neuroendocrine axis has been implicated in the control of circadian rhythmicity. The present work examined the ability of a thyroid hormone-inhibiting agent, propylthiouracil (PTU), to modulate phase and period of the hamster wheel-running circadian rhythm. The circadian period (tau) of blind male hamsters was lengthened by approximately 0.2 h when they were fed a diet containing 0.6% PTU. Removal of the PTU reversed the change in tau. Pinealectomy did not alter the tau response to PTU. Blind ovariectomized female hamsters showed changes in tau during and after PTU treatment that were similar to those of males. Males were also tested with 0.3, 0.6, or 1.2% PTU diets, and a dose-response relationship was established. Under 14:10 light-dark (LD 14:10) conditions, the phase of activity onset relative to lights off (psi) was not affected by 0.6% PTU. In LD 6:18, mean psi was 16.7 h, but this shortened to 13.3 h during PTU, returning to 16.0 h after PTU removal. In intact males under LD 14:10, the three PTU diet concentrations failed to differentially suppress thyroxine and triiodothyronine levels. Food intake and body weight were differentially reduced by the PTU treatments. A 0.5% quinine hydrochloride diet also reduced food intake and body weight but did not change tau. The inconsistency between the dose-tau response and the dose-thyroid hormone response suggest that PTU may affect circadian rhythmicity independent of its action on the thyroid neuroendocrine axis.

Topics: Animals; Body Weight; Circadian Rhythm; Cricetinae; Dose-Response Relationship, Drug; Eating; Female; Male; Mesocricetus; Motor Activity; Propylthiouracil; Thyroid Gland; Thyroxine; Triiodothyronine

The effect of propylthiouracil (PTU) pretreatment on in vivo and in vitro oxidative drug metabolism was determined in the rat. Whereas pentobarbital sleeping time (PBST) and zoxazolamine paralysis time (ZZPT) were used as indices of in vivo drug metabolizing activity, biotransformation of aminopyrine and aniline by hepatic microsomal preparations were used as indices of in vitro drug metabolizing enzymes activities. PTU pretreatment significantly prolonged both PBST and ZZPT. Whereas PTU did not affect microsomal protein concentration or cytochrome P-450 content, it significantly decreased microsomal cytochrome c reductase and aniline hydroxylase activities. These changes in enzymatic activities were observed in microsomal preparations from either non-fasted or 24-hr fasted rats. Our results suggest that PTU-induced hypothyroidism modifies the metabolism and effectiveness or toxicity of concomitantly administered drugs.

Topics: Aminopyrine; Aniline Compounds; Animals; Biotransformation; Body Weight; Cytochrome P-450 Enzyme System; Hypothyroidism; Liver; Male; Pentobarbital; Propylthiouracil; Rats; Rats, Inbred Strains; Zoxazolamine

Young laboratory rats received a daily subcutaneous injection of thyroxine (T4) and propylthiouracil (PTU) in saline, from birth until the period of spontaneous weaning. The rate of growth and the time of eye opening as well as the spontaneous weaning was assessed. The intake of maternal milk was followed directly, i.e. by the transport of 85Sr in maternal milk from the maternal body to the sucklings. In the young treated with T4 the eyes opened earlier than in the young treated with PTU. The body mass differed in both groups between the 4th and 20th day of life (the T4 pups were heavier). The 85Sr transfer in maternal milk was higher in the PTU young from the 22nd day of life. The PTU sucklings weaned spontaneously one week later than those receiving T4. A hypothesis has been proposed on the primary significance of maturation of oral mechanisms of sucking for spontaneous weaning.

Topics: Animal Population Groups; Animals; Animals, Suckling; Body Weight; Drinking; Female; Lactation; Milk; Ocular Physiological Phenomena; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Strontium Radioisotopes; Thyroxine

Hypothyroidism was induced in Wistar-Kyoto rats by adding propylthiouracil to the drinking water (0.8 mg/ml). Initial heat, total activity-related heat, and resting heat rate were measured in left ventricular papillary muscle preparations of propylthiouracil-treated and control rats contracting isometrically at 12 beats/min (21 degrees C), using Hill type, planar vacuum-deposited bismuth and antimony thermopiles. In the propylthiouracil preparations, relative to control, time-to-peak tension increased from 288 +/- 27 (mean +/- SD) to 411 +/- 25 msec (P less than 0.001), dp/dtmax decreased from 38.3 +/- 9.5 to 20.4 +/- 3.5 g X mm-2/sec (P less than 0.001), and peak developed tension decreased from 6.11 +/- 1.75 to 4.64 +/- 0.89 g X mm-2 (P less than 0.05). In the propylthiouracil preparations, initial heat was significantly (P less than 0.001) reduced by 27 or 43% when normalized to peak twitch tension or tension-time integral, respectively. In experiments where the papillary muscles were tetanized, the slope of the linear function of total activity-related heat versus tension-time integral was decreased by 43% (P less than 0.001) in the propylthiouracil preparations, indicating an improved economy of isometric tension maintenance. The predominant myosin isoenzyme of the left ventricular wall, as well as the papillary muscle myocardium, was the V3 variety in the propylthiouracil animals, in contrast to V1 in the controls. Myofibrillar actomyosin calcium-magnesium-stimulated adenosine triphosphatase activity was significantly (P less than 0.02) decreased from 55 +/- 18 (control) to 31 +/- 8 nmol inorganic phosphate ion/mg X min (propylthiouracil).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Actomyosin; Adenosine Triphosphatases; Animals; Body Weight; Ca(2+) Mg(2+)-ATPase; Calcium-Transporting ATPases; Energy Metabolism; Hypothyroidism; Isoenzymes; Isometric Contraction; Myocardial Contraction; Myofibrils; Myosins; Organ Size; Papillary Muscles; Propylthiouracil; Rats; Rats, Inbred WKY

Chronic ethanol administration (4-5 weeks) to female spontaneously hypertensive (SH) rats led to a marked increase in the rate of ethanol metabolism. This was accompanied by an increase in hepatic alcohol dehydrogenase (ADH) and by an increase in the rate of oxygen consumption in perfused livers of these animals. Treatment with the antithyroid drug 6-n-propyl-2-thiouracil (PTU) during the last 9 days (40 mg/kg/day) of the chronic administration of ethanol reduced hepatic oxygen consumption, resulting in a net diminution of the metabolic tolerance to ethanol, despite a further elevation in ADH activity. In these animals, microsomal ethanol-oxidizing system (MEOS) activity was not affected by chronic ethanol administration or by treatment with PTU. Data strongly suggest that in the female SH rat all the metabolic tolerance to ethanol proceeds via the ADH pathway, and that the increase in hepatic oxygen consumption is more important in the development of metabolic tolerance to ethanol than the increased ADH levels.

Topics: Alcohol Dehydrogenase; Alcohol Oxidoreductases; Animals; Body Weight; Cytochrome P-450 Enzyme System; Drug Tolerance; Ethanol; Female; Liver; Organ Size; Oxidation-Reduction; Oxygen Consumption; Perfusion; Propylthiouracil; Rats; Rats, Inbred SHR; Thyroid Gland

Topics: Abdomen; Anorexia; Body Weight; Dexamethasone; Diagnosis, Differential; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Humans; Hyperthyroidism; Middle Aged; Pain; Potassium Iodide; Propranolol; Propylthiouracil; Vomiting

The antithyroid drug propylthiouracil (PTU) is a potent inducer of hypothyroidism in the rat. To evaluate the effects of PTU on serum thyroxine (T4) concentration, growth, and weaning progression during development, five doses of PTU (0.0001, 0.0005, 0.001, 0.005, and 0.01 g/100 ml) were administered to infant rats via drinking water of the dam. The highest dose, 0.01%, is commonly used in developmental studies. The results indicate that 0.001% PTU creates hypothyroid pups without the debilitating characteristics of pups raised on 0.01% PTU. A second experiment examined the effects of 0.001% PTU on serum T4 concentration, growth, and weaning progression during the fourth postnatal week. Serum T4 concentration was depressed throughout the study period to 25% of controls. The hypothyroid pups continued to grow, although they were significantly smaller than untreated controls. Weaning was initiated by postnatal day 22 and completed on day 29. For normal untreated pups, weaning is initiated by day 17 and completed by day 26. Thus hypothyroidism delays but does not abolish the weaning process.

Topics: Animal Population Groups; Animals; Animals, Suckling; Body Weight; Dose-Response Relationship, Drug; Female; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Weaning

Cockerels and pullets fed with T3 or T4 for 2 weeks showed a decrease in both body weight gain and feed efficiency. The reduction in body weight gain and feed efficiency was dose related in cockerels where T3 or T4 were fed at 0.1, 1.0, and 10.0 ppm levels. T3 and T4 at 0.1 and 1.0 ppm had no significant effects on growth or feed efficiency in pullets, but the 10.0-ppm level of T3 and T4 caused a reduction of -55.24 and -28.18%, respectively, in body weight gain as compared with control birds. T3 was more active than T4 in reducing growth and was toxic when fed at 10.0 ppm both in cockerels and pullets. Both propylthiouracil (PTU)- and methimazole-treated cockerels showed a decrease in rates of gain. T3 and T4 at a dietary level of 0.1 ppm were equipotent in promoting growth in these PTU- and methimazole-treated cockerels, but 10.0 ppm caused a further reduction in body weight gain. Plasma T3 levels were found to be significantly higher in birds that were fed either T3 or T4. Plasma T4 levels were higher in T4-fed birds, but significantly lower in T3-fed birds as compared with controls. Both PTU- and methimazole-treated cockerels had significantly lower plasma T3 and T4 concentrations, but elevated plasma GH concentrations. Dietary T3 and T4 at 1.0 and 10.0 ppm significantly lowered plasma GH concentrations. In summary, these results indicated that T3 was more active than T4 in reducing body weight gain in intact normal birds, but that they were equally potent in promoting growth in PTU- and methimazole-treated hypothyroid birds.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Chickens; Diet; Female; Growth; Growth Hormone; Hypothyroidism; Male; Methimazole; Propylthiouracil; Thyroxine; Triiodothyronine

