propylthiouracil and Disease-Models--Animal

Neutrophil extracellular traps (NETs) are characterized by the presence of extracellular DNA fibers studded with antimicrobial proteins, including myeloperoxidase (MPO). Although NETs play an important role in the innate immune system, the scattered extracellular enzymes, such as MPO, pose risks to the host. Therefore, NETs are strictly regulated by DNase I in the serum, which prevents them from persisting. Recent studies have demonstrated that dysregulation of NETs could be involved in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. In this review, we interpret the association of disordered NETs with autoimmune diseases, especially propylthiouracil-induced MPO-ANCA-associated vasculitis.

Topics: alpha-Defensins; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Deoxyribonuclease I; Disease Models, Animal; Humans; Neutrophils; Peroxidase; Propylthiouracil

Recent studies provided new insights into the pathogenesis of vasculitides associated with antineutrophil cytoplasm antibodies (ANCA). They yield more information about the pathogenic role of ANCA, the initiation of the immune response against proteinase 3, the expression of ANCA target antigens on neutrophil surfaces, endothelial damage and the mechanisms of vasculitis associated with propylthiouracil. The pathogenic role of antimyeloperoxidase antibodies has been established in vitro and in vivo in animal models and in human. A pathogenic role for antiproteinase 3 antibodies has not yet been clearly established in vivo although it is well documented in vitro.

Topics: Adult; Animals; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Chemokines; Churg-Strauss Syndrome; Dendritic Cells; Disease Models, Animal; Epitopes; Female; Granulomatosis with Polyangiitis; Humans; Infant, Newborn; Male; Mice; Myeloblastin; Peroxidase; Polymorphism, Genetic; Propylthiouracil; Rats; Rats, Inbred WKY; Risk; Vasculitis

Topics: Animals; Calcinosis; Calcium; Calcium Chloride; Clinical Trials as Topic; Disease Models, Animal; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Parathyroid Glands; Phosphates; Propylthiouracil; Rats; Skin Diseases; Thyroid Function Tests; Thyroid Gland; Thyroidectomy

Goiter with hypothyroidism occurs in several thyroid diseases. Xiao-Luo-Wan (XLW), which contains Scrophularia ningpoensis Hemsl., Fritillaria thunbergii Miq. and Ostrea gigas Thunberg, has been used as an effective Chinese medicine for the treatment of goiters in China for hundreds of years. Based on clinical observations and experimental studies, XLW also exerts a certain effect on hypothyroidism. However, the therapeutic mechanism of XLW remains unclear.. The present study aimed to investigate the therapeutic effect of XLW on propylthiouracil (PTU)-induced goiter with hypothyroidism in rats and to uncover the underlying molecular mechanism using ultra high-performance liquid chromatography-mass spectrometry (UPLC/MS), network pharmacology, and molecular docking simulations.. After successful modeling, the remaining rats were randomly divided into a model group, an Euthyrox group, an XLW group, and a control group. The corresponding drugs were given by gavage for four consecutive weeks. The growth status was monitored, the relative thyroid weight was calculated, and the total serum T3, T4, and TSH content were detected. Hematoxylin-eosin (H&E) staining was used to observe the pathological changes in the thyroid glands. The chemical components of the XLW were identified by UPLC/MS and the putative targets of XLW were predicted using multiple databases. We performed network pharmacology based on the intersection of goiter/hypothyroidism-related targets and XLW targets. Then, we performed KEGG pathway enrichment analysis, and key targets were further screened using protein-protein interaction (PPI) networks. Finally, molecular docking was used to predict the binding ability of XLW identified components and the key targets.. XLW significantly increased the levels of T3 and T4, and reduced TSH, increased body weight, and decreased swollen thyroid glands in PTU-induced rats. XLW promoted the morphological recovery of thyroid follicles and epithelial cells. Twenty-one main chemical components of XLW were identified using UPLC/MS. 270 potential gene targets of XLW and 717 known targets of goiter/hypothyroidism disease were obtained by searching the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), Swiss Target Prediction, and UniProt databases. A total of 83 KEGG pathways were enriched with phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) and RAS signaling pathways. PPI analysis revealed nine key targets of kinase-protein kinase B (AKT) 1, interleukin (IL) 6, vascular endothelial growth factor A (VEGFA), tumor necrosis factor (TNF), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), epidermal growth factor receptor (EGFR), GTPase HRas (HRAS), matrix metalloproteinase (MMP) 9, and heat shock protein 90 alpha family class A member 1 (HSP90AA1). Molecular docking verified which drug components had good binding ability to key targets (all ≤5 kcal/mol).. For PTU-induced goiter with hypothyroidism in rats, XLW improves thyroid function, reduces goiter, increases body weight, and promotes the recovery of thyroid follicles and epithelial cells. The underlying molecular mechanism suggests that XLW may regulate thyroid hormone signaling by regulating the PI3K-AKT, RAS, and other signaling pathways. This study provides a pharmacological and biological basis for using XLW to treat goiter with hypothyroidism.

Topics: Animals; Chromatography, High Pressure Liquid; Disease Models, Animal; Drugs, Chinese Herbal; Goiter; Hypothyroidism; Male; Mass Spectrometry; Molecular Docking Simulation; Network Pharmacology; Phosphatidylinositol 3-Kinase; Propylthiouracil; Proto-Oncogene Proteins c-akt; ras Proteins; Rats; Rats, Wistar

Thyroid hormones have a wide range of effects on growth, differentiation, evolution, metabolism, and physiological function of all tissues, including the vascular bed. In this study, the effect of fetal hypothyroidism on impairment of aortic vasorelaxation responses in adulthood was investigated with emphasis on possible involvement of hydrogen sulfide (H2S)/nitric oxide interaction. Two groups of female rats were selected. After mating and observation of vaginal plaque, one group received propylthiouracil (200 ppm in drinking water) until the end of pregnancy and another group had no propylthiouracil treatment during the fetal period. In adult rats, aortic relaxation responses to l-arginine and GYY4137 were assessed in the presence or absence of Nω-nitro-L-arginine methyl ester hydrochloride and dl-propargylglycine in addition to the biochemical measurement of thyroid hormones and some related factors. Obtained findings showed a lower vasorelaxation response for GYY4137 and l-arginine in the fetal hypothyroidism group, and preincubation with Nω-nitro-L-arginine methyl ester hydrochloride or dl-propargylglycine did not significantly aggravate this weakened relaxation response. In addition, aortic levels of sirtuin 3, endothelial nitric oxide synthase, cystathionine gamma-lyase, and H2S were significantly lower in the fetal hypothyroidism group. Meanwhile, no significant changes were obtained regarding serum levels of thyroid hormones including free triiodothyronine;, total triiodothyronine, free thyroxine, total thyroxine, and thyroid-stimulating hormone in adult rats. It can be concluded that hypothyroidism in the fetal period has inappropriate effects on the differentiation and development of vascular bed with subsequent functional abnormality that persists into adulthood, and part of this vascular abnormality is mediated through weakened interaction and/or cross talk between H2S and nitric oxide.

Topics: Animals; Aorta; Cell Differentiation; Disease Models, Animal; Female; Fetal Diseases; Gasotransmitters; Gestational Age; Hydrogen Sulfide; Hypothyroidism; Male; Nitric Oxide; Pregnancy; Propylthiouracil; Rats, Wistar; Signal Transduction; Vasodilation

Mutations in lysyl oxidase (LOX) genes cause severe vascular anomalies in mice and humans. LOX activity can be irreversibly inhibited by the administration of β-aminoproprionitrile (BAPN). We investigated the mechanisms underlying the damage to the ascending thoracic aorta induced by LOX deficiency and evaluated whether 6-propylthiouracil (PTU) can afford protection in rats. BAPN administration caused disruption of the ascending aortic wall, increased the number of apoptotic cells, stimulated TGF-β signaling (increase of nuclear p-SMAD2 staining), and up-regulated the expression of metalloproteinases-2 and -9. In BAPN-treated animals, PTU reduced apoptosis, p-SMAD2 staining, MMP-2, and -9 expression, and markedly decreased the damage to the aortic wall. Our results suggest that, as in some heritable vascular diseases, enhanced TGF-β signaling and upregulation of MMP-2 and -9 can contribute to the pathogenesis of ascending aorta damage caused by LOX deficiency. We have also shown that PTU, a drug already in clinical use, protects against the effects of LOX inhibition. MMP-2 and -9 might be potential targets of new therapeutic strategies for the treatment of vascular diseases caused by LOX deficiency.

Topics: Animals; Antimetabolites; Aorta, Thoracic; Aortic Diseases; Biomarkers; Disease Models, Animal; Immunohistochemistry; In Situ Nick-End Labeling; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Pilot Projects; Propylthiouracil; Protein-Lysine 6-Oxidase; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

The role that thyroid hormone deficiency plays in depression and synaptic plasticity in adults has only begun to be elucidated. This paper analyzes the possible link between depression and hypothyroidism in cognitive function alterations, using Wistar-Kyoto (WKY-an animal model of depression) rats and control Wistar rats under standard and thyroid hormone deficiency conditions (propylthiouracil administration-PTU). A weakening of memory processes in the WKY rats is shown behaviorally, and in the reduction of long-term potentiation (LTP) in the dentate gyrus (DG) and CA1 hippocampal regions. PTU administration decreased LTP and increased basal excitatory transmission in the DG in Wistar rats. A decrease in short-term synaptic plasticity is shown by the paired-pulse ratio measurement, occurring during hypothyroidism in DG and CA1 in WKY rats. Differences between the strains may result from decreases in the p-CaMKII, p-AKT, and the level of acetylcholine, while in the case of the co-occurrence of depression and hypothyroidism, an increase in the p-ERK1-MAP seemed to be important. Obtained results show that thyroid hormones are less involved in the inhibition of glutamate release and/or excitability of the postsynaptic neurons in WKY rats, which may indicate a lower sensitivity of the hippocampus to the action of thyroid hormones in depression.