Three Latin-square trials were conducted to determine the effects of feeding the thyroid depressant propylthiouracil (PTU) on plasma concentrations of thyroxine (T4) and triiodothyronine (T3) in feedlot steers. In trial 1, four steers were fed 0, 1, 2 or 4 mg PTU/kg body weight daily during five 35-d experimental periods. In trial 2, eight steers were fed 0, .5, 1 or 2 mg PTU/kg body weight daily during five 28-d periods. In trial 3, three steers were fed 0, 1 or 4 mg PTU/kg body weight daily during the first 3 d in each of three 28-d periods. In general, feeding PTU caused increases in plasma T4 concentrations that peaked 5 to 7 d after feeding started. Concurrently, T3 concentrations tended to decrease when PTU was fed. The effects of PTU on hormone concentrations were apparent within approximately 1 to 4 h after PTU feeding started. Furthermore, when PTU was not fed, T4 and T3 concentrations appeared to have rhythmic cycles of 90 and 111 min, respectively, and PTU treatment appeared to interrupt this cyclical pattern. After the initial PTU response, the dose response relationship between PTU level and plasma hormone concentration was not linear. Both 4 and 2 mg PTU appeared to depress both T4 and T3 concentrations, suggesting direct inhibition of the thyroid gland and, for the 1-mg PTU treatment, T4 tended to stabilize at concentrations significantly greater than for 0 mg PTU, while T3 concentrations for 1 mg PTU were slightly lower than for 0 mg PTU.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Cattle; Dose-Response Relationship, Drug; Food Additives; Male; Periodicity; Propylthiouracil; Thyroxine; Triiodothyronine

Neurogenesis in the motor and mesencephalic nuclei of the trigeminal nerve was examined using autoradiographic techniques. Two groups of pregnant rats (control and experimental) were injected with two successive daily doses of 3H thymidine in an overlapping series starting from day nine of gestation in order to label in their progeny, the dividing precursor of neurons of the motor nucleus and mesencephalic nucleus of the trigeminal nerve. Control group of rats was raised on a standard diet, while the experimental group was made hypothyroid by propylthiouracil (PTU). At postnatal ages ranging between 20-30 days in the pups of both the control group and experimental group, the percentage of cells labelled and the proportion of cells added during each embryonic day were determined quantitatively throughout the rostro-caudal extent for both motor and mesencephalic nuclei. The neurons of the mesencephalic nucleus undergo their final cell divisions between gestational days 9 and 10 (E9 and E10). More than 80% of the population is generated by E10. The neurons of the motor nucleus undergo their final cell divisions between E9 and E11, and nearly 88% of the cells is generated by E11. In the thyroid deficient rats, in both nuclear centers, only 61% of the cells is generated by E12, and labelled cells are observed even as late as E18 and E19. In the hypothyroid state, there is a significant lengthening of the proliferative period. On the basis of absolute datings and duration of neuron production, it is postulated that in normal development, thyroid hormone determines the duration of the proliferative period, and push cells into the differentiative phase by taking them out of the proliferative phase.

Topics: Animals; Animals, Newborn; Body Weight; Female; Histocytochemistry; Hypothyroidism; Litter Size; Mesencephalon; Motor Cortex; Pregnancy; Propylthiouracil; Rats; Thymidine; Trigeminal Nerve; Tritium

The present paper describes the effects of long-term (17-19 months) feeding of high-iodine eggs on lipid metabolism and thyroid function of rats, and also the effects of inorganic iodine on lipid metabolism. Rats were meal-fed on a diet containing 1% (w/w) of ordinary egg powder (OE diet as control: 35 micrograms I/100 g) or high-iodine egg powder (IE diet: 392 micrograms I/100 g). After the 19-month dietary treatment, rats fed on the IE diet, compared with the controls, showed a higher tissue lipoprotein lipase activity, a lower lipid peroxide level in the brain and a trend toward lower serum triacylglycerol levels and body fat storage without alterations in serum levels of thyroid-related hormones (TSH, T3 and T4). From the results of cold exposure and anti-thyroid drug-treatment conducted on rats fed on the OE and IE diets for 17 months, high-iodine eggs seemed to improve the age-related defects in thermogenic and thyroid hormone responses to cold, and also to result in a resistance to the anti-thyroid drug. The effects of the IE diet on lipid metabolism of rats were partly exhibited by feeding of the OE diet with an equivalent amount of iodine added as KI or KIO3. Thus, it is suggested that iodine ingestion through high-iodine eggs modulates both lipid metabolism and thyroid function in rats.

Topics: Animals; Body Temperature; Body Weight; Cold Temperature; Diet; Eggs; Iodine; Lipid Metabolism; Lipids; Lipoprotein Lipase; Male; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Function Tests; Thyroid Gland; Time Factors

Exposure of rats to higher environmental temperature (36-37 degrees C) decreased the capacity of their kidney mitochondria to oxidize succinate. The decrease was corrected on the addition of exogenous cytochrome c. Kidney mitochondria of heat-exposed animals showed decreased rates of H2O2 generation when alpha-glycerophosphate, but not succinate, was used as electron donor. These mitochondria also showed decreased activity of alpha-glycerophosphate dehydrogenase but not of succinate dehydrogenase. The content of cytochrome c in kidney mitochondria of heat-exposed animals was low even though the concentration of the pigment in the whole tissue did not decrease. Starvation as well as administration of an antithyroid agent like propylthiouracil simulated some of the effects of heat exposure on kidney mitochondria, but the cytochrome c-dependent reversal of inhibition of oxidation was obtained only in heat exposure.

Topics: Animals; Body Weight; Cytochromes; Glycerophosphates; Hot Temperature; Hydrogen Peroxide; Kidney; Male; Mitochondria; Organ Size; Oxidation-Reduction; Oxidative Phosphorylation; Propylthiouracil; Rats; Starvation; Succinates; Succinic Acid

The effect of diisopropyl 1,3-dithiolan-2-ylidenemalonate (NKK-100) on experimental fatty livers was investigated in chicks administered an antithyroid agent plus synthetic estrogen or in estrogenized, starved-refed chicks. NKK-100 was added at levels of 250, 500, 1000, and 1500 mg/kg diet. Liver weight was significantly decreased by administration of NKK-100 at 1500 mg/kg diet in the estrogen-administered chicks. Liver lipid content and liver lipid deposition were significantly and inversely decreased with increasing NKK-100 concentration in the diet in the estrogen administered chicks. Plasma transaminase activity, which was elevated by the estrogen administration, was reduced by the administration of NKK-100. These results suggest that NKK-100 may be of value in preventing fatty livers in poultry.

Topics: Animals; Aspartate Aminotransferases; Body Weight; Chickens; Dienestrol; Estradiol; Fatty Liver; Lipid Metabolism; Liver; Male; Organ Size; Poultry Diseases; Propylthiouracil; Thiophenes

A patient presenting with hyperthyroidism had a rapidly enlarging thyroid mass that histopathologically was a diffuse histiocytic lymphoma arising in a gland with Hashimoto's thyroiditis. The concurrent development of both hyperthyroidism and lymphoma may have resulted from similar immunologic abnormalities. Appreciation of the relationship between thyroid lymphoma and Hashimoto's thyroiditis, and their presentation with either hypothyroidism or hyperthyroidism should lead to an earlier diagnosis of lymphoma and improved survival.

Topics: Body Weight; Female; Humans; Hyperthyroidism; Lymphoma; Middle Aged; Propranolol; Propylthiouracil; Thyroid Neoplasms; Thyroidectomy; Thyroiditis

Newborn rats of both sexes were treated from birth with the anti-thyroid goitrogen, n-propylthiouracil (PTU) given in the drinking water of the litter (0.1% w/v). One group received the treatment for 25 days, another for 50 days, and a third group for 120 days. The experimental rats showed growth retardation as well as all other classical signs of developmental arrest or delays induced by postnatal hypothyroidism. In order to assess the ability of the hypothyroid animals to recover spontaneously from the retarded state, at days 25, 50 and 120 postnatal the PTU water was replaced with tap water. In each case, within 5-7 days after PTU withdrawal the animals began to show marked compensatory growth accompanied by many signs of behavioral and physiological recovery. In general, the male rats showed higher compensatory growth rates as compared to the females, enabling them to attain significantly higher body weights. However, when growth recovery was followed for up to 6 months it was found that the male rats were unable to attain complete catch-up growth, regardless of the age at which recovery began, while the females of all age groups were able to achieve this goal. In view of the severity of PTU-induced growth retardation, these results suggest significant plasticity of growth processes in the rat, especially in the female. It is suggested that male and female rats recovering from prolonged PTU-induced growth retardation offer a good model system for the study of biochemical, anatomical and physiological aspects of growth recovery and catch-up growth at both the cellular and organismic levels, particularly in relation to the effects of thyroid, growth hormone, and other growth-promoting factors.

Topics: Aging; Animals; Animals, Newborn; Animals, Suckling; Body Weight; Female; Growth Disorders; Hypothyroidism; Male; Propylthiouracil; Rats; Sex Factors; Sexual Maturation; Weaning

The proportion of total, helper and suppressor T lymphocytes among mononuclear cell preparations from blood and spleen of rats made hypo- and hyperthyroid was measured using three monoclonal antibodies specifically directed against total, helper and suppressor T cells. Compared to normal rats, hypothyroid (thyroidectomized or treated with 6-propyl-2-thiouracil (PTU) rats had a decreased proportion of suppressor T cells in the spleen, which produced an increase in the helper/suppressor T cells ratio. The opposite alterations (increased suppressor T cells and decreased ratio) was found in the blood of the same animals. Triiodothyronine (T3) added to PTU in the drinking water prevented these alterations. Animals treated with high doses of T3 for 17 days did not develop any alteration either in the proportions or in the ratio of helper/suppressor T cells. Our results suggest that hypothyroidism but not hyperthyroidism alters the normal balance between helper and suppressor T cells in rats.

Topics: Animals; Antibodies, Monoclonal; Body Weight; Hyperthyroidism; Hypothyroidism; Leukocyte Count; Male; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains; Spleen; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Thyroidectomy; Triiodothyronine

The interaction of glucocorticoid (GC) and thyroxine (T4) in the generation of the hepatic enzyme overshoot and lipid response to starvation-refeeding was studied. Male Sprague-Dawley rats were either left intact, or treated with propylthiouracil (PTU), or adrenalectomized (ADX), or ADX and/or PTU treated and treated with GC and/or T4. One-half of each of these treatment groups was fed a 65% glucose diet while the remaining rats were starved for 48 hours and refed the glucose diet for 48 hours. After decapitation, hepatic lipid and glucose-6-phosphate dehydrogenase (G6PD) activity were determined. Rats treated with only PTU had less of an enzyme overshoot than nontreated rats, and the full overshoot response was restored with T4 treatment. ADX rats did not have the typical enzyme overshoot response to starvation-refeeding. However, ADX rats had their overshoot response restored with GC. PTU-treated ADX rats had more of an overshoot response than did ADX rats. When T4 was administered to PTU-treated ADX rats there was less of an enzyme overshoot; however, when both T4 and GC were administered to the PTU-treated ADX rats, the overshoot response was fully restored. The liver lipid response to starvation-refeeding followed a similar pattern except that in PTU-treated rats the liver lipid levels were significantly higher in the starved-refed rats than in the ad libitum-fed rats. These results indicate that T4 and GC play a role in the G6PD and liver lipid response to starvation-refeeding.

Topics: Adrenalectomy; Animals; Body Weight; Drug Interactions; Food; Glucosephosphate Dehydrogenase; Hydrocortisone; Lipid Metabolism; Liver; Male; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains; Starvation; Thyroxine

The growth of fetuses of 50% calorie-restricted (R) rats was retarded by approximately 1 day as compared with that of ad libitum fed control (C) rats. Nevertheless, the thyroid glands in such growth-retarded fetuses developed in proportion to the size of fetuses, as did the thyroid follicular cell height and the follicular diameter. Pregnant rats were treated with 40 mg propylthiouracil (PTU) each day for 2 days and autopsied on the third day in various gestational periods of Days 17-19, 18-20, 19-21, and 20-22. PTU given to C rats on Days 17 and 18 of gestation did not alter the fetal thyroid weight and histology on Day 19. When given on Days 18 and 19, or later, PTU caused a significant increase in the thyroid weight and follicular cell height. However, when given to R rats on Days 18 and 19, PTU did not influence the fetal thyroid. When given on Days 19 and 20, or later, PTU was effective in R rats. Thus, in fetuses of the R rats, the reciprocal relationship between the pituitary and the thyroid appears to be established with a 1-day delay as compared with the C rats, similar to the 1-day retardation in body weight gain.

Topics: Animals; Body Weight; Female; Fetus; Food Deprivation; Gestational Age; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland

Repeated intraperitoneal administration of propylthiouracil (PTU, 0.5-1.5 mmole/Kg) to rats caused a dose related decrease in body weight. A dose dependent increase in liver weight and a decrease in spleen weight were also seen. Leukocyte counts were markedly reduced in all PTU treated animals. Histopathological changes were observed. These consisted of congestion of red pulp of the spleen and vacuolization of the liver.

Topics: Animals; Blood Cell Count; Body Weight; Male; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains

The contents of immunoreactive somatostatin (IR-SRIF) and beta-endorphin (IR-beta-EP) in 12 brain regions were examined in rats exposed neonatally to propylthiouracil (PTU) through the mother's milk. Since the dose of PTU used in this study is lower than the usual dose employed to induce hypothyroidism, a milder form of neonatal hypothyroidism resulted. This conclusion is supported by the only mild subnormal growth of rats to adulthood and serum T4 and T3 concentrations in the normal range. Adult rats treated with PTU neonatally had significantly higher IR-SRIF contents in several brain regions compared to controls, whereas IR-beta-EP levels were not significantly different (significant increase only in the thalamus) in most regions. The results indicate that even mild hypothyroidism during early postnatal development causes permanent impairment of brain function, which manifests itself in part by an altered brain content of IR-SRIF.

Topics: Animals; beta-Endorphin; Body Weight; Brain Chemistry; Endorphins; Female; Male; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Somatostatin; Thyroxine; Tissue Distribution; Triiodothyronine

Topics: Adult; Blood Pressure; Body Weight; Female; Graves Disease; Humans; Ipodate; Kinetics; Male; Middle Aged; Propylthiouracil; Pulse; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Animals; Birds; Body Weight; Lipids; Propylthiouracil; Seasons; Thyroidectomy; Thyroxine; Triiodothyronine

Reproductive traits and histology of the adenohypophysis were studied in adult White Leghorn cockerels after surgical thyroidectomy or .1% propylthiouracil (PTU) food supplementation. Both treatments caused hypothyroidism as judged by a marked reduction in plasma thyroxine levels, a decrease in resting metabolic rate values, an increase in liver and adipose tissue weights, and a marked elevation in the alcianophilic cell population in the adenohypophysis. Both the PTU-treated and thyroidectomized birds demonstrated reduced testes and comb weights. However, although thyroidectomy was found to increase the number of PAS-positive cells in the adenohypophysis, the PTU treatment reduced them. This phenomena is discussed.

Topics: Animals; Body Weight; Chickens; Comb and Wattles; Male; Organ Size; Organ Specificity; Pituitary Gland, Anterior; Propylthiouracil; Testis; Thyroid Gland; Thyroidectomy

The effects of propylthiouracil (PTU) on the ontogeny of suckling behavior in rats were examined. The drug was given at two dosage levels of 0.3% and 0.5% respectively mixed with rat diet throughout gestation and suckling. The thyroid glands of treated fetuses and pups and of untreated control animals of the same age groups were monitored by histologic examination. At the behavioral level, the frequency of individual movements of head, forelimbs and mouth was significantly reduced in treated fetuses. The combination movements of head, mouth and forelimbs showed severe deficits both quantitatively and qualitatively for all ages in the experimental group from day 18 of gestation. Hypothyroid pups of dams raised on 0.5% PTU were unable to attach to the nipple of the mother and died within a few days. Pups of dams raised on 0.3% PTU showed longer latencies for nipple attachment, and their gross motor movements of rooting and suckling were greatly impaired. These results have been discussed in relation to the development of suckling behavior to indicate that, during ontogeny, some decisive step in the integration of individual movements takes place in utero from day 18 of gestation. This coincides with the establishment of pituitary thyroid relationship, which is continued through postnatal stages.

Topics: Animals; Body Weight; Female; Gestational Age; Hypothyroidism; Maternal-Fetal Exchange; Motor Activity; Muridae; Pituitary Gland; Pregnancy; Propylthiouracil; Sucking Behavior; Thyroid Hormones

Caudal arterial lesions form spontaneously with age in the male Wistar rat and are characterized by a break in the internal elastic lamina (IEL), with associated damage to endothelium and underlying smooth muscle cells followed by rapid repair. Such lesions have been studied under conditions of hypercholesterolaemia. Diet-induced hypercholesterolaemia did not enhance the formation of these lesions compared to age-matched control rats. Lesioned areas of caudal arteries from hypercholesterolaemic rats showed marked or slight focal lipid deposits depending upon their location along the artery. Studies in rats of different ages suggest that the majority of lipid probably accumulates during the phase of lesion repair and that the absence of the IEL per se does not appear to be responsible for the lipid accumulation. The effect of hypertension associated with hypercholesterolaemia on caudal arterial lesions was studied using DOCA salt-Wistar and spontaneously hypertensive rats. The association of these two factors did not increase lesions either in the caudal artery or in the renal artery studied for comparison. In caudal artery the number of fatty lesions appeared to be related more to the level of cholesterolaemia than to blood pressure. The extent of lipid accumulation within lesions in the caudal artery appears not to correlate with that in the renal artery, demonstrating the importance of local factors.

Topics: Animals; Arteries; Body Weight; Cholesterol; Diet, Atherogenic; Dietary Fats; Elastic Tissue; Hypercholesterolemia; Hypertension; Lipid Metabolism; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Rats, Mutant Strains; Renal Artery; Tail

Hypothyroidism was induced in 38-day old male rats by feeding the animals a chow diet supplemented with propylthiouracil (PTU, 0.1% by weight) for 43 days. Wheel activity of PTU animals was not significantly different from that of euthyroid, ad lib feeding controls it was significantly lower when compared to pairfed controls. Body weight was significantly lower than that of euthyroid ad lib controls. After 75 days of PTU discontinuation catch-up growth of PTU animals was not complete: body weight and tibia length were significantly lower in the PTU condition in comparison to euthyroid, ad lib feeding condition. However, no difference existed between the catch-up growth of PTU and pairfed animals. It was suggested that growth arrest observed in early hypothyroidism may be partly due to factors nonspecific to thyroxine absence, such as hypophagia.