Topics: Animals; CA1 Region, Hippocampal; Cognitive Dysfunction; Dentate Gyrus; Depression; Disease Models, Animal; Gene Expression; Hippocampus; Humans; Hypothyroidism; Long-Term Potentiation; Male; Memory; Neuronal Plasticity; Propylthiouracil; Rats; Rats, Inbred WKY; Rats, Wistar; Thyroid Hormones

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

During pregnancy, maternal metabolic disease and hormonal imbalance may alter fetal beta cell development and/or proliferation, thus leading to an increased risk for developing type 2 diabetes in adulthood. Although thyroid hormones play an important role in fetal endocrine pancreas development, the impact of maternal hypothyroidism on glucose homeostasis in adult offspring remains poorly understood.. We investigated this using a mouse model of hypothyroidism, induced by administration of an iodine-deficient diet supplemented with propylthiouracil during gestation.. Here, we show that, when fed normal chow, adult mice born to hypothyroid mothers were more glucose-tolerant due to beta cell hyperproliferation (two- to threefold increase in Ki67-positive beta cells) and increased insulin sensitivity. However, following 8 weeks of high-fat feeding, these offspring gained 20% more body weight, became profoundly hyperinsulinaemic (with a 50% increase in fasting insulin concentration), insulin-resistant and glucose-intolerant compared with controls from euthyroid mothers. Furthermore, altered glucose metabolism was maintained in a second generation of animals.. Therefore, gestational hypothyroidism induces long-term alterations in endocrine pancreas function, which may have implications for type 2 diabetes prevention in affected individuals.

Topics: Animals; Antithyroid Agents; Blood Glucose; Cell Proliferation; Diet, High-Fat; Disease Models, Animal; Female; Glucose Intolerance; Hyperinsulinism; Hypothyroidism; Insulin Resistance; Insulin-Secreting Cells; Iodine; Islets of Langerhans; Mice; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Stress, Physiological

Hypothyroidism frequently manifests with altered mood and disturbed cognition. Kynurenic acid may influence cognition through antagonism of N-methyl-d-aspartate receptors (NMDA) and α7 nicotinic receptors. In here, thyroid hormones effects on kynurenic acid synthesis in rat cortical slices and on kynurenine aminotransferases (KATs) activity in semi-purified cortical homogenates were studied. Furthermore, brain kynurenic acid levels and KATs activities were evaluated in experimental model of hypothyroidism, induced by chronic administration of 0.05% propylthiouracil in drinking water. In vitro, L-thyroxine (T

Topics: Animals; Brain; Disease Models, Animal; Hypothyroidism; Kynurenic Acid; Male; Propylthiouracil; Rats, Wistar; Thyroid Gland; Thyroxine; Transaminases; Triiodothyronine; Up-Regulation

Recent studies have demonstrated that hypothyroidism is associated with infertility. This work was undertaken to evaluate the protective effects of Aframomum melegueta on testicular functions and fertility of hypothyroid male rats. Male rats were orally treated with propylthiouracil (PTU: 10 mg/kg) in combination with plant aqueous or methanol seed extract (20 and 100 mg/kg) for 56 days. Vitamin E and clomiphene citrate served as positive controls. On day 47 of treatment, each male was mated with two adult females for fertilization potential evaluation. At the end of the treatment, genital sex organ weights, sperm characteristics, testicular histology, oxidative status, plasmatic hormones and fertility potential were evaluated. Results indicated that PTU created hypothyroidism characterised by a significant increase in TSH with reduction of T3 and T4. PTU also lowered genital sex organ weights, sperm count, viability and motility, plasmatic levels of luteinising hormone, follicle-stimulating hormone and testosterone, and increased prolactin, cholesterol and testicular oxidative stress. Alteration in sperm morphology, testis and epididymis histology, and fertilization potential was also noticed. Co-administration with A. melegueta extracts successfully reversed PTU-induced infertility without any effect on thyroid hormones. These results provide evidence that A. melegueta has a protective effect on fertility in hypothyroid condition.

Topics: Animals; Disease Models, Animal; Epididymis; Female; Fertility; Humans; Hypothyroidism; Infertility; Male; Organ Size; Plant Extracts; Propylthiouracil; Rats; Reproduction; Sperm Motility; Spermatogenesis; Testis; Thyroid Hormones; Zingiberaceae

Hypothyroidism has been claimed to generate sexual dysfunctions such as ejaculatory disorders. Aframomum melegueta is an aphrodisiac plant with pro-ejaculatory properties. We investigated the protective effects of aqueous extract (AE) and methanolic extract (ME) of A. melegueta on the ejaculatory function of hypothyroid male rats.. Forty sexually experienced male rats were partitioned into 8 groups (5 rats per group) and treated for 28 d as follows: Group 1, Control; Group 2, propylthiouracil (PTU, 10 mg/kg) + distilled water (DW, 10 mL/kg); Group 3, PTU + 5% Tween 80 (10 mL/kg); Group 4, PTU + bromocriptine (6 mg/kg); Group 5, PTU + AE (20 mg/kg); Group 6, PTU + AE (100 mg/kg); Group 7, PTU + ME (20 mg/kg), and Group 8, PTU + ME (100 mg/kg). On days 0, 7, 14 and 28 of treatment, each male rat was paired with primed receptive female for measurement of ejaculatory latency time (ELT) and post-ejaculatory interval (PEI) for 1.5 h. On day 29, each male rat was urethane-anesthetized and the spinal cord was transected. Thereafter, following urethral/penile stimulations and intravenous injection of dopamine, contractions of the bulbospongiosus muscles and the intraseminal pressure were registered. After these recordings, blood was collected through the catheterization of abdominal artery and plasma was used for thyroid-stimulating hormone (TSH), prolactin and testosterone assays.. PTU-induced hypothyroidism was characterized by a significant elevation (P < 0.001) of plasmatic TSH and prolactin levels, but a decline (P < 0.001) in plasmatic testosterone, compared to untreated group. ELT, PEI, contractions of the bulbospongiosus muscles and the intraseminal pressure were also altered by PTU treatment. On the contrary, A. melegueta extracts elevated testosterone (AE, 100 mg/kg, P < 0.01; ME, 100 mg/kg, P < 0.05) and decreased prolactin (AE, 100 mg/kg, P < 0.05; ME, 20 mg/kg, P < 0.05) levels, compared to corresponding controls. With regard to DW + PTU group, prolactin concentration was lowered (P < 0.05) in rats administered with bromocriptine. Treatment with A. melegueta extracts significantly prevented the lengthening of ELT (P < 0.05) and PEI (P < 0.001). Hypothyroid state also altered the fictive ejaculation by increasing the latency and decreasing the number and frequency of bulbospongiosus muscle contractions. There was also a decrease in the intraseminal pressure. These alterations were significantly (P < 0.05) alleviated in plant extract-treated groups.. This study highlighted the ejaculatory disturbance of hypothyroidism in male rats and its prevention with A. melegueta extracts.

Topics: Animals; Disease Models, Animal; Ejaculation; Female; Hypothyroidism; Male; Plant Extracts; Propylthiouracil; Rats; Rats, Wistar; Zingiberaceae

Adult-onset hypothyroidism induces cognitive impairments in learning and memory. Thyroxin (T4) replacement therapy appears to be effective in biochemically restoring euthyroidism, as evidenced by serum T4 and triiodothyronine concentrations within the normal range, although some the patients still exhibit cognitive dysfunctions. Here, we investigated the cognitive functions of propylthiouracil-induced hypothyroid mice in C57BL/6j and 129/Sv strains using the passive avoidance task and the novel object recognition test. Cognitive dysfunctions in hypothyroid mice were found only in the C57BL/6j strain, not in the 129/Sv strain. Further, we found that cholinergic neurons in the basal forebrain increased the membrane potential and input resistance with decreased capacitance, and that they decreased the amplitude and width of action potential in hypothyroid mice in the C57BL/6j strain but not in those in the 129/Sv strain, compared with the controls for each strain. Additionally, the excitability of cholinergic neurons in the basal forebrain was reduced in the hypothyroid mice in the C57BL/6j strain. These results indicated that transgenic mice with the C57BL/6j genetic background are more suitable for revealing the mechanism underlying hypothyroidism-induced cognitive dysfunction, and that the cholinergic basal forebrain may be the appropriate target for treating cognitive dysfunction in adult-onset hypothyroidism.

Topics: Animals; Basal Forebrain; Cholinergic Neurons; Cognitive Dysfunction; Disease Models, Animal; Hypothyroidism; Learning; Male; Membrane Potentials; Memory; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Propylthiouracil; Thyroid Hormones

In this study, the effect of thymoquinone (TQ) on propylthiouracil (PTU)-induced memory impairment was investigated in juvenile rats. The rats were grouped into control, Hypo, Hypo-TQ5 and Hypo-TQ10. Propylthiouracil increased latency time in the Morris water maze test and decreased delay in entering the dark compartment in the passive avoidance test. Both 5 mg/kg and 10 mg/kg doses of TQ decreased latency time in the Morris water maze test and increased delay in entering the dark compartment in a passive avoidance test. The PTU also increased malondialdehyde and nitric oxide metabolites in the brain while reduced the thiol content and superoxide dismutase and catalase activities and serum T4 level. Both doses of TQ decreased malondialdehyde and nitric oxide metabolites in the brain while enhanced the thiol content and superoxide dismutase and catalase activities and serum T4 level. The results of the present study showed that TQ protected against PTU-induced memory impairments in rats.

Topics: Animals; Antioxidants; Antithyroid Agents; Avoidance Learning; Benzoquinones; Brain Injuries; Catalase; Disease Models, Animal; Hippocampus; Hypothyroidism; Learning Disabilities; Male; Malondialdehyde; Maze Learning; Memory Disorders; Nitric Oxide; Oxidative Stress; Propylthiouracil; Rats, Wistar; Superoxide Dismutase

Mild perinatal hypothyroidism may result from inadequate iodine intake, insufficient treatment of congenital hypothyroidism, or exposure to endocrine-disrupting chemicals. Because thyroid hormones are critical for brain development, severe hypothyroidism that is untreated in infancy causes irreversible cretinism. Milder hypothyroidism may also affect cognitive development; however, the effects of mild and/or moderate hypothyroidism on brain development are not fully understood. In this study, we examined the behavior of adult male mice rendered mildly hypothyroid during the perinatal period using low-dose propylthiouracil (PTU). PTU was administered through drinking water (5 or 50 ppm) from gestational day 14 to postnatal day 21. Cognitive performance, studied by an object in-location test (OLT), was impaired in PTU-treated mice at postnatal week 8. These results suggest that, although the hypothyroidism was mild, it partially impaired cognitive function. We next measured the concentration of neurotransmitters (glutamate, γ-aminobutyric acid, and glycine) in the hippocampus using in vivo microdialysis during OLT. The concentrations of neurotransmitters, particularly glutamate and glycine, decreased in PTU-treated mice. The expression levels of N-methyl-d-aspartate receptor subunits, which are profound regulators of glutamate neurotransmission and memory function, also were decreased in PTU-treated mice. These data indicate that mild perinatal hypothyroidism causes cognitive disorders in adult offspring. Such disorders may be partially induced secondary to decreased concentrations of neurotransmitters and receptor expression.