Topics: Animals; Body Weight; Bone Development; Hypothyroidism; Male; Motor Activity; Propylthiouracil; Rats

Sprague-Dawley rats were fed Purina Lab Chow with or without propylthiouracil (PTU), 0.001%, 0.01% or 0.1% PTU, ad libitum from weaning to vaginal opening. Mean values for all pubertal measurements are included in Tables 1 and 2. Growth rate (mean +/- S.E.) was significantly reduced (Neuman-Keuls test; P less than 0.05 level) in all PTU-fed rats (controls 4.9 +/- 0.1 g/day, 0.001% PTU 4.2 +/- 0.2 g/day, 0.01% PTU 3.4 +/- 0.2 g/day, 0.1% PTU 2.5 +/- 0.1 g/day), while age at vaginal opening in rats fed 0.001% PTU (35.8 +/- 0.6 days) or 0.01% PTU (36.1 +/- 0.9 days) was not significantly different from controls (36.0 +/- 0.6 days). Nevertheless, body weight at vaginal opening was lower in rats fed 0.1% PTU (87.6 +/- 4.7 g) than in controls (113.6 +/- 3.7 g). Pubertal body weight of rats fed 0.1% PTU was also reduced (88.6 +/- 3.7 g) but vaginal opening delayed (40.4 +/- 0.8 days). Proportions of body fat (6.1 - 5.1%), protein (15.0 - 14.1%), and water (72.4 - 71.3%) at vaginal opening were the same in control and PTU groups. Serum T4 was greatly diminished and similar in all 3 PTU groups, 0.2 - 0.3 microgram/100 ml, vs 4.8 +/- 0.2 microgram/100 ml in controls; in rats fed 0.1% and 0.01% PTU, T3 was 0.9 +/- 0.4 ng/100 ml and 0.9 +/- 0.6 ng/100 ml, respectively vs 72.6 +/- 5.6 ng/100 ml in controls, but not significantly reduced in the 0.001% PTU-fed group (60.7 +/- 7.9 ng/100 ml). In a second experiment, a group of weanling rats (pair-fed) was selected in which each member was fed the daily amount of control diet eaten by a corresponding age- and weight-matched 0.01% PTU-fed rat. During the experiment, both groups maintained the same body weight, growth rate, and food intake, however, only 45% (n = 11) of the pair-fed animals had vaginal opening by the time their 0.01% PTU-fed counterparts attained first estrus. Although one of the pair-fed (undernourished) rats attained first estrus, no eggs were found. Despite greatly reduced body weight (105.3 +/- 3.5 g vs controls 127.5 +/- 6.6 g), growth rate (3.5 +/- 0.2 g/day vs controls 5.5 +/- 0.1 g/day) and food intake (13.9 +/- 0.7 g/100g BWt/day vs controls 10.1 +/- 0.3 g/100g BWt/day), the 0.01% PTU-fed rats exhibited vaginal opening (36.9 +/- 0.8 days vs controls 35.6 +/- 1 days) and first estrus (39.6 +/- 0.9 days vs controls 36.4 +/- 1 days) at the usual age. In contrast, pair-fed rats had a lower % fat (4.5 +/- 0.1% vs PTU 6.8 +/- 0.4%) and higher % protein (16.5 +/- 0.3% vs PTU 14.3 +/- 0.3%) at the age when

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Female; Hypothyroidism; Nutrition Disorders; Prolactin; Propylthiouracil; Rats; Sexual Maturation

Topics: Aging; Animals; Body Weight; Eating; Half-Life; Hypothyroidism; Lipoproteins, LDL; Male; Metabolic Clearance Rate; Propylthiouracil; Rats

Topics: Animals; Antibody Formation; Body Weight; Chickens; Concanavalin A; Hyperthyroidism; Immunity; Male; Organ Size; Propylthiouracil; Spleen; Thymus Gland; Thyroid Gland; Thyroxine

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Female; Hypothyroidism; Mammary Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Propylthiouracil; Rats; Thyroxine; Time Factors; Triiodothyronine

The changes in the developmental pattern of 3-oxo acid CoA-transferase activity in the brain of hypothyroid rats and the effect of triiodothyronine on this enzyme activity have been investigated. Hypothyroid rats showed lower activity than controls during the suckling period. However, higher enzyme levels were found in treated rats after weaning in contrast to control animals. The results suggest that thyroid hormones promote the development of enzymes of ketone-body metabolism in the brain.

Topics: Aging; Animals; Animals, Suckling; Body Weight; Brain; Coenzyme A-Transferases; Female; Hypothyroidism; Keto Acids; Organ Size; Pregnancy; Propylthiouracil; Rats; Succinates; Sulfurtransferases; Triiodothyronine

Topics: Animals; Body Weight; Cholesterol; Fasting; Female; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Rats; Species Specificity; Thyroid Gland; Thyroxine; Triglycerides

Topics: Animals; Body Weight; Cortisone; Fasting; Growth Disorders; Growth Hormone; Iodine Radioisotopes; Male; Metabolic Clearance Rate; Propylthiouracil; Rats

Recent evidence indicates that the paraventricular nucleus of the hypothalamus (PVN) contains both neurons that produce thyrotropic releasing hormone (TRH) and neurons that are destroyed or disconnected by the knife cuts that produce hypothalamic hyperphagia and obesity. This, and other evidence, suggested linkage between thyroid regulation and appetite control. As predicted, hyperthyroidism potentiated and hypothyroidism tempered the weight gains of knife cut rats. However, these effects were due entirely to increased and decreased, respectively, linear growth, not to differences in the degree of obesity. Enhanced linear growth and elevated growth hormone levels are a minor component of the enhanced weight gain of hypothalamically knife cut rats. Most of the weight gain is due to fat deposition. Only the enhanced linear growth and growth hormone aspect appear to possibly be mediated via the thyroid. In addition, obesifying knife cuts did not reduce goiterogenesis in PTU treated rats, as would be expected if the elaboration of TRH were blocked by obesifying knife cuts. Thus, neither TRH nor thyroxine is involved in the etiology of hypothalamic obesity.

Topics: Animals; Body Weight; Brain; Hyperthyroidism; Hypothalamus; Hypothyroidism; Male; Obesity; Paraventricular Hypothalamic Nucleus; Propylthiouracil; Rats

1. The effect of propylthiouracil (PTU)-induced hypothyroidism on carbohydrate and lipid metabolism was studied in the chick embryo. 2. A single dose of PTU (250 micrograms/embryo) was administered on day 11 and embryos sacrificed on day 20 of incubation. 3. Thyroid glands were significantly enlarged (6 fold) by PTU administration. 4. Increased thyroid weight was associated with growth retardation and decreased plasma thyroxine levels. 5. Plasma glucose level was lower and phospholipids were significantly higher in the hypothyroid embryo. 6. Liver lipid concentrations in the control and hypothyroid embryos were not different but were significantly higher in both groups when compared to previously reported values in the young chick. 7. In contrast to PTU treatment after hatching, liver glycogen levels were not increased in the hypothyroid chick embryo. This was attributed to the high lipid nutrient condition of the chick embryo since a high lipid diet in the young chick decreased hepatic glycogen accumulation significantly.

Topics: Animals; Blood Glucose; Body Weight; Carbohydrate Metabolism; Chick Embryo; Cholesterol; Glucose-6-Phosphatase; Hypothyroidism; Lipid Metabolism; Liver; Organ Size; Phospholipids; Propylthiouracil; Thyroid Gland; Triglycerides

To study the possible mechanisms involved in growth retardation associated with hypothyroidism, serum T4, GH, the GH-dependent somatomedin, insulin-like growth factor (IGF), and its carrier protein (CP) were measured in hypothyroid rats and their age-matched controls. Three groups of rats were studied: infant, immature, and adult. Marked hypothyroidism (serum T4, less than 1 microgram/dl) was produced in experimental animals by providing them with drinking water containing 0.05% propylthiouracil. Infant and immature hypothyroid rats weighed markedly less than normal controls and had significantly reduced serum levels of GH, IGF, and CP. Normal adult rats, treated with propylthiouracil for 60 days, also weighed considerably less than control animals and exhibited a significant drop in serum GH, IGF, and CP during this period. The administration of bovine GH to hypothyroid adult rats for 7 days did not restore either IGF or CP levels to normal, indicating that their decrease in serum was, in part, a direct result of hypothyroidism per se. These results indicate that serum levels of GH, IGF, and CP are at least partly under thyroid hormone control. Furthermore, these studies suggest that the growth retardation associated with hypothyroidism may be mediated through somatomedin activity.

Topics: Aging; Animals; Body Weight; Carrier Proteins; Female; Growth Disorders; Growth Hormone; Hypothyroidism; Male; Nonsuppressible Insulin-Like Activity; Propylthiouracil; Rats; Somatomedins; Thyroxine

Hypothyroidism was induced in neonatal Sprague-Dawley rats by adding propylthiouracil to the lactating female's food and water. Behavioral evaluation on a 6-item battery occurred from 70 to 114 days of age. Results indicated long-lasting behavioral changes in the neonatal hypothyroid animals characterized by increased activity and decreased performance on avoidance and escape learning. Serum thyroxine levels were reduced in the hypothyroid animals throughout the 120-day period. Experimental animals also had fewer synaptic contacts in the cerebellar cortex when analyzed at 90 days of age.

Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Cerebellar Cortex; Female; Hypothyroidism; Male; Nerve Fibers; Propylthiouracil; Rats; Synapses; Thyroxine

The survival of Buffalo rats brearing Morris Hepatoma 7800 was increased significantly (23 to 31%) after induction of hypothyroidism by propylthiouracil (PTU) (0.1% in Purina rat chow) or 131I. The concentration of PTU used was in the optimal range as 0.03% PTU was less effective than 0.1%, while 0.4% PTU appeared to be toxic. Exogenous thyroxine (8 microgram/kg body weight) reversed the effects of PTU and actually shortened survival. Because food consumption and body weights of hypothyroid rats were decreased, the survival of pair-fed controls was studied and found to be the same as in untreated controls. We conclude that the hypothyroid state increases the survival of rats bearing Morris Hepatoma 7800. We have not yet been able to define any anatomical or biochemical parameters which may be responsible for this effect.