Topics: Animals; Animals, Newborn; Cognition; Disease Models, Animal; Hippocampus; Hypothyroidism; Male; Mice; Propylthiouracil; Rats; Synapses

Thyroid hormones (THs) play a critical role in the development of ovarian cells. Although the\ effects of THs on female reproduction are of great interest, the mechanism remains unclear. We\ investigated the effects of TH dysregulation on reproductive hormones in rats. Propylthiouracil (PTU)\ and L-thyroxine were administered to rats to induce hypo- and hyperthyroidism, respectively, and the\ reproductive hormone profiles were analyzed by radioimmunoassay (RIA). Ovarian histology was\ evaluated with hematoxylin and eosin (H&E) staining, and gene protein level or mRNA content was\ analyzed by western blotting or reverse transcription polymerase chain reaction (RT-PCR). The serum\ levels of gonadotropin releasing hormone (GnRH) and follicle stimulating hormone (FSH) in both rat\ models were significantly decreased on day 21, although there were no significant changes at earlier\ time points. There were no significant differences in luteinizing hormone (LH) or progesterone (P4)\ levels between the treatment and the control groups. Both PTU and L-thyroxine treatments downregulated\ estradiol (E2) concentrations; however, the serum testosterone (T) level was increased only in\ hypothyroid rats at day 21. In addition, the expression levels of FSH receptor, cholesterol side-chain\ cleavage enzyme (P450scc), and steroidogenic acute regulatory protein (StAR) were decreased in both\ rat models. Moreover, the onset of puberty was significantly delayed in the hypothyroid group. These\ results provide evidence that TH dysregulation alters reproductive hormone profiles, and that the\ initiation of the estrous cycle is postponed in hypothyroidism.

Topics: Animals; Biomarkers; Cholesterol Side-Chain Cleavage Enzyme; Disease Models, Animal; Estradiol; Estrous Cycle; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hyperthyroidism; Hypothyroidism; Luteinizing Hormone; Ovary; Phosphoproteins; Progesterone; Propylthiouracil; Rats, Sprague-Dawley; Sexual Maturation; Testosterone; Thyroid Gland; Thyroid Hormones; Thyroxine; Time Factors

Thyroid hormones (THs) play an important role in maintaining the link between metabolism and reproduction and the altered THs status is associated with induction of oxidative stress in various organs like brain, heart, liver and testis. Further, reactive oxygen species play a pivotal role in regulation of glucose homeostasis in several organs, and glucose utilization by Leydig cells is essential for testosterone biosynthesis and thus is largely dependent on glucose transporter 8 (GLUT8). Glucose uptake by Sertoli cells is mediated through glucose transporter 3 (GLUT3) under the influence of THs to meet energy requirement of developing germ cells. THs also modulate level of gap junctional protein such as connexin 43 (Cx43), a potential regulator of cell proliferation and apoptosis in the seminiferous epithelium. Although the role of transient neonatal hypothyroidism in adult testis in terms of testosterone production is well documented, the effect of THs deficiency in early developmental period and its role in testicular glucose homeostasis and oxidative stress with reference to Cx43 in immature mice remain unknown. Therefore, the present study was conducted to evaluate the effect of neonatal hypothyroidism on testicular glucose homeostasis and oxidative stress at postnatal days (PND) 21 and 28 in relation to GLUT3, GLUT8 and Cx43. Hypothyroidism induced by 6-propyl-2-thiouracil (PTU) markedly decreased testicular glucose level with considerable reduction in expression level of GLUT3 and GLUT8. Likewise, lactate dehydrogenase (LDH) activity and intratesticular concentration of lactate were also decreased in hypothyroid mice. There was also a rise in germ cell apoptosis with increased expression of caspase-3 in PTU-treated mice. Further, neonatal hypothyroidism affected germ cell proliferation with decreased expression of proliferating cell nuclear antigen (PCNA) and Cx43. In conclusion, our results suggest that neonatal hypothyroidism alters testicular glucose homeostasis via increased oxidative stress in prepubertal mice, thereby affecting germ cell survival and proliferation.

Topics: Age Factors; Animals; Animals, Newborn; Antioxidants; Apoptosis; Cell Proliferation; Connexin 43; Disease Models, Animal; Down-Regulation; Glucose; Glucose Transport Proteins, Facilitative; Glucose Transporter Type 3; Homeostasis; Hypothyroidism; L-Lactate Dehydrogenase; Lactic Acid; Lipid Peroxidation; Male; Mice; Oxidative Stress; Proliferating Cell Nuclear Antigen; Propylthiouracil; Testis; Time Factors

The hippocampus maintains a capacity for neurogenesis throughout life, a capacity that is reduced in models of adult onset hypothyroidism. The effects of developmental thyroid hormone (TH) insufficiency on neurogenesis in the adult hippocampus, however, has not been examined. Graded degrees of TH insufficiency were induced in pregnant rat dams by administration of 0, 3 or 10ppm of 6-propylthiouracil (PTU) in drinking water from gestational day (GD) 6 until weaning. Body, brain, and hippocampal weight were reduced on postnatal day (PN) 14, 21, 78 and hippocampal volume was smaller at the 10 but not 3ppm dose level. A second experiment examined adult hippocampal neurogenesis following developmental or adult onset hypothyroidism. Two male offspring from 0 and 3ppm exposed dams were either maintained on control water or exposed to 3ppm PTU to create 4 distinct treatment conditions (Control-Control; Control-PTU, PTU-Control, PTU-PTU) based on developmental and adult exposures. Beginning on the 28th day of adult exposure to 0 or 3ppm PTU, bromodeoxyuridine (BrdU, 50mg/kg, ip) was administered twice daily for 5days, and one male from each treatment was sacrificed 24h and 28days after the last BrdU dose and brains processed for immunohistochemistry. Although no volume changes were seen in the hippocampus of the neonate at 3ppm, thinning of the granule cell layer emerged in adulthood. Developmental TH insufficiency produced a reduction in newly born cells, reducing BrdU+ve cells at 1 with no further reduction at 28-days post-BrdU. Similar findings were obtained using the proliferative cell marker Ki67. Neuronal differentiations was also altered with fewer doublecortin (Dcx) expressing cells and a higher proportion of immature Dcx phenotypes seen after developmental but not adult TH insufficiency. An impaired capacity for neurogenesis may contribute to impairments in synaptic plasticity and cognitive deficits previously reported by our laboratory and others following moderate degrees of developmental TH insufficiency induced by this PTU model.

Topics: Analysis of Variance; Animals; Animals, Newborn; Antimetabolites; Bromodeoxyuridine; Cell Count; Cell Differentiation; Disease Models, Animal; Dose-Response Relationship, Drug; Doublecortin Domain Proteins; Doublecortin Protein; Female; Hippocampus; Hypothyroidism; Ki-67 Antigen; Microtubule-Associated Proteins; Neurogenesis; Neuropeptides; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Long-Evans; Thyroid Hormones

Severe thyroid hormone (TH) deficiency during critical phases of brain development results in irreversible neurological and cognitive impairments. The mechanisms accounting for this are likely multifactorial, and are not fully understood. Here we pursue the possibility that one important element is that TH affects basal and activity-dependent neurotrophin expression in brain regions important for neural processing. Graded exposure to propylthiouracil (PTU) during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. In contrast to small PTU-induced reductions in basal expression of several genes, developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes (Bdnft, Bdnfiv, Arc, and Klf9) in adulthood and was accompanied by deficits in hippocampal-based learning. These data demonstrate that mild TH insufficiency during development not only reduces expression of important neurotrophins that persists into adulthood but also severely restricts the activity-dependent induction of these genes. Considering the importance of these neurotrophins for sculpting the structural and functional synaptic architecture in the developing and the mature brain, it is likely that TH-mediated deficits in these plasticity mechanisms contribute to the cognitive deficiencies that accompany developmental TH compromise.

Topics: Animals; Antithyroid Agents; Behavior, Animal; Brain-Derived Neurotrophic Factor; Conditioning, Psychological; Congenital Hypothyroidism; Cytoskeletal Proteins; Disease Models, Animal; Early Growth Response Protein 1; Fear; Female; Hippocampus; Kruppel-Like Transcription Factors; Male; Maze Learning; Nerve Growth Factor; Nerve Tissue Proteins; Neuronal Plasticity; Neurotrophin 3; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Long-Evans; Severity of Illness Index; Thyroxine; TOR Serine-Threonine Kinases; Triiodothyronine

Pancreatic progenitors derived from human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating diabetes and are currently being tested in clinical trials. Yet, how the milieu of pancreatic progenitor cells, including exposure to different factors after transplant, may influence their maturation remains unclear. Here, we examined the effect of thyroid dysregulation on the development of hESC-derived progenitor cells in vivo. Hypothyroidism was generated in SCID-beige mice using an iodine-deficient diet containing 0.15% propyl-2-thiouracil, and hyperthyroidism was generated by addition of L-thyroxine (T4) to drinking water. All mice received macroencapsulated hESC-derived progenitor cells, and thyroid dysfunction was maintained for the duration of the study ("chronic") or for 4 weeks posttransplant ("acute"). Acute hyperthyroidism did not affect graft function, but acute hypothyroidism transiently impaired human C-peptide secretion at 16 weeks posttransplant. Chronic hypothyroidism resulted in severely blunted basal human C-peptide secretion, impaired glucose-stimulated insulin secretion, and elevated plasma glucagon levels. Grafts from chronic hypothyroid mice contained fewer β-cells, heterogenous MAFA expression, and increased glucagon(+) and ghrelin(+) cells compared to grafts from euthyroid mice. Taken together, these data suggest that long-term thyroid hormone deficiency may drive the differentiation of human pancreatic progenitor cells toward α- and ε-cell lineages at the expense of β-cell formation.

Topics: Animals; Antithyroid Agents; Biomarkers; Cell Differentiation; Cell Line; Cells, Immobilized; Diabetes Mellitus, Type 1; Disease Models, Animal; Heterografts; Human Embryonic Stem Cells; Humans; Hyperthyroidism; Hypothyroidism; Insulin-Secreting Cells; Iodine; Male; Mice, SCID; Propylthiouracil; Random Allocation; Thyroxine; Transplantation, Heterologous; Transplantation, Heterotopic

The present study is aimed at bringing out the information on the effect of berberine chloride in hyper and hypo thyroidal model with two dose levels.. The research article also reviewed details of various existing patents associated with comprehensive compilation regarding the therapeutic application of berberine and related forms.. Sixty female wistar rats weighing between 150-250 gm were divided in to 10 groups. The animals were grouped in to solvent control; hypothyroid; hyperthyroid; prophylactic with two different doses of berberine chloride (50 and 100 mg/kg); treatment groups similar to that of the prophylactic and therapeutic group. To substantiate the dose dependent effect of berberine chloride in 6-n-propyL-2-thiouracil (PTU) induced hypothyroidism, lipid profile, thyroid profile, enzymes profiles and blood profiles, in addition to histopathological studies were also carried out. There was no any significant difference in the lipid profile among solvent control, treatment and prophylactic groups. However, there was a significant difference (***p<0.001) in serum triglycerides, LDL and VLDL of hypothyroid group when compound to that of the rest.. As far as thyroid profile is concerned, T3 level of berberine chloride (50 mg/kg) treated groups (prophylactic+ treatment) showed a significant rise compared to hypothyroid group. TSH level in prophylactic groups was far higher than the rest of the groups (3.002±0.0192, 1.051±0.0008 against the solvent control, 0.308±0.008). SGOT, SGPT levels were significantly higher with the therapeutic group than that of the normal and hypo-thyroidal group. Blood profile of berberine chloride (100 mg/kg) treated therapeutic group was comparable to that of the solvent control than all other groups. The probable mechanism underlying may be that inactivation of type I 5.-iodothyronine deiodinase (5.DI) enzyme by NF-kB pathway.. From the findings of the current study it can be concluded that berberine chloride possesses both thyroid stimulating and suppressing activities depending on its dose, especially berberine chloride 50 mg/kg supports thyroid stimulating property.

Topics: Animals; Antithyroid Agents; Berberine; Biomarkers; Chlorides; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hyperthyroidism; Hypothyroidism; Lipids; Patents as Topic; Propylthiouracil; Rats, Wistar; Thyroid Gland; Thyroid Hormones; Time Factors

Hypothyroidism during early development leads to numerous morphological, biochemical and functional changes in developing brain. In this study, we investigated the effects of voluntary and treadmill exercise on learning, memory and hippocampal BDNF levels in both hypothyroid male and female rat pups. To induce hypothyroidism in the mothers, 6-propyl-2-thiouracil (PTU) was added to their drinking water (100mg/L) from their embryonic day 6 to their postnatal day (PND) 21. For 14days, from PNDs 31 to 44, the rat pups were trained with one of the two different exercise protocols, namely the mild treadmill exercise and the voluntary wheel exercise. On PNDs 45-52, a water maze was used for testing their learning and memory ability. The rats were sacrificed one day later and their BDNF levels were then measured in the hippocampus. The findings of the present study indicate that hypothyroidism during the fetal period and the early postnatal period is associated with the impairment of spatial learning and memory and reduced hippocampal BDNF levels in both male and female rat offspring. Both the short-term treadmill exercise and the voluntary wheel exercise performed during the postnatal period reverse the behavioral and neurochemical deficits induced by developmental thyroid hormone insufficiency in both male and female rat offspring. The findings of this study thus demonstrate a marked reversibility of both behavioral and neurochemical disorders induced by developmental thyroid hormone insufficiency through the performance of exercise.

Topics: Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Female; Hippocampus; Hypothyroidism; Learning Disabilities; Male; Maze Learning; Memory Disorders; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Random Allocation; Rats, Wistar; Running; Spatial Memory

Preclinical Research The aim of the present study was to evaluate the effects of thyroid dysfunction on markers of oxidative stress in rat pancreas. Hypothyroidism and hyperthyroidism were, respectively, induced in rats via administration of propylthiouracil (PTU) and L-thyroxine sodium salt in drinking water for 45 days. The activities of superoxide dismutase (SOD), catalase (CAT), glutathioen peroxidase (GPx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), xanthine oxidase (XO), and nonenzymatic markers of oxidative stress including malondialdehyde (MDA), protein carbonyl (PC), reduced glutathione (GSH), and total thiols (T-SH) were determined in the rat pancreas. In hyperthyroid rats, pancreatic CAT, SOD, GPx, GR, XO, G6PD activities were increased compared with those in hypothyroid and control groups. There were no differences in activities of antioxidant enzymes between hypothyroid and control rats. Pancreatic MDA and PC in hyperthyroid rats increased compared with hypothyroid and the control animals. Whereas, hyperthyroid rats had decreased levels of tissue GSH and T-SH compared with hypothyroid and the control groups. The findings showed that only GSH level has decreased significantly in the hypothyroid group compared with control groups. In conclusion, our results showed that experimental hyperthyroidism induces oxidative stress in pancreas of rats, but hypothyroidism has no major impact on oxidative stress markers. Drug Dev Res 77 : 199-205, 2016.   © 2016 Wiley Periodicals, Inc.

Topics: Animals; Antioxidants; Biomarkers; Disease Models, Animal; Glutathione; Hyperthyroidism; Hypothyroidism; Male; Oxidative Stress; Pancreas; Propylthiouracil; Rats; Rats, Wistar; Sulfhydryl Compounds; Thyroxine

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

Uveal melanoma is highly metastatic, prognosis is poor and there are no effective treatments to extend survival. Accumulating evidence suggests that thyroid hormones have a mitogenic effect via binding to αvβ3 integrin. We aimed to examine the impact of thyroid status on survival in a murine B16F10 model for ocular melanoma, highly expressing the integrin. In two independent experiments oral propylthiouracil (PTU) was used to induce hypothyroidism (n=9), thyroxine to induce hyperthyroidism (n=11) and mice given plain water served as control (n=8). At day 21, the subretinal space was inoculated with 10(2) B16F10 cells. In non-inoculated mice (n=6 of each group) serum free T4 (FT4) levels were measured and additional non-inoculated mice (3 given PTU and 4 given thyroxine or water) served as internal control to demonstrate the impact of the dissolved substance. The PTU-inoculated mice showed clinical evidence of intraocular tumor growth significantly later than the thyroxine mice (P=0.003) and survival time was significantly longer (P<0.001). FT4 levels differed significantly between groups (P<0.001) and with no signs of illness in the internal control group. Our findings suggest that hyperthyroidism shortens survival, whereas relative hypothyroidism may have a protective role in metastatic ocular melanoma.

Topics: Animals; Antithyroid Agents; Disease Models, Animal; Eye Neoplasms; Hyperthyroidism; Hypothyroidism; Lung Neoplasms; Male; Melanoma; Mice; Mice, Inbred C57BL; Propylthiouracil; Survival Rate; Thyroxine

In systemic sclerosis (SSc) vasculopathy affects small arteries and capillaries, but recent evidences show also macrovascular alterations. Experimental data suggest that propylthiouracil (PTU) abrogates the development of cutaneous and pulmonary fibrosis during SSc. The aim of this study was to evaluate the effect of propylthiouracil on aortic lipid peroxidation, intima-media thickness and myofibroblasts differentiation in experimental SSc.. SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) for 6weeks. Mice (n=25) were randomized to receive daily: HOCl (n=10), HOCl+PTU (n=10), or vehicle (n=5). Thoracic aorta was evaluated by histological methods to measure intima-media thickness and by immunostaining for α-smooth muscle actin (α-SMA) to assess myofibroblast differentiation. Aortic and plasma levels of malondialdehyde (MDA) were also measured.. HOCl induced a significant increase in aortic intima-media thickness compared to controls (p<0.001), while PTU administration prevented intima-media thickening (p<0.01). Myofibroblast differentiation was also less evident in HOCl+PTU-treated animals (p<0.05) compared to mice treated with HOCl alone. The increase in aortic and plasma MDA levels induced by HOCl, was significantly prevented by PTU administration (p<0.05).. PTU, by reducing lipid peroxidation, prevents aortic thickening and myofibroblast differentiation induced by HOCl, reducing macrovascular alterations in experimental SSc.

Topics: Animals; Antithyroid Agents; Aorta, Thoracic; Disease Models, Animal; Female; Lipid Peroxidation; Mice; Mice, Inbred BALB C; Oxidative Stress; Propylthiouracil; Scleroderma, Systemic

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

Gamma-secretase-mediated Notch3 signaling is involved in smooth muscle cell (SMC) hyper-activity and proliferation leading to pulmonary arterial hypertension (PAH). In addition, Propylthiouracil (PTU), beyond its anti-thyroid action, has suppressive effects on atherosclerosis and PAH. Here, we investigated the possible involvement of gamma-secretase-mediated Notch3 signaling in PTU-inhibited PAH. In rats with monocrotaline-induced PAH, PTU therapy improved pulmonary arterial hypertrophy and hemodynamics. In vitro, treatment of PASMCs from monocrotaline-treated rats with PTU inhibited their proliferation and migration. Immunocyto, histochemistry, and western blot showed that PTU treatment attenuated the activation of Notch3 signaling in PASMCs from monocrotaline-treated rats, which was mediated via inhibition of gamma-secretase expression especially its presenilin enhancer 2 (Pen-2) subunit. Furthermore, over-expression of Pen-2 in PASMCs from control rats increased the capacity of migration, whereas knockdown of Pen-2 with its respective siRNA in PASMCs from monocrotaline-treated rats had an opposite effect. Transfection of PASMCs from monocrotaline-treated rats with Pen-2 siRNA blocked the inhibitory effect of PTU on PASMC proliferation and migration, reflecting the crucial role of Pen-2 in PTU effect. We present a novel cell-signaling paradigm in which overexpression of Pen-2 is essential for experimental pulmonary arterial hypertension to promote motility and growth of smooth muscle cells. Propylthiouracil attenuates experimental PAH via suppression of the gamma-secretase-mediated Notch3 signaling especially its presenilin enhancer 2 (Pen-2) subunit. These findings provide a deep insight into the pathogenesis of PAH and a novel therapeutic strategy.