Topics: Animals; Body Weight; Hypothyroidism; Liver Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Organ Size; Propylthiouracil; Rats; Thyroid Gland; Thyroxine; Time Factors

Topics: Animals; Birds; Body Weight; Clomiphene; Endocrine Glands; Feeding Behavior; Male; Obesity; Propylthiouracil; Testosterone; Thyroxine

Topics: Aging; Animals; Animals, Newborn; Body Weight; Female; Hypothalamo-Hypophyseal System; Iodine; Propylthiouracil; Rats; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone

Topics: Animals; Body Weight; Castration; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hypothyroidism; Luteinizing Hormone; Male; Organ Size; Propylthiouracil; Prostate; Rats; Seminal Vesicles; Testis; Testosterone

Topics: Adenylyl Cyclases; Animals; Body Weight; Male; Methimazole; Organ Size; Phospholipids; Propylthiouracil; Rats; Thyroid Gland

Topics: Animals; Body Weight; Brain Injuries; Cartilage; Cortisone; Disease Models, Animal; Fasting; Growth; Growth Disorders; Growth Hormone; Humans; Intellectual Disability; Pituitary Gland; Propylthiouracil; Radiation Injuries, Experimental; Rats; Somatomedins; Sulfates

Chronic dietary administration of theophylline (0.625, 1.25 or 2.50 g/kg food) for 7--9 weeks prevented the decrease in resting oxygen consumption, heart rate and systolic blood pressure characteristically observed in rats treated simultaneously with either of the antithyroid drugs, aminotriazole (ATZ; 0.25 g/kg food) or propylthiouracil (1.0 g/kg food). However, theophylline failed to restore both the food intake and growth rate of hypothyroid rats to that of euthyroid controls. Measurements of 131I uptake by the thyroid gland, thyroid acinar cell height and protein-bound iodine failed to reveal an effect of theophylline in either control or hypothyroid animals although theophylline increased thyroid to body weight ratio in both groups. Thus, the restoration of rate of oxygen consumption, heart rate and systolic blood pressure of hypothyroid rats to that of euthyroid controls was apparently not exerted through an increase in thyroid activity. The reduction in rate of oxygen consumption, heart rate and systolic blood pressure, generally associated with lack of thyroid hormone, appear more likely to be associated with reduced responsiveness to catecholamines in the hypothyroid rats. The results suggest that an increase in the half-life of cAMP by administration of theophylline to hypothyroid rats returned these functions to the level of euthyroid controls.

Topics: Amitrole; Animals; Blood Pressure; Body Weight; Diet; Drug Evaluation, Preclinical; Growth; Heart Rate; Hypothyroidism; Iodine; Male; Oxygen Consumption; Propylthiouracil; Rats; Theophylline; Thyroid Gland

Topics: Animals; Body Weight; Calcitonin; Calcium; Diet; Female; Goiter; Iodine; Male; Organ Size; Phosphates; Propylthiouracil; Rats; Thyroid Gland; Thyrotropin

Mice on an atherogenic diet for 40 days show a decrease in brain content of catecholamines, cyclic AMP and in dopamine degradation, and modification of the glycolytic pathway. The metabolic changes are paralleled by changes in behaviour, i.e. decrease in spontaneous motor activity and in conditioning avoidance response. The decrease in dopamine degradation and in behaviour parameters is partly due to the propylthiouracil present in the diet. Endovenous treatment with sonicated dispersions of bovine brain phospholipids induces a modification in the parameters of behaviour and metabolism. The possibility is discussed that some of the defects arising during the atherogenic diet are related with the establishment of a hypoxic state.

Topics: Animals; Avoidance Learning; Behavior, Animal; Blood Glucose; Body Weight; Brain; Catecholamines; Cattle; Cholesterol, Dietary; Cyclic AMP; Diet, Atherogenic; Dopamine; Glycogen; Homovanillic Acid; Hypoxia; Lactates; Mice; Motor Activity; Phospholipids; Propylthiouracil; Pyruvates

Topics: Animals; Animals, Newborn; Aspartate Carbamoyltransferase; Body Weight; Cerebellum; DNA; Hypothyroidism; Organ Size; Phosphotransferases; Propylthiouracil; Rats; Uridine Kinase

Basal hypothalamic deafferentation extending from the posterior border of the optic chiasm to the mid-mammillary bodies resulted in depression of plasma TSH, thyroxine (T4), and triiodothyronine (T3) concentration to 50% of normal controls within 7 days. Administration of 0.15% propylthiouracil (PTU) in the diet form postoperative day 26 caused a pronounced drop in the plasma T3 level and a rise in plasma TSH level within two days in the control animals, but had little effect during this interval in the deafferented animals. After 12 days of PTU, plasma T3 and T4 concentrations had dropped to undetectable concentrations in the control animals but both were still detectable in the deafferented animals. After 25 days of PTU, plasms T4 and T3 levels were undetectable and plasma TSH levels were significantly elevated above normal in all animals. Thyroid hypertrophy at that time was as great in the deafferented as in the control rats, although plasma TSH concentration was 50% lower in the former. Administration of 0.1 mug/100 g BW TRH iv on postoperative day 37, when plasma T4 and T3 were undetectable in the controls but still present in the deafferented animals, produced an equally high concentration of plasma TSH in all animals. We interpret these data to support the concepts that: 1) a major source of neural drive of that TRH which stimulates the secretion of TSH by the adenohypophysis lies outside the medial basal hypothalamus, 2) a decrease in TRH reaching the adenohypophysis causes a lower setting of the "thyrostat" sensitive to the concentration of circulating thyroid hormone, and 3) increased TSH secretion and resultant goitrogenesis is delayed in animals with impaired TRH secretion because of the slower rate of secretion of thyroid hormone than in intact controls and the longer time thus required to markedly reduce the concentration of circulating thyroid hormone.

Topics: Afferent Pathways; Animals; Body Weight; Denervation; Female; Hypothalamus; Organ Size; Pituitary Gland; Propylthiouracil; Rats; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine

Topics: Aging; Animals; Body Height; Body Weight; Chick Embryo; Chickens; Diet; Male; Methimazole; Muscles; Organ Size; Propylthiouracil; Triiodothyronine

Topics: Administration, Oral; Animals; Body Weight; Chickens; Cholesterol; Liver; Liver Glycogen; Organ Size; Potassium; Propylthiouracil; Sodium; Thyroid Gland

Topics: Age Factors; Animals; Basal Ganglia; Body Weight; Brain; Brain Stem; Congenital Hypothyroidism; Hypothalamus; Mixed Function Oxygenases; Organ Size; Propylthiouracil; Rats; Tryptophan Hydroxylase; Tyrosine 3-Monooxygenase; Water

The late consequences of a brief period of perinatal hypothyroidism were studied in the rat by giving propylthiouracil (PTU) prenatally to the mothers and/or neonatally for 5 days to the pups. Perinatal hypothyroidism produced a delay in eye opening, a diminution in weaning weight, a delay in puberty and first estrus, and a prolongation of estrus cycles. The neo-PTU rats usually had a persistently enlarged thyroid gland associated with an elevated pituitary, hypothalamic, and serum thyroid-stimulating hormone (TSH) concentration. The metabolic clearance rate of TSH and response to luteinizing hormone-releasing hormone (LH-RH) were normal. The response to thyrotropin-releasing hormone (TRH) stimulation was significantly blunted in adult neo-PUT males, suggesting secondary or tertiary hypothyroidism. As a result of these studies, serious thought should be given to the possible consequences of antithyroid drug therapy of pregnant women, and certainly all pregnant hypothyroid women should receive full replacement therapy.

Topics: Animals; Animals, Newborn; Body Weight; Endocrine Glands; Female; Fetal Diseases; Hypothyroidism; Luteinizing Hormone; Male; Organ Size; Pregnancy; Pregnancy Trimester, Third; Propylthiouracil; Rats; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone

Further examination of rat pituitary cell line GH3/C14 showed that at least the physiologic concentration of L-thyroxine was required for estrogen-dependent growth in vivo. Two L-thyroxine synthesis inhibitors, 6-n-propyl-2-thiouracil (propylthiouracil) and 1-methylimidazole-2-thiol (methimazole), were administered concurrently with estrogen to GH3/C14-inoculated hosts. Propylthiouracil administration to estrogen-treated males, intact females, and estrogen-treated ovariectomized females inhibited tumor formation by 93, greater than 95, and 68%, respectively, as compared to tumor formation in controls not treated with propylthiouracil. Methimazole treatment of estrogen-primed males and intact females inhibited tumor formation by 78 and 95%, respectively. Concentrations of total L-thyroxine and free L-thyroixine in sera from normal and inhibitor-treated hosts were depressed 70-80% by propylthiouracil and 60-70% by methimazole. Administration of either drug caused greater inhibition of tumor growth than of total body weight gain. In addition, the administration of a combination of L-thyroxine and L-triiodothyronine to male rats promoted tumor formation even in the absence of exogenous estrogen.

Topics: Animals; Body Weight; Castration; Cell Division; Cell Line; Estrogens; Female; Male; Methimazole; Neoplasms, Experimental; Ovary; Pituitary Neoplasms; Propylthiouracil; Rats; Rats, Inbred WF; Thyroxine

The effect of thyroid status on plasma and tissue levels of labeled nonextractable iodine (NEI) derived from the metabolism of radioiodothyronines was examined in the rat. Concentrations of radioiodoprotein were substantially elevated in plasma, kidney, and liver in thyroidectomized animals 72 h postinjection of [125I]triiodothytonine ([125I]T3). Similarly, total rat concentrations of radioactive NEI were increased (52%) 72 h after injection of [125I]T3. NE125I concentrations from [125I]T3 in plasma, kidney, and liver were diminished progressively in thyroidectomized animals maintained on increasing doses of thyroxine replacement, demonstrating that iodoprotein levels were inversely related to thyroid state. The plasma disappearance rate of radioiodoprotein from [125I]T3 was markedly slowed in hypothyroid animals and accelerated in intact controls rendered hyperthyroid with daily injections of T4, 8 mug/100 g BW. Propylthiouracil (PTU) treatment of thyroidectomized rats maintained on T4, 2 mug/100 g BW per day resulted in increased NE125I from [125E]T3 in plasma, kidney, and liver. The results of the foregoing investigations suggest that thyroid hormone regulates levels of iodothyronine-derived iodoproteins by influencing the rate of degradation of iodoproteins. Moreover, the observed elevation of iodoprotein levels in T4-maintained thyroidectomized animals after PTU administration appears consistent with the modification of thyroid status due to the peripheral antithyroxine effect of PTU.