Topics: Amyloid Precursor Protein Secretases; Animals; Cell Movement; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Gene Expression; Hypertension, Pulmonary; Lung; Male; Presenilin-2; Propylthiouracil; Rats, Sprague-Dawley; Receptor, Notch3; Receptors, Notch; Signal Transduction

Congenital thyroid hypofunction can cause a variety of developmental disorders. Hippocampus is an important structure participating in the cognitive activities. Neural function damage is able to induce hippocampal neuron apoptosis. As a miRNA expressed specifically and abundantly in brain tissue, miR-124 has protective effect to neuron apoptosis caused by cerebral apoplexy. However, its role in neuron apoptosis caused by thyroid hypofunction is still unclear. The rats were divided into four groups including normal group, thyroid hypofunction group, miR-124 negative control group, and miR-124 mimics group. Propylthiouracil (50 mg/d) was injected to the stomach to the rats with 15 d pregnancy till the newborn rats were born. Inducing the thyroid hypofunction rat model and then injecting miR-124 mimics to ventricle. Serum TSH, FT3 and FT4 were detected to confirm the model. Immunohistochemistry was carried out to calculate neuron number. Tunel assay was used to detect neuron apoptosis. Western blot was applied to detect apoptosis related protein Caspase-3, Bcl-2 and Bax expression. After brain injection miR-124 mimics, hippocampal neuron number and morphology both improved in 15 d newborn mice compared with thyroid hypofunction group. Tunel staining found positive neurons reduced, which indicated that miR-124 can inhibit hippocampal neuron apoptosis in thyroid hypofunction rats. Further Western blot results revealed that apoptosis inhibition might be related to down-regulating activated Caspase-3 and Bax levels, and up-regulating tumor-suppressor gene Bcl-2 expression. MiR-124 can protect neuron apoptosis in thyroid hypofunction rat.

Topics: Animals; Animals, Newborn; Apoptosis; Apoptosis Regulatory Proteins; Congenital Hypothyroidism; Disease Models, Animal; Female; Gestational Age; Hippocampus; MicroRNAs; Neurons; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats, Sprague-Dawley; Signal Transduction; Thyroid Hormones

Previous studies have recently shown that maternal hypothyroidism leads to impaired glucose metabolism and reduced insulin secretion in adult offspring in rats. The aim of this study was to locate the defect in the insulin secretion pathway induced by maternal hypothyroidism. Pregnant Wistar rats were divided into two groups; the control group consumed water, while the hypothyroid (FH) group received water containing 0.025% 6-propyl-2-thiouracil during gestation. An intravenous glucose tolerance test was carried out on 5-month-old male offspring. In in vitro studies, the effects of various secretagogues and inhibitors acting at different levels of the insulin secretion cascade were investigated, and insulin content, insulin secretion and glucokinase activity of the islets were compared. Although insulin content of the FH islets did not differ from that of control islets, insulin secretion from FH islets was reduced when it was challenged by glucose or arginine. Compared with control islets, activities of both hexokinase and glucokinase were also significantly decreased in the FH islets. Although, in both groups, increasing glibenclamide and nifedipine concentrations in the presence of 16.7 mmol l(-1) glucose increased and decreased insulin secretion, respectively, the percentage of changes in secretion of FH islets was significantly lower compared with control islets. The response of FH islets to high extracellular potassium concentration and diazoxide was also significantly lower than that of the control islets. These findings demonstrate that impaired insulin secretion in the FH group is probably related to alterations in different steps of the insulin secretion pathway and not in the insulin pool of β-cells.

Topics: Age Factors; Animals; Blood Glucose; Disease Models, Animal; Female; Glucokinase; Glucose Tolerance Test; Hexokinase; Hypothyroidism; Insulin; Insulin Secretion; Islets of Langerhans; Male; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats, Wistar; Time Factors

Fetal/neonatal iron (Fe) and iodine/TH deficiencies lead to similar brain developmental abnormalities and often coexist in developing countries. We recently demonstrated that fetal/neonatal Fe deficiency results in a mild neonatal thyroidal impairment, suggesting that TH insufficiency contributes to the neurodevelopmental abnormalities associated with Fe deficiency. We hypothesized that combining Fe deficiency with an additional mild thyroidal perturbation (6-propyl-2-thiouracil [PTU]) during development would more severely impair neonatal thyroidal status and brain TH-responsive gene expression than either deficiency alone. Early gestation pregnant rats were assigned to 7 different treatment groups: control, Fe deficient (FeD), mild TH deficient (1 ppm PTU), moderate TH deficient (3 ppm PTU), severe TH deficient (10 ppm PTU), FeD/1 ppm PTU, or FeD/3 ppm PTU. FeD or 1 ppm PTU treatment alone reduced postnatal day 15 serum total T4 concentrations by 64% and 74%, respectively, without significantly altering serum total T3 concentrations. Neither treatment alone significantly altered postnatal day 16 cortical or hippocampal T3 concentrations. FeD combined with 1 ppm PTU treatment produced a more severe effect, reducing serum total T4 by 95%, and lowering hippocampal and cortical T3 concentrations by 24% and 31%, respectively. Combined FeD/PTU had a more severe effect on brain TH-responsive gene expression than either treatment alone, significantly altering Pvalb, Dio2, Mbp, and Hairless hippocampal and/or cortical mRNA levels. FeD/PTU treatment more severely impacted cortical and hippocampal parvalbumin protein expression compared with either individual treatment. These data suggest that combining 2 mild thyroidal insults during development significantly disrupts thyroid function and impairs TH-regulated brain gene expression.

Topics: Animals; Brain; Cerebral Cortex; Disease Models, Animal; Female; Gene Expression; Gene Expression Regulation; Hippocampus; Iron Deficiencies; Male; Maternal Exposure; Parvalbumins; Pregnancy; Propylthiouracil; Radioimmunoassay; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sex Factors; Thyroid Gland; Thyroid Hormones

Hypothyroidism is known to exert significant structural and functional changes to the developing central nervous system, and can lead to the establishment of serious mental retardation and neurological problems. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil-induced experimental hypothyroidism on crucial brain enzyme activities of Wistar rat offspring, at two time-points of their lives: at birth (day-1) and at 21 days of age (end of lactation). Under all studied experimental conditions, offspring brain acetylcholinesterase (AChE) activity was found to be significantly decreased due to maternal hypothyroidism, in contrast to the two studied adenosinetriphosphatase (Na(+),K(+)-ATPase and Mg(2+)-ATPase) activities that were only found to be significantly altered right after birth (increased and decreased, respectively, following an exposure to gestational maternal hypothyroidism) and were restored to control levels by the end of lactation. As our findings regarding the pattern of effects that maternal hypothyroidism has on the above-mentioned crucial offspring brain enzyme activities are compared to those reported in the literature, several differences are revealed that could be attributed to both the mode of the experimental simulation approach followed as well as to the time-frames examined. These findings could provide the basis for a debate on the need of a more consistent experimental approach to hypothyroidism during neurodevelopment as well as for a further evaluation of the herein presented and discussed neurochemical (and, ultimately, neurodevelopmental) effects of experimentally-induced maternal hypothyroidism, in a brain region-specific manner.

Topics: Acetylcholinesterase; Adenosine Triphosphatases; Aging; Animals; Brain; Disease Models, Animal; Enzyme Activation; Female; Hypothyroidism; Male; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar

The present study was performed to determine target gene profiles associated with pathological mechanisms of developmental neurotoxicity. For this purpose, we selected a rat developmental hypothyroidism model because thyroid hormones play an essential role in both neuronal and glial development. Region-specific global gene expression analysis was performed at postnatal day (PND) 21 on four brain regions representing different structures and functions, i.e., the cerebral cortex, corpus callosum, dentate gyrus and cerebellar vermis of rats exposed to 6-propyl-2-thiouracil in the drinking water at 3 and 10ppm from gestational day 6 to PND 21. Expression changes of gene clusters of neuron differentiation and development, cell migration, synaptic function, and axonogenesis were detected in all four regions. Characteristically, gene expression profiles suggestive of affection of ephrin signaling and glutamate transmission were obtained in multiple brain regions. Gene clusters suggestive of suppression of myelination and glial development were specifically detected in the corpus callosum and cerebral cortex. Immunohistochemically, immature astrocytes immunoreactive for vimentin and glial fibrillary acidic protein were increased, and oligodendrocytes immunoreactive for oligodendrocyte lineage transcription factor 2 were decreased in the corpus callosum. Immunoreactive intensity of myelin basic protein was also decreased in the corpus callosum and cerebral cortex. The hippocampal dentate gyrus showed downregulation of Ptgs2, which is related to synaptic activity and neurogenesis, as well as a decrease of cyclooxygenase-2-immunoreactive granule cells, suggesting an impaired synaptic function related to neurogenesis. These results suggest that multifocal brain region-specific microarray analysis can determine the affection of neuronal or glial development.

Topics: Age Factors; Animals; Brain; Cluster Analysis; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Hypothyroidism; Male; Neurogenesis; Neuroglia; Neurons; Oligonucleotide Array Sequence Analysis; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroid Hormones

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

Thyroid hormone deficiency during perinatal development results in significant alterations in neurological functions. The relationship between such events and brain metabolism is not completely understood. The aim of this study was to investigate the effects of hypothyroidism on leucine, mannose, glucose and lactate metabolism in rat cerebellar slices. Experimental hypothyroidism was induced by exposing mothers and pups to propylthiouracil (PTU) until weaning - postnatal day 21. Metabolic analyses were performed in postnatal day 10 (PND10) and 21 (PND21) animals. A matching group of animals received the same oral treatment also after weaning until adulthood PND60 with T3 supplement during lactation (P1-P21). In PND21 animals, PTU treatment significantly increased the rate of leucine oxidation to CO2, although glucose and lactate oxidations were not affected. PTU treatment also increased the oxidation of leucine to CO2 at PND60 (adult animals). PND10 hypothyroidism animals showed a decrease in conversion of mannose to glycolipids and glycoprotein compared with the control group. However, PTU treatment increased the conversion of mannose to glycolipids and glycoprotein in PND21 animals. The replacement of T3 normalized mannose and leucine metabolism in adult rats. These results indicate that deficits in thyroid hormones during lactation could delay or alter brain development and metabolism.