Topics: Animals; Body Weight; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Iodoproteins; Kidney; Liver; Male; Propylthiouracil; Rats; Thyroid Gland; Thyroid Hormones; Thyroidectomy; Thyroxine; Triiodothyronine

Biosynthesis of phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin was studied in liver endoplasmic reticulum obtained from newly hatched chicks which were made hypothyroid by feeding 0.2% propylthiouracil. In vitro measurements were made of the specific activities of phosphorylcholine-glyceride (cholinephosphotransferase (EC 2.7.8.2), hosphorylethanolamine-glyceride (ethanolamine-phosphotransferase (EC 2.7.8.1)), and phosphorylcholine-ceramide (ceramide cholinephosphotransferase (EC 2.7.8.3)) transferases in control and hypothyroid chick liver for a period of 40 days. The specific activity of all three transferases began to decline after the chicks were on the propylthiouracil-containing diet for 5 days and steadily declined, reaching levels 10-15% of the controls after 15 days. These low levels were maintained for as long as the chicks were on this diet. Administration of L-thyroxine (15 mug/100 g of body weight) to the hypothyroid chicks caused a marked increase in the specific activities of all three transferases, reaching levels similar to those seen in the control chicks in 36-48 h. The specific activities then declined as the chicks were maintained on the diet of propylthiouracil, reaching the former low levels after 120 h. Administration of cycloheximide alone to the hypothyroid chicks caused a rise in the specific activities of the transferases after 24 h approximately equal to that caused by thyroxine alone, while thyroxine and cycloheximide together were no different than either alone. These studies indicate that in some manner circulating thyroxine controls the activities of enzymes involved in the biosynthesis of phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin in chick liver endoplasmic reticulum. There was no evidence that induction of hypothyroidism by propylthiouracil had any effect on the activities of these enzymes in the CNS.

Topics: Animals; Body Weight; Chickens; Hypothyroidism; Lipids; Liver Glycogen; Microsomes, Liver; Organ Size; Phosphatidylcholines; Phosphatidylethanolamines; Phosphotransferases; Propylthiouracil; Sphingomyelins; Thyroxine

Partial thyroidectomy caused a significant increase in the number of intranuclear inclusions per field (2-83 +/- 0-10 inclusions as compared with 0-15 +/- 0-03 inclusions for sham-controls). The inclusions occurred exclusively within mammotrophs. Thyrotrophs were stimulated: an increased cell size, numerous secretory granules, an enlarged Golgi apparatus and hypertrophic rough endoplasmic reticulum. Propylthiouracil caused similar ultrastructural changes although sighificantly fewer inclusions were observed (0-64 +/- 0-06 inclusions). Suppression of thyroid function with thyroxine produced no change in the number of inclusions (0-17 +/- 0-03 inclusions) although when combined with estrogen there were significantly fewer inclusions (1-62 +/- 0-07) when compared to estrogen alone (2-69 +/- 0-09). Intranuclear inclusions appear to be a unique reaction of mammotrophs to cellular hyperfunction in the Mongolian gerbil.

Topics: Animals; Body Weight; Cell Membrane; Cell Nucleus; Endoplasmic Reticulum; Estrogens; Female; Gerbillinae; Golgi Apparatus; Inclusion Bodies; Mammary Glands, Animal; Organ Size; Propylthiouracil; Thyroid Gland; Thyroxine

Although the extent of proptosis in exophthalmic Graves' disease has been measured directly and shown to correlate with serum content of a bioassayable exophthalmus-producing factor (EPS;1), a comparable relationship in an experimental model has not been reported. Progressive exophthalmos, measured from photographs and expressed as a ratio of intercorneal distance to intersupraorbital ridge distance, was produced in male guinea pigs when thyroid status was altered either by surgical thyroidectomy supplemented with 131-I treatment or by the administration of 6-propyl-2 thiouracil (0.1% in chow). In both groups, at time of sacrifice, serum content of EPF estimated by a modified goldfish bioassay using a known exophthalmogeric TSH preparation (Ambinon, Organon-Oss) as standard was positively correlated (r equals 0.804) with the terminal degree of exophthalmos. Daily replacement therapy with T4 (15mug/kg body wt) failed to alter significantly the exophthalmos which developed, even when replacement was initiated prior to the alterations of thyroid gland function; this observation tends to eliminate thyroid hormone deficiency per se as the causal event in exophthalmos. T4 treatment did, however, reverse or prevent the rises in serum TSH levels (McKenzie bioassay) thus dissociating TSH activity from EPF activity in the guinea pig. Treatment of guinea pigs with synthetic TRH (0.5, 1.0 OR 10 mug/kg body wt) for 21 days failed to produce demonstrable exophthalmos or assayable EPF levels although plasma TSH was significantly elevated.

Topics: Animals; Biological Assay; Body Weight; Exophthalmos; Goldfish; Guinea Pigs; Iodine; Iodine Radioisotopes; Male; Organ Size; Propylthiouracil; Thyroid Gland; Thyroidectomy; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine

Neonatal rats were underfed or overfed and then, at weaning, placed on a normal diet and allowed to mature. Although overfed rats were obese at weaning, they were of normal weight when mature. The underfed rats remained smaller all their lives. The endocrine organs did not share in this retardation, and were actually larger in several instances when expressed per 100 g body weight. Underfed rats also had delayed eye-opening, normal puberty and normal estrous cycles. Pituitary, hypothalamic and serum TSH concentrations were normal, or even increased (in the underfed females). The responses to propylthiouracil and to thyrotropin-releasing hormone (TRH) were both normal. Thus the tertiary hypothyroidism reported in underfed rats 16 days old did not persist into adult life. In all comparisons the males had higher serum TSH concentrations than females and usually had a greater response to TRH stimulation. The various persistent endocrine abnormalities resulting from neonatal thyrotoxicosis differ from those seen after neonatal caloric deprivation in all pertinent regards except that both have reduced body weights.

Topics: Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Body Weight; Female; Genitalia, Female; Genitalia, Male; Gonads; Male; Nutrition Disorders; Organ Size; Ovary; Pituitary Gland; Propylthiouracil; Prostate; Rats; Testis; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone; Uterus

To study the role of T4 to T3 conversion in the biologic action of T4, thyroidectomized, hypothyroid rats were given subcutaneous T4 (0.8 or 1.6 mug/100g/day) with or without intraperitoneal propylthiouracil (PTU) (1 mg/100g/day). Rats were killed after 5, 10, 12, or 15 days of treatment and serum T3 and T4 levels were correlated with serum TSH, liver mitochondrial alphaGPD activity and weight gain. In rats killed at 5 days, PTU treatment resulted in higher serum T4, lower serum T3, and a markedly elevated serum T4:T3 ratio, demonstrating that PTU inhibits peripheral conversion of T4 to T3 in the rat. Despite higher T4 levels, mean serum TSH was higher in the two groups receiving PTU as well as T4. In rats receiving 0.8 mug T4, growth rate was also slower with concomitant PTU administration. In other groups of rats treated with 0.8 mug T4 for 10 and 15 days, PTU treatment resulted in similar differences in T3, T4, and T4:T3 ratios and serum TSH. At 15 days, rats treated with 0.8 mug T4 mptu had significantly lower alphaGPD activity than rats receiving 0.8 mug T4 alone. PTU treatment had no effect on alphaGPD activity in rats maintained on 0.1 mug T3/100g/day indicating that there was no inhibition of this biologic response to T3 by this agent. PTU without T4 had no significant effect on TSH, weight gain, or alphaGPD activity. In addition, the dialyzable fraction of T3 and T4 in serum was not altered by this agent. These data show that in animals treated with T4, with and without PTU, TSH suppression, alphaGPD activity and growth correlate better with serum T3 concentrations than with serum T4. This suggests that for maximum biologic activity, T4 must be converted to T3.

Topics: Animals; Body Weight; Glucosephosphate Dehydrogenase; Growth; Male; Mitochondria, Liver; Propylthiouracil; Rats; Thyroid Hormones; Thyroidectomy; Thyrotropin; Thyroxine; Triiodothyronine

The potentiation of the propylthiouracil (PTU)-induced goitrogenesis after chronic administration of small doses of thyroid hormone has been attributed to the high circulating level of thyrotrophin (TSH) or to the re-instatement of insulin. In re-examining this problem radioimmunoassayable concentrations of TSH, thyroxine (T4), insulin, and growth hormone (GH) were observed in sera of rats at sequential intervals after surgical or chemical thyroidectomy and after thyroidectomy and replacement therapy with GH or T4. In addition, TSH, GH or a combination of both hormones were injected into hypophysectomized recipients in a further attempt to delineate the effect of either hormone on the thyroid. As expected, the rate of body growth was inversely proportional to the apparent severity of the hypothyroidism achieved in the several experimental groups. Goitrogenesis was enhanced after T4 treatment but evidently was not the exclusive result of increased blood levels of TSH or insulin. Evidence is presented that suggest the enhancement of goitrogenesis may be a growth phenomenon involving the additive or synergistic action of GH and TSH and possible of other hormones.

Topics: Animals; Body Weight; Female; Goiter; Growth Hormone; Insulin; Male; Organ Size; Propylthiouracil; Rats; Stimulation, Chemical; Thyroid Gland; Thyroidectomy; Thyrotropin; Thyroxine

Topics: Animals; Biological Assay; Body Weight; Depression, Chemical; Female; Growth Hormone; Hypothyroidism; Iodine Radioisotopes; Male; Microscopy, Electron; Pituitary Gland; Propylthiouracil; Radioimmunoassay; Rats; Sex Factors; Thyroid Function Tests; Thyroidectomy; Thyrotropin; Thyroxine

Topics: Adrenalectomy; Animals; Body Weight; Corticosterone; Electrophoresis, Polyacrylamide Gel; Insulin; Iodine; Iodine Radioisotopes; Male; Organ Size; Perchlorates; Potassium; Propylthiouracil; Radioimmunoassay; Rats; Stimulation, Chemical; Thyroid Gland; Thyrotropin; Thyroxine-Binding Proteins

Topics: Adenylyl Cyclases; Animals; Body Weight; Carbon Radioisotopes; Cyclic AMP; Depression, Chemical; Diet; Dinitrophenols; Electrophoresis; Growth Hormone; Hypothalamus; Hypothyroidism; In Vitro Techniques; Male; Pituitary Gland; Prolactin; Propylthiouracil; Rats; Stimulation, Chemical; Thyroxine; Triiodothyronine

Topics: Administration, Oral; Age Factors; Animals; Animals, Newborn; Body Weight; Carbon Radioisotopes; Electrophoresis, Polyacrylamide Gel; Estrus; Female; Gonads; Growth Hormone; Hypothyroidism; Injections, Subcutaneous; Labor, Obstetric; Lactation; Leucine; Organ Size; Pituitary Gland; Pregnancy; Prolactin; Propylthiouracil; Rats; Thyroxine; Vagina; Vaginal Smears

Topics: Adrenal Glands; Animals; Body Weight; Goiter; Hypothalamo-Hypophyseal System; Male; Morphine; Organ Size; Pituitary Gland; Propylthiouracil; Rats; Testis; Thyroid Gland; Thyrotropin; Time Factors

Topics: Adrenal Glands; Adrenalectomy; Animals; Blood Glucose; Blood Proteins; Body Weight; Growth Hormone; Hypophysectomy; Insulin; Insulin Secretion; Iodine; Male; Organ Size; Pituitary Gland; Potassium; Propylthiouracil; Rats; Thyroidectomy

Topics: Adrenal Glands; Age Factors; Animals; Blood Glucose; Body Weight; Chlorates; Diet; Female; Goiter; Gonads; Growth Hormone; Insulin; Iodine; Male; Organ Size; Pituitary Gland; Potassium; Propylthiouracil; Rats; Sex Factors; Thyroid Function Tests; Thyroid Gland; Thyrotropin

Topics: Animals; Animals, Newborn; Biometry; Body Weight; Female; Fetus; Mitosis; Organ Size; Pregnancy; Propylthiouracil; Rats; Thyroid Gland

Topics: Animals; Animals, Newborn; Body Weight; Cell Division; Cerebellum; DNA; Fetus; Hyperthyroidism; Hypothyroidism; Nerve Tissue Proteins; Nutrition Disorders; Organ Size; Propylthiouracil; Rats; RNA; Spectrophotometry, Ultraviolet; Thyroxine

Topics: Adrenal Glands; Animals; Body Weight; Estrus; Female; Follicle Stimulating Hormone; Hypothyroidism; Luteinizing Hormone; Male; Organ Size; Ovary; Pituitary Gland; Pregnancy; Propylthiouracil; Prostate; Radioimmunoassay; Rats; Seminal Vesicles; Testis; Thyroid Gland; Thyroxine; Uterus

Topics: Adrenal Glands; Animals; Animals, Newborn; Body Weight; Female; Goiter; Gonads; Humans; Male; Morphine Dependence; Organ Size; Pituitary Gland; Pituitary-Adrenal System; Propylthiouracil; Thyroid Gland; Thyrotropin; Time Factors

Topics: Animals; Aspartate Aminotransferases; Body Weight; Carboxy-Lyases; Chickens; Glucose-6-Phosphatase; Glucosyltransferases; Liver; Liver Glycogen; Malate Dehydrogenase; Male; Organ Size; Phosphoenolpyruvate; Propylthiouracil; Stimulation, Chemical; Thyroxine

Topics: Animals; Body Weight; Dextrans; Dimethyl Sulfoxide; Guinea Pigs; Histamine; Male; Mast Cells; Organ Size; p-Methoxy-N-methylphenethylamine; Perchlorates; Polymyxins; Propylthiouracil; Rats; Thyroid Gland; Thyrotropin; Thyroxine

Topics: Adrenalectomy; Animals; Body Weight; Corticosterone; Cyanates; Goiter; Growth Hormone; Insulin; Male; Organ Size; Potassium; Propylthiouracil; Rats; Stimulation, Chemical; Thyroid Gland; Thyrotropin

Topics: Alanine Transaminase; Animals; Body Weight; Chickens; Cholesterol; Comb and Wattles; Hypothyroidism; Iodine Isotopes; Liver; Liver Glycogen; Male; Organ Size; Propylthiouracil; Radiation Effects; Testosterone; Thyroid Gland

Topics: Animals; Animals, Newborn; Body Temperature; Body Temperature Regulation; Body Weight; Colon; Female; Manometry; Oxygen Consumption; Propylthiouracil; Rats; Thyroid Hormones; Thyroxine

Topics: Acetylcholine; Acyltransferases; Aging; Animals; Animals, Newborn; Behavior, Animal; Body Weight; Brain; Brain Chemistry; Choline; Depression, Chemical; Organ Size; Propylthiouracil; Rats

Topics: Analysis of Variance; Animals; Animals, Newborn; Autoradiography; Body Weight; Cell Differentiation; Cerebellar Cortex; Hyperthyroidism; Hypothyroidism; Organ Size; Propylthiouracil; Rats; Sodium Chloride; Thymidine; Thyroid Hormones; Thyroxine; Tritium

Topics: Animals; Body Weight; Cortisone; Fasting; Growth; Growth Hormone; Male; Metabolism; Propylthiouracil; Rats; Time Factors

Topics: Adaptation, Physiological; Animals; Body Weight; Cold Temperature; Hot Temperature; Hypothalamo-Hypophyseal System; Hypothyroidism; Iodine Isotopes; Male; Organ Size; Pituitary Gland; Propylthiouracil; Rats; Secretory Rate; Thyroid Function Tests; Thyroid Gland; Thyrotropin

Topics: Birth Weight; Body Weight; Digitalis Glycosides; Exophthalmos; Female; Humans; Hyperthyroidism; Infant, Newborn; Infant, Newborn, Diseases; Propylthiouracil; Tachycardia; Thyroid Function Tests

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Androstanes; Animals; Animals, Newborn; Body Weight; Butanones; Depression, Chemical; Female; Fetus; Hypophysectomy; Iodine; Iodine Isotopes; Ketosteroids; Maternal-Fetal Exchange; Methandrostenolone; Nitriles; Pituitary Gland; Pregnancy; Propylthiouracil; Rats; Thyroid Gland; Thyrotropin

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Brain; Diencephalon; Female; Fetus; Gestational Age; Goiter; Hypophysectomy; Hypothalamus; Maternal-Fetal Exchange; Organ Size; Pituitary Gland; Pregnancy; Propylthiouracil; Rats; Thiourea; Thyroid Gland; Thyrotropin-Releasing Hormone; Vitamin A

Topics: Animals; Body Weight; Cholesterol; Coronary Disease; Coronary Vessels; Death, Sudden; Diet, Atherogenic; Disease Models, Animal; Electrocardiography; Male; Myocardial Infarction; Myocardium; Propylthiouracil; Radiation Injuries, Experimental; Swine

Topics: Age Factors; Animals; Animals, Newborn; Body Weight; Diet; Female; Fetus; Film Dosimetry; Iodine; Iodine Isotopes; Male; Methods; Mice; Propylthiouracil; Radiation Dosage; Radiation Effects; Stimulation, Chemical; Thyroid Gland; Time Factors

Topics: Animals; Body Weight; Chickens; Diiodotyrosine; Humans; Iodides; Iodine Isotopes; Male; Monoiodotyrosine; Organ Size; Propylthiouracil; Substance Withdrawal Syndrome; Thyroid Gland; Thyroid Hormones; Thyroxine; Triiodothyronine

Topics: Age Factors; Animals; Blood; Body Fluids; Body Weight; Chlorides; Guinea Pigs; Hypophysectomy; Male; Membrane Potentials; Nephrectomy; Organ Size; Potassium; Propylthiouracil; Rats; Sodium; Thyroid Gland; Thyrotropin; Water

Topics: Body Weight; Diarrhea; Female; Humans; Hyperthyroidism; Infant; Propylthiouracil; Thyroid Function Tests

Topics: Animals; Blood Pressure; Body Weight; Desoxycorticosterone; Female; Hypertension; Hypertension, Renal; Iodine Radioisotopes; Male; Organ Size; Pituitary Gland; Propylthiouracil; Rats; Species Specificity; Thyroid Function Tests; Thyroid Gland; Thyroxine

Topics: Animals; Antithyroid Agents; Blood Proteins; Body Weight; Goiter; Hypothyroidism; Insulin; Iodine; Male; Methimazole; Organ Size; Perchlorates; Propylthiouracil; Protein Binding; Rats; Rhenium; Thiocyanates; Thyroid Gland; Thyroidectomy; Thyrotropin; Thyroxine

Topics: Animals; Body Weight; Chickens; Hyperthyroidism; Hypothyroidism; Male; Organ Size; Phosphates; Phosphorus Isotopes; Pituitary Gland; Propylthiouracil; Secretory Rate; Stimulation, Chemical; Testis; Thyrotropin; Thyroxine

Topics: Animals; Animals, Newborn; Biological Assay; Body Weight; Female; Gonads; Hypothyroidism; Male; Organ Size; Pituitary Function Tests; Pituitary Gland; Pregnancy; Propylthiouracil; Rats; Thyroid Function Tests; Thyrotropin

Topics: Aging; Alkaline Phosphatase; Animal Feed; Animals; Body Weight; Calcium; Chickens; Female; Propylthiouracil; Protein Binding; Thyroid Gland; Thyroxine; Uterus

Topics: Animals; Body Weight; Ethanol; Hyperthyroidism; Hypothyroidism; Liver; Male; Organ Size; Oxidation-Reduction; Oxygen Consumption; Propylthiouracil; Rats; Sorbitol; Thyroid Diseases; Triiodothyronine

Topics: Alcohol Drinking; Alcohol Oxidoreductases; Animals; Body Weight; Depression, Chemical; Diet; Ethanol; Hyperthyroidism; Hypothyroidism; Liver; Male; Organ Size; Oxygen Consumption; Propylthiouracil; Proteins; Rats; Sorbitol; Stimulation, Chemical; Triiodothyronine

The rate of calcium transport by isolated sarcoplasmic reticulum from rat skeletal muscle increases markedly during the first 4 wk of life and thereafter remains relatively constant. When animals are made hypothyroid during the first 3 wk of life, there is a marked inhibition of the increase in calcium transport by the sarcoplasmic reticulum. Production of hypothyroidism after 4 wk of age, at which time the calcium transport by sarcoplasmic reticulum has reached maximum levels, results in a depression in the rate of calcium transport. There is no clear alteration in ATPase activity of the sarcoplasmic reticulum to account for the low calcium transport in hypothyroidism. It is proposed that the decrease in calcium transport by sarcoplasmic reticulum may account for observed alterations in the intrinsic contractile properties of muscle in the hypothyroid animal.