Topics: Animals; Carbon Dioxide; Cerebellum; Disease Models, Animal; Female; Glucose; Hypothyroidism; Lactation; Lactic Acid; Leucine; Mannose; Oxidation-Reduction; Pregnancy; Propylthiouracil; Rats; Rats, Wistar

The atherogenic effects of hypothyroidism on lipid metabolism could result, in part, from the reduced clearance of remnant lipoproteins. In this study, we investigated the expression of hepatic low-density lipoprotein receptor-related protein 1 (LRP1), a receptor for remnant lipoproteins, in hypothyroidism and the effect of 3,3',5-triiodo-L-thyronine (T3) treatment on hepatic LRP1 expression.. C57BL/6 mice were fed a normal diet (control group) or a low-iodine diet supplemented with 0.15% propylthiouracil (PTU/LI group) for 4 weeks. Mice in the PTU/LI group were injected intraperitoneally with T3 (0, 30, and 150 μg/kg of body weight) for 7 days. HepG2 cells were incubated in fetal bovine serum or charcoal-stripped fetal bovine serum with various concentrations of T3. The expression and function of LRP1 in liver samples and cells were analyzed.. Hypothyroidism was successfully induced in PTU/LI mice. Hepatic LRP1 protein expression was lower in the PTU/LI group than in the control group. T3 treatment upregulated hepatic LRP1 protein expression in PTU/LI mice. LRP1 expression in HepG2 cells was reduced after incubation in the medium containing charcoal-stripped fetal bovine serum, which mimics hypothyroidism in vitro, and was recovered by T3 treatment. The protein expression of LRP1 in HepG2 cells was increased by T3 treatment in a dose-dependent manner up to 2.0 nM T3. However, LRP1 mRNA transcription was not affected by hypothyroidism conditions or T3 treatment, either in liver samples or in HepG2 cells. T3 treatment on HepG2 cells increased cellular uptake of lipid-conjugated apolipoprotein E through LRP1.. Our data demonstrate that hepatic LRP1 expression and function decrease in hypothyroidism and are regulated by the thyroid hormone. These results suggest that in hypothyroidism, decreased expression of hepatic LRP1 may be associated with reduced clearance of circulating remnant lipoproteins.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Down-Regulation; Dyslipidemias; Hep G2 Cells; Humans; Hypothyroidism; Liver; Low Density Lipoprotein Receptor-Related Protein-1; Male; Mice, Inbred C57BL; Propylthiouracil; Receptors, LDL; RNA, Messenger; Triiodothyronine; Tumor Suppressor Proteins

Recent advances suggest that the cellular redox state may play a significant role in the progression of fibrosis in systemic sclerosis (SSc). Another, and as yet poorly accounted for, feature of SSc is its overlap with thyroid abnormalities. Previous reports demonstrate that hypothyroidism reduces oxidant stress. The aim of this study was therefore to evaluate the effect of propylthiouracil (PTU), and of the hypothyroidism induced by it, on the development of cutaneous and pulmonary fibrosis in the oxidant stress murine model of SSc.. Chronic oxidant stress SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) for 6 weeks. Mice (n = 25) were randomized into three arms: HOCl (n = 10), HOCl plus PTU (n = 10) or vehicle alone (n = 5). PTU administration was initiated 30 minutes after HOCl subcutaneous injection and continued daily for 6 weeks. Skin and lung fibrosis were evaluated by histologic methods. Immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in cutaneous and pulmonary tissues was performed to evaluate myofibroblast differentiation. Lung and skin concentrations of vascular endothelial growth factor (VEGF), extracellular signal-related kinase (ERK), rat sarcoma protein (Ras), Ras homolog gene family (Rho), and transforming growth factor (TGF) β were analyzed by Western blot.. Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. PTU treatment prevented both dermal and pulmonary fibrosis. Myofibroblast differentiation was also inhibited by PTU in the skin and lung. The increase in cutaneous and pulmonary expression of VEGF, ERK, Ras, and Rho in mice treated with HOCl was significantly prevented in mice co-administered with PTU.. PTU, probably through its direct effect on reactive oxygen species or indirectly through thyroid function inhibition, prevents the development of cutaneous and pulmonary fibrosis by blocking the activation of the Ras-ERK pathway in the oxidant-stress animal model of SSc.

Topics: Actins; Animals; Antithyroid Agents; Blotting, Western; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Female; Fibrosis; Hypochlorous Acid; Hypothyroidism; Immunohistochemistry; Mice; Mice, Inbred BALB C; Muscle, Smooth; Oxidants; Propylthiouracil; Pulmonary Fibrosis; Random Allocation; ras Proteins; Scleroderma, Systemic; Skin; Thyrotropin; Thyroxine; Triiodothyronine; Vascular Endothelial Growth Factor A

Hypothyroidism has a variety of adverse effects on cognitive function. The treatment of levothyroxine alone cannot restore cognitive defects of hypothyroid patients. Antioxidant vitamin E supplementation could be useful in disturbances which are associated with oxidative stress and could effectively slow the progression of Alzheimer disease. Thus, the purpose of this study was to evaluate oxidative stress status of the serum and hippocampus in hypothyroidism and to examine the effects of levothyroxine replacement therapy with vitamin E supplementation on cognitive deficit. Sprague-Dawley rats were randomly divided into five groups: control group, PTU group, PTU + Vit E group, PTU + L-T4 group, and PTU + L-T4 + Vit E group. Serum and hippocampus malondialdehyde (MDA) levels were determined using the thiobarbituric-acid reactive substances method. Serum and hippocampus superoxide dismutase (SOD) levels were determined by measuring its ability to inhibit the photoreduction of nitroblue tetrazolium. Learning and memory was assessed by Morris water maze test. In the present study, we found that the rats of PTU + Vit E group spent less time to find the platform on days 2, 3, 4, and 5 than the PTU group. Moreover, the rats of PTU + L-T4 + Vit E group spent less time to find the platform on days 4 and 5 than the PTU + L-T4 group. The time spent in the target quadrants was measured in the probe test and no difference was observed in all groups. Oxidative damage has been observed in the serum and hippocampus of hypothyroidism rat. SOD levels of serum and hippocampus tissue were significantly increased and MDA levels were significantly decreased in the PTU + Vit E and PTU + L-T4 + Vit E groups than the PTU and PTU + L-T4 groups. Therefore, these findings indicate that levothyroxine replacement therapy with vitamin E supplementation may ameliorate cognitive deficit in PTU-induced hypothyroidism through the decrease of oxidative stress status.

Topics: Animals; Cognition Disorders; Dietary Supplements; Disease Models, Animal; Hippocampus; Hormone Replacement Therapy; Hypothyroidism; Male; Malondialdehyde; Maze Learning; Oxidative Stress; Propylthiouracil; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thyroxine; Vitamin E

Thyroid hormones are recognized as the key metabolic hormones that play a critical role in the development of central nervous system (CNS) throughout life. The present study was designed to determine the changes in brain monoamine concentrations in 6-n-propyl thiouracil (PTU)-induced hypothyroid rats, in addition to the ameliorating role of folic acid treatment. Fifty male albino rats were equally divided into five groups; first and second groups were the control and folic acid groups, respectively, while the third group was the hypothyroid group in which the rats received PTU in drinking water for 6 weeks. The fourth and fifth groups were co- and post-treated folic acid groups with hypothyroid rats, respectively. Our results revealed that serotonin and norepinephrine concentrations were significantly decreased in the hypothalamus and cortex, while it significantly increased in the hippocampus of hypothyroid rats when compared with control group. Serotonin and norepinephrine concentrations were decreased in hypothalamus and cortex in co- and post-treated folic acid groups with hypothyroid rats, while the concentration of dopamine were significantly increased in the hypothalamus and hippocampus of the hypothyroid rats and co-treated folic acid group with hypothyroid rats. In cortex, the dopamine concentration was significantly increased in hypothyroid rats and post-treated folic acid group with hypothyroid rats, while it significantly decreased in co-treated folic acid group with hypothyroid rats when compared with the control group. Also, our results revealed that, folic acid treatment was better if it is administered as an adjuvant after returning to the euthyroid state by withdrawing PTU from the drinking water.

Topics: Animals; Brain; Brain Chemistry; Cerebral Cortex; Chromatography, High Pressure Liquid; Disease Models, Animal; Drug Therapy, Combination; Folic Acid; Hypothalamus; Hypothyroidism; Male; Norepinephrine; Propylthiouracil; Rats; Serotonin; Thyrotropin; Triiodothyronine; Vitamin B Complex

Thyroid cancers are the most common malignancy of the endocrine system in humans. To understand the molecular genetic events underlying thyroid carcinogenesis, we have generated a mouse model that spontaneously develops follicular thyroid carcinoma similar to human thyroid cancer (Thrb(PV/PV) mouse). This mutant mouse harbors a dominant-negative mutated thyroid hormone receptor β (denoted PV). The PV mutation was identified in a patient with resistance to thyroid hormone (TH). Thrb(PV/PV) mice exhibit highly elevated serum thyroid-stimulating hormone levels and increased TH. We have previously shown that thyroid-stimulating hormone is required, but not sufficient to induce metastatic follicular thyroid cancer in Thrb(PV/PV) mice. However, whether the elevated TH also contributes to the thyroid carcinogenesis of Thrb(PV/PV) mice was not elucidated. To understand the role of TH in thyroid carcinogenesis, we blocked the production of TH by treating Thrb(PV/PV) mice with propylthiouracil (Thrb(PV/PV)-PTU mice) and compared the development of thyroid cancer in Thrb(PV/PV)-PTU and untreated Thrb(PV/PV) mice. We found that thyroid tumor growth was reduced by ∼42% in Thrb(PV/PV)-PTU mice as compared with Thrb(PV/PV) mice. Analysis by bromodeoxyuridine-nuclear labeling showed decreased incorporation of bromodeoxyuridine in thyroid tumor cells of Thrb(PV/PV)-PTU mice, indicative of decreased tumor cell proliferation. However, cleaved-caspase 3 staining showed no apparent changes in apoptosis of tumor cells in Thrb(PV/PV)-PTU mice. Molecular studies identified a marked attenuation of the PI3K-AKT-β-catenin signaling pathway that led to decreased protein levels of cyclin D2, thereby decreasing tumor cell proliferation in Thrb(PV/PV)-PTU mice. Furthermore, matrix metalloproteinase-2, a downstream target of β-catenin and a key regulator during tumor invasion and metastasis, was also decreased. Thus, the present study uncovers a critical role of TH in promoting the thyroid carcinogenesis of Thrb(PV/PV) mice via membrane signaling events. Importantly, these findings suggest that anti-thyroid drugs could be considered as possible therapeutic agents of thyroid cancer.