Topics: Adenosine Triphosphatases; Aging; Animals; Animals, Newborn; Biological Transport; Body Weight; Calcium; Cytoplasm; Hypothyroidism; Iodine; Muscle Development; Muscle Proteins; Muscles; Propylthiouracil; Protein Binding; Rats; Triiodothyronine

Topics: Adrenal Glands; Adrenalectomy; Animals; Body Temperature Regulation; Body Weight; Colon; Fasting; Female; Hypothyroidism; Propylthiouracil; Rats; Thirst

Topics: Animals; Biometry; Body Weight; Bone Development; Cortisone; Fasting; Female; Growth; Growth Disorders; Male; Propylthiouracil; Rats; Tail

Topics: Animals; Body Weight; Female; Hyperthyroidism; Hypothalamo-Hypophyseal System; Hypothyroidism; Male; Propylthiouracil; Radiation Injuries, Experimental; Rats; Thyroid Gland; Thyroxine; Time Factors

Topics: Acetates; Animals; Anticholesteremic Agents; Body Weight; Butyrates; Carbon Isotopes; Cholesterol; Hyperlipidemias; Hypolipidemic Agents; Lipids; Liver; Male; Organ Size; Phospholipids; Piperidines; Propylthiouracil; Rats; Triglycerides

Topics: Androgens; Animals; Animals, Newborn; Body Weight; Estrus; Female; Growth; Hypothalamus; Hypothyroidism; Injections, Subcutaneous; Organ Size; Ovary; Pregnancy; Propylthiouracil; Rats; Testosterone; Thyroid Gland; Thyroxine; Time Factors; Vaginal Smears

Topics: Animals; Antithyroid Agents; Body Weight; Iodides; Iodine; Iodine Isotopes; Male; Pituitary Gland; Propylthiouracil; Rats; Thyroid Gland; Thyrotropin

Topics: Animals; Antithyroid Agents; Body Weight; Bursa of Fabricius; Caseins; Chickens; Comb and Wattles; Fasting; Hepatomegaly; Hypertrophy; Hypothyroidism; Liver; Liver Glycogen; Male; Organ Size; Propylthiouracil; Testis; Thiouracil; Thyroid Gland

Topics: Animals; Body Weight; Chickens; Dietary Proteins; Glutathione; Hypothyroidism; Liver; Methionine; Muscles; Myocardium; Probability; Propylthiouracil

Topics: Animals; Body Weight; Cestoda; Growth; Growth Substances; Hypothyroidism; Propylthiouracil; Rats; Sparganosis

Topics: Analysis of Variance; Animal Nutritional Physiological Phenomena; Animals; Behavior, Animal; Body Weight; Bone Development; Cats; Defecation; Environment; Female; Hypoxia; Male; Maternal Behavior; Maternal Deprivation; Propylthiouracil; Sucking Behavior; Tooth Eruption; Urination; Vocalization, Animal

Topics: Acetohexamide; Animals; Blood Proteins; Body Weight; Carbutamide; Chlorpropamide; Diiodotyrosine; Iodides; Iodine; Iodine Isotopes; Iodoproteins; Male; Propylthiouracil; Protein Binding; Rats; Thyroid Gland; Thyroxine; Tolbutamide; Triiodothyronine; Tyrosine

Topics: Animals; Body Weight; Goiter; Male; Organ Size; Oxygen Consumption; Pituitary Gland; Propylthiouracil; Rats; Thyroidectomy; Thyrotropin; Triiodothyronine

Topics: Animals; Biological Transport; Body Weight; Guinea Pigs; Iodides; Iodine Isotopes; Kinetics; Male; Models, Theoretical; Organ Size; Propylthiouracil; Protein Binding; Thyroid Gland

Topics: Animals; Biological Assay; Body Weight; Diet; DNA; Male; Organ Size; Pituitary Gland; Potassium Iodide; Propylthiouracil; Rats; RNA; Thyroid Gland; Thyrotropin

Topics: Animals; Body Weight; Goiter; Inbreeding; Male; Mice; Organ Size; Propylthiouracil; Secretory Rate; Thyroid Gland; Thyroid Hormones; Thyroxine

Topics: Amides; Animals; Animals, Laboratory; Body Weight; Coenzyme A; Cricetinae; Diet; Erythrocyte Count; Female; Glutamates; Glutathione; Hematocrit; Hemoglobins; Liver; Male; Malonates; Organ Size; Propylthiouracil; Thyroid Hormones; Vitamin B 12 Deficiency

Topics: Animals; Body Weight; Cholesterol; Diet; Hypothyroidism; Iodine Radioisotopes; Male; Organ Size; Propylthiouracil; Rats; Thyroid Function Tests; Thyroid Gland; Thyroxine

Topics: Animals; Antithyroid Agents; Body Weight; Fluorides; Goiter; Hypophysectomy; In Vitro Techniques; Iodides; Iodine; Nitrates; Perchlorates; Propylthiouracil; Rats; Rhenium; Thyroid Gland; Thyrotropin

Topics: Animals; Appetite; Behavior, Animal; Body Weight; Iodine Radioisotopes; Liver; Male; Propylthiouracil; Rats; Sodium Chloride; Thirst; Thyroid Gland; Thyroxine

Topics: Adult; Body Weight; Cortisone; Humans; Hypercalcemia; Hyperparathyroidism; Hyperthyroidism; Iodine Isotopes; Male; Propylthiouracil; Thyroidectomy; Thyroxine

Topics: Animals; Body Weight; Female; Goiter; Male; Poultry; Propylthiouracil; Secretory Rate; Species Specificity; Thyroid Gland; Thyroxine

Topics: Antithyroid Agents; Body Weight; Iodine Isotopes; Methimazole; Organ Size; Perchlorates; Pharmacology; Pituitary Gland; Pituitary Hormones, Anterior; Propylthiouracil; Rats; Research; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Toxicology

Topics: Animals; Bile Acids and Salts; Body Weight; Cholesterol; Dietary Fats; Fibrinogen; In Vitro Techniques; Liver; Male; Propylthiouracil; Rats; Thrombosis

Topics: Blood Chemical Analysis; Body Weight; Erythrocytes; Iodine; Iodine Isotopes; Metabolism; Physiology; Propylthiouracil; Rats; Research; Thyroid Function Tests; Thyroid Gland; Thyroxine; Triiodothyronine

Topics: Amylases; Body Weight; Castration; DNA; Fasting; Hypothyroidism; Pancreas; Pancreatic Extracts; Parotid Gland; Pathology; Peptide Hydrolases; Perchlorates; Pharmacology; Potassium; Propylthiouracil; Rats; Research; Salivary Glands; Submandibular Gland; Thyroid Function Tests; Thyroidectomy

Topics: Adrenal Glands; Animals; Arteriosclerosis; Atherosclerosis; Blood Proteins; Body Weight; Cholesterol; Heart; Hypothyroidism; Iodine Isotopes; Lipids; Liver; Pharmacology; Physiology; Pituitary Gland; Propylthiouracil; Rabbits; Research; Thyroid Gland; Thyroidectomy; Thyroxine

Topics: Blood; Body Weight; Hypothyroidism; Metabolism; Pharmacology; Physiology; Pituitary Gland; Propylthiouracil; Rats; Research; Thyroid Gland; Thyrotropin; Thyroxine

Topics: Body Weight; Body Weights and Measures; Glycosaminoglycans; Hoarseness; Hypothyroidism; Iodine Isotopes; Larynx; Metabolism; Mucins; Pathology; Propylthiouracil; Rats; Research; Thyroid Function Tests; Vocal Cords

Topics: Adrenalectomy; Adrenocorticotropic Hormone; Animals; Blood; Body Weight; Cortisone; Desoxycorticosterone; Dexamethasone; Female; Growth; Growth Hormone; Humans; Kidney; Lactotrophs; Liver; Mammary Glands, Animal; Neoplasm Transplantation; Organ Size; Ovary; Pharmacology; Pituitary Neoplasms; Prolactin; Propylthiouracil; Rats; Research; Spleen; Thymus Gland; Thyroidectomy; Thyroxine

Topics: Acclimatization; Animals; Appetite; Behavior, Animal; Body Weight; Cold Temperature; Eating; Hypothyroidism; Locomotion; Methylphenidate; Pharmacology; Propylthiouracil; Rats; Research

Topics: Animals; Body Weight; Body Weights and Measures; Diet; Metabolism; Oxygen Consumption; Propylthiouracil; Rats; Thyroid Hormones; Thyronines; Thyroxine; Triiodothyronine

Topics: Animals, Newborn; Body Weight; Growth; Iodine Isotopes; Pharmacology; Propylthiouracil; Rats; Research; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine

Topics: Body Weight; Carcinogens; Guinea Pigs; Iodides; Iodine; Neoplasms; Neoplasms, Experimental; Pathology; Propylthiouracil; Research; Thyroid Neoplasms; Thyroiditis; Toxicology

Topics: Adrenal Cortex; Adrenal Glands; Ascorbic Acid; Body Weight; Body Weights and Measures; Cholesterol; Propylthiouracil; Thiouracil