Topics: Adenocarcinoma, Follicular; Animals; Antithyroid Agents; Cell Proliferation; Cyclin D2; Disease Models, Animal; Mice; Propylthiouracil; Signal Transduction; Thyroid Hormone Receptors beta; Thyroid Hormones; Thyroid Neoplasms; Thyrotropin

The present study was carried out to elucidate the effectiveness of curcumin in ameliorating the expression of superoxide dismutase (SOD) in cerebral cortex and cerebellum of rat brain under 6-propyl-2-thiouracil (PTU)-induced hypothyroidism. Induction of hypothyroidism in adult rats by PTU resulted in augmentation of lipid peroxidation (LPx), an index of oxidative stress in cerebellum but not in cerebral cortex. Curcumin-supplementation to PTU-treated (hypothyroid) rats showed significant reduction in the level of LPx in both the regions of brain. The decreased translated products (SOD1 and SOD2) and the unchanged activity of SOD in cerebral cortex of PTU-treated rats were increased on supplementation of curcumin to the hypothyroid rats. Declined translated products of SOD1 and SOD2 in cerebellum of PTU-treated rats were alleviated on administration of curcumin to hypothyroid rats. On the other hand, the decreased activity of SOD in cerebellum of PTU-treated rats was further declined on administration of curcumin to the hypothyroid rats. Results of the present investigation indicate that curcumin differentially modulates the expression of superoxide dismutase in rat brain cortex and cerebellum under PTU-induced hypothyroidism.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antithyroid Agents; Cerebellum; Cerebral Cortex; Curcumin; Disease Models, Animal; Hypothyroidism; Lipid Peroxidation; Male; Oxidative Stress; Propylthiouracil; Rats; Rats, Wistar; Superoxide Dismutase; Superoxide Dismutase-1; Thiobarbituric Acid Reactive Substances

The protective effect of hypothyroidism against ischemic or toxic conditions has been shown in various tissues. We investigated the effect of propylthiouracil (PTU)/methimazole (MMI)-induced hypothyroidism and acute local effect of MMI on the outcome of lethal ischemia in random-pattern skin flaps.. Dorsal flaps with caudal pedicles were elevated at midline and flap survival was measured at the seventh day after surgery. The first group, as control, received 1 mL of 0.9% saline solution in the flap before flap elevation. In groups 2 and 3, hypothyroidism was induced by administration of either PTU 0.05% or MMI 0.04% in drinking water. The next four groups received local injections of MMI (10, 20, 50, or 100 μg/flap) before flap elevation. Local PTU injection was ignored due to insolubility of the agent.. Hypothyroidism was induced in chronic PTU- and MMI-treated groups, and animals in these groups showed significant increase in their flap survival, compared to control euthyroid rats (79.47% ± 10.49% and 75.48% ± 12.93% versus 52.26% ± 5.75%, respectively, P < 0.01). Acute local treatment of skin flaps with MMI failed to significantly affect the flap survival.. This study demonstrates for the first time that hypothyroidism improves survival of random-pattern skin flaps in rats.

Topics: Animals; Antithyroid Agents; Dermatologic Surgical Procedures; Disease Models, Animal; Hypothyroidism; Ischemia; Male; Methimazole; Plastic Surgery Procedures; Propylthiouracil; Rats; Rats, Sprague-Dawley; Skin; Surgical Flaps; Thyroid Gland

Study of physiological angiogenesis and associated signalling mechanisms in adult heart has been limited by the lack of a robust animal model. We investigated thyroid hormone-induced sprouting angiogenesis and the underlying mechanism. Hypothyroidism was induced in C57BL/6J mice by feeding with propylthiouracil (PTU). One year of PTU treatment induced heart failure. Both 12 weeks- (young) and 1 year-PTU (middle age) treatment caused a remarkable capillary rarefaction observed in capillary density. Three-day Triiodothyronine (T3) treatment significantly induced cardiac capillary growth in hypothyroid mice. In cultured left ventricle (LV) tissues from PTU-treated mice, T3 also induced robust sprouting angiogenesis where pericyte-wrapped endothelial cells formed tubes. The in vitro T3 angiogenic response was similar in mice pre-treated with PTU for periods ranging from 1.5 to 12 months. Besides bFGF and VEGF(164) , PDGF-BB was the most robust angiogenic growth factor, which stimulated notable sprouting angiogenesis in cultured hypothyroid LV tissues with increasing potency, but had little effect on tissues from euthyroid mice. T3 treatment significantly increased PDGF receptor beta (PDGFR-β) protein levels in hypothyroid heart. PDGFR inhibitors blocked the action of T3 both on sprouting angiogenesis in cultured LV tissue and on capillary growth in vivo. In addition, activation of Akt signalling mediated in T3-induced angiogenesis was blocked by PDGFR inhibitor and neutralizing antibody. Our results suggest that hypothyroidism leads to cardiac microvascular impairment and rarefaction with increased sensitivity to angiogenic growth factors. T3-induced cardiac sprouting angiogenesis in adult hypothyroid mice was associated with PDGF-BB, PDGFR-β and downstream activation of Akt.

Topics: Age Factors; Angiogenesis Inducing Agents; Animals; Becaplermin; Coronary Vessels; Disease Models, Animal; Female; Heart; Heart Ventricles; Hypothyroidism; Mice; Mice, Inbred C57BL; Myocardium; Neovascularization, Physiologic; Platelet-Derived Growth Factor; Propylthiouracil; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-sis; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Tissue Culture Techniques; Triiodothyronine

Neutrophil extracellular traps (NETs) are composed of DNA and antimicrobial proteins, including myeloperoxidase (MPO). Recent studies have demonstrated that impaired regulation of NETs could trigger an autoimmune response. Propylthiouracil (PTU), an antithyroid drug, is associated with a risk of MPO antineutrophil cytoplasmic antibody (ANCA) production and MPO ANCA-associated vasculitis (MPO AAV). This study was undertaken to clarify the mechanism of MPO ANCA production, using the PTU-induced model of MPO AAV.. NETs were induced by treating human neutrophils with phorbol myristate acetate (PMA) in vitro. We examined whether the addition of PTU influenced the NET formation induced by PMA and the degradation of NETs by DNase I, which is regarded as a regulator of NETs. Furthermore, we examined whether NETs generated by the combination of PMA and PTU induced MPO ANCA and MPO AAV in vivo in rats.. When NETs were induced by PMA with PTU using human neutrophils in vitro, abnormal conformation of NETs was observed. Interestingly, the abnormal NETs were hardly digested by DNase I. Moreover, rats immunized with the abnormal NETs, which had been induced by PMA with PTU using rat neutrophils, produced MPO ANCA and developed pulmonary capillaritis. When rats were given oral PTU with intraperitoneal injection of PMA, pauci-immune glomerulonephritis and pulmonary capillaritis occurred with MPO ANCA production in the serum.. Our findings indicate that abnormal conformation and impaired degradation of NETs induced by PTU are involved in the pathogenesis of PTU-induced MPO ANCA production and MPO AAV. These findings suggest that disordered NETs can be critically implicated in the pathogenesis of MPO AAV.

Topics: alpha-Defensins; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antimetabolites; Carcinogens; Deoxyribonuclease I; Disease Models, Animal; DNA; Humans; Neutrophils; Nucleic Acid Conformation; Peroxidase; Propylthiouracil; Rats; Rats, Inbred WKY; Tetradecanoylphorbol Acetate

The objective of this study was to evaluate fetal weight, histomorphometric changes and proliferative activity, apoptosis and angiogenesis of the placenta in rats with hypothyroidism. Thirty-six adult female rats were divided into two groups with 18 animals each: control and hypothyroidism. Hypothyroidism was induced by daily administration of propylthiouracil (1 mg/animal). The administration began five days before becoming pregnant and the animals were sacrificed at 14 or 19 days of gestation. The control group received a placebo. The number and weight of fetuses and the rate of fetal death was determined, as well as the morphometric characteristics, the immunohistochemical expression of cell division control protein 47 (CDC)-47 and vascular endothelial growth factor (VEGF) and the number of apoptotic cells in the placental disk. The data were analysed by Mann-Whitney U test. Hypothyroidism reduced the weight of fetuses and of the uterus and placenta (P<0.05), altered the thickness of the placental labyrinth and spongiotrophoblast (P<0.05), increased the population of glycogen cells in the spongiotrophoblast (P<0.05), interfered with the vascular development of the placental labyrinth and decreased VEGF expression (P<0.05), reduced the expression of CDC-47 and cellularity and increased the apoptotic rate in the placental disk (P<0.05). We conclude that hypothyroidism affects fetal weight by altering the proliferative activity, apoptosis and vascularisation of the placenta.

Topics: Adenosine Triphosphatases; Animals; Apoptosis; Biomarkers; Cell Proliferation; Disease Models, Animal; DNA-Binding Proteins; Down-Regulation; Female; Fetal Death; Fetal Growth Retardation; Fetal Weight; Gestational Age; Glycogen; Hypothyroidism; Immunohistochemistry; Minichromosome Maintenance Complex Component 7; Neovascularization, Physiologic; Placenta; Pregnancy; Propylthiouracil; Rats; Trophoblasts; Vascular Endothelial Growth Factor A

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 study aimed to predict effective human jejunal permeability (P(eff)) using a biophysical model based on parametrized paracellular, aqueous boundary layer, and transcellular permeabilities, and the villus-fold surface area expansion factor (k(VF)). Published human jejunal data (119 P(eff), 53 compounds) were analyzed by a regression procedure incorporating a dual-pore size paracellular model. Transcellular permeability, scaled by k(VF), was equated to that of Caco-2 at pH 6.5. The biophysical model predicted human jejunal permeability data within the experimental uncertainty. This investigation revealed several surprising predictions: (i) many molecules permeate predominantly (but not exclusively) by the paracellular route, (ii) the aqueous boundary layer thickness in the intestinal perfusion experiments is larger than expected, (iii) the mucosal surface area in awake humans is apparently nearly entirely accessible to drug absorption, and (iv) the relative "leakiness" of the human jejunum is not so different from that observed in a number of published Caco-2 studies.

Topics: Animals; Disease Models, Animal; Dogs; Humans; Jejunal Diseases; Kidney Diseases; Models, Biological; Permeability; Porosity; Regression Analysis

Developmental iodine deficiency leads to inadequate thyroid hormone, which damages the hippocampus. In the present study, we implicate hippocampal caveolin-1 and synaptophysin in developmental iodine deficiency and hypothyroidism. Two developmental rat models were established: pregnant rats were administered either an iodine-deficient diet or propylthiouracil (PTU)-adulterated (5 p.p.m. or 15 p.p.m.) drinking water from gestational day 6 until postnatal day (PN) 28. Nissl staining and the levels of caveolin-1 and synaptophysin in several hippocampal subregions were assessed on PN14, PN21, PN28 and PN42. The results obtained show that surviving cells in the iodine-deficient and PTU-treated rats were lower than in controls. Up-regulation of caveolin-1 and down-regulation of synaptophysin were observed in the iodine-deficient and PTU-treated rats. Our findings implicate decreases in the number of surviving cells and alterations in the levels of caveolin-1 and synaptophysin in the impairments in neural development induced by developmental iodine deficiency and hypothyroidism.

Topics: Animals; Caveolin 1; Cell Count; Cell Survival; Diet; Disease Models, Animal; Female; Hippocampus; Hypothyroidism; Iodine; Male; Neurons; Propylthiouracil; Pyramidal Cells; Random Allocation; Rats; Rats, Wistar; Synaptophysin; Time Factors

Thyroid hormone (TH) has prominent effects on the heart, and hyperthyroidism is occasionally found to be a cause of dilated cardiomyopathy (DCM). We aim to explore the potential role of TH in the pathogenesis of DCM.. The pathophysiological role of TH in the heart was investigated using a knock-in mouse model of inherited DCM with a deletion mutation DeltaK210 in the cardiac troponin T gene. Serum tri-iodothyronine (T(3)) levels showed no significant difference between wild-type (WT) and DCM mice, whereas cardiac T(3) levels in DCM mice were significantly higher than those in WT mice. Type 2 iodothyronine deiodinase (Dio2), which produces T(3) from thyroxin, was up-regulated in the DCM mice hearts. The cAMP levels were increased in DCM mice hearts, suggesting that transcriptional up-regulation of Dio2 gene is mediated through the evolutionarily conserved cAMP-response element site in its promoter. Propylthiouracil (PTU), an anti-thyroid drug, prevented the hypertrophic remodelling of the heart in DCM mice and improved their cardiac function and life expectancy. Akt and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation increased in the DCM mice hearts and PTU treatment significantly reduced the phosphorylation levels, strongly suggesting that Dio2 up-regulation is involved in cardiac remodelling in DCM through activating the TH-signalling pathways involving Akt and p38 MAPK. Dio2 gene expression was also markedly up-regulated in the mice hearts developing similar eccentric hypertrophy after myocardial infarction.. Local hyperthyroidism via transcriptional up-regulation of the Dio2 gene may be an important underlying mechanism for the hypertrophic cardiac remodelling in DCM.

Topics: Animals; Antithyroid Agents; Cardiomyopathy, Dilated; Cells, Cultured; Cyclic AMP; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Myocardium; Oligonucleotide Array Sequence Analysis; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Propylthiouracil; Proto-Oncogene Proteins c-akt; Transcription, Genetic; Triiodothyronine; Troponin T; Up-Regulation; Ventricular Remodeling

The antithetical regulation of cardiac α- and β-myosin heavy chain (MHC) genes by thyroid hormone (T(3)) is not well understood but appears to involve thyroid hormone interaction with its nuclear receptor and MHC promoters as well as cis-acting noncoding regulatory RNA (ncRNA). Both of these phenomena involve epigenetic regulations. This study investigated the extent that altered thyroid state induces histone modifications in the chromatin associated with the cardiac MHC genes. We hypothesized that specific epigenetic events could be identified and linked to cardiac MHC gene switching in response to a hypothyroid or hyperthyroid state. A hypothyroid state was induced in rats by propylthiouracil treatment (PTU), whereas a hyperthyroid (T(3)) was induced by T(3) treatment. The left ventricle was analyzed after 7 days for MHC pre-mRNA expression, and the chromatin was assessed for enrichment in specific histone modifications using chromatin immunoprecipitation quantitative PCR assays. At both the α-MHC promoter and the intergenic region, the enrichment in acetyl histone H3 at K9/14 (H3K9/14ac) and trimethyl histone H3 at K4 (H3K4me3) changed in a similar fashion. They were both decreased with PTU treatment but did not change under T(3), except at a location situated 5' to the antisense intergenic transcription start site. These same marks varied differently on the β-MHC promoter. For example, H3K4me3 enrichment correlated with the β-promoter activity in PTU and T(3) groups, whereas H3K9/14ac was repressed in the T(3) group but did not change under PTU. Histone H3K9me was enriched in chromatin of both the intergenic and α-MHC promoters in the PTU group, whereas histone H4K20me1 was enriched in chromatin of β-MHC promoter in the normal control and T(3) groups. Collectively, these findings provide evidence that specific epigenetic phenomena modulate MHC gene expression in altered thyroid states.

Topics: Acetylation; Animals; Binding Sites; Chromatin Assembly and Disassembly; Chromatin Immunoprecipitation; Disease Models, Animal; DNA, Intergenic; Epigenesis, Genetic; Female; Gene Expression Regulation; Histones; Hyperthyroidism; Hypothyroidism; Methylation; Myocardium; Myosin Heavy Chains; Polymerase Chain Reaction; Promoter Regions, Genetic; Propylthiouracil; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; RNA Precursors; RNA, Messenger; Time Factors; Transcription, Genetic; Triiodothyronine; Ventricular Myosins

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

Environmental chemicals have a potential impact on neuronal development and children's health. The current developmental neurotoxicity (DNT) guideline studies to assess their underlying risk are costly and time-consuming; therefore the more efficient protocol for DNT test is needed. Hypothyroidism in rats induced by perinatal exposure to propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, offers an advantageous model of developmental neurotoxicity (DNT). Understanding the associated alterations in gene expression in brain is a key to elucidate mechanisms and find appropriate molecular markers. The purpose of the present study was to identify PTU treatment-affected transcriptomes in the rat cerebral cortex and the hippocampus using DNA microarrays, and to specify candidate genes linked to DNT. We used an approximately 9000 probe microarray to examine differentially expressed genes between PTU-dosed and vehicle-dosed rats at postnatal days 4, 14, 22 and 70. Expression of immediate early genes (IEGs) such as activity-regulated cytoskeleton-associated protein (Arc), Homer 1, early growth response 1 (Egr 1), myelin-associated genes such as myelin-associated oligodendrocytic basic protein (MOBP), myelin basic protein (MBP) and proteolipid protein (PLP) and Kcna1 was apparently affected by perinatal administration of PTU. The results suggest that the alterations may be responsible for the detrimental effects caused by PTU treatment on the nervous system.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Apoptosis Regulatory Proteins; Carrier Proteins; Cerebral Cortex; Disease Models, Animal; Early Growth Response Protein 1; Gene Expression Regulation; Genes, Immediate-Early; Hippocampus; Homer Scaffolding Proteins; Hypothyroidism; Kv1.1 Potassium Channel; Male; Muscle Proteins; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Nerve Tissue Proteins; Oligonucleotide Array Sequence Analysis; Propylthiouracil; Rats; RNA, Messenger; Transcription Factors

This study addressed the influence of propylthiouracil (PTU)-induced hypothyroidism on postnatal and adult neurogenesis. PTU was administered from birth to postnatal day 10 (P10) or P21, leading to decreased neural stem cell/progenitor proliferation in the dentate gyrus, as well as significantly fewer granule cells and reduced hippocampal volume. Upon P22 PTU withdrawal, plasma thyroid hormone levels were normal by P90, there was no difference in the number of dentate gyrus or subventricular proliferating cells, but brain weight was smaller. In addition, dentate gyrus density of surviving BrdU-labeled cells increased, with no changes to the olfactory bulb. Quantitative PCR revealed decreased FGF-2, NGF, Wnt3a, and VEGF-A hippocampal expression during PTU treatment, with recovery in adulthood. Pro-apoptotic Bax was up-regulated, and anti-apoptotic Bcl-2 was down-regulated, during PTU treatment, both of which were normalized in the adult brain. In contrast, apoptosis-inducing factor (AIF) was down-regulated in the adult. These results suggest that mechanisms in the adult brain attempt to compensate for decreased neurogenesis due to postnatal hypothyroidism.

Topics: Aging; Animals; Animals, Newborn; Antithyroid Agents; Apoptosis Regulatory Proteins; Atrophy; Brain; Cell Count; Cognition Disorders; Dentate Gyrus; Disease Models, Animal; Down-Regulation; Hypothyroidism; Neurogenesis; Neurons; Organ Size; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormones

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

Propylthiouracil (PTU) enhances nitric oxide production and inhibits smooth muscle cell proliferation, suggesting a possible role in the prevention of pulmonary arterial hypertension (PAH).. The 30 male Sprague-Dawley rats were randomized to receive saline injection only (group 1), monocrotaline (MCT) (70 mg/kg) only (group 2) or MCT + 0.1% PTU in drinking water (group 3) given on day 5 after MCT administration. By day 35, western blot showed lower connexin43 (Cx43) and membranous protein kinase C-epsilon expressions in the right ventricle (RV) of group 2 animals than in the other groups (all P<0.05). Conversely, Cx43 expression in the lung was higher in group 2 than in other groups (all P<0.02). Additionally, mRNA expressions of matrix metalloproteinase-9, tissue necrotic factor-alpha, and caspase-3 were higher, whereas Bcl-2 and endothelial nitric oxide synthase were lower, in the lungs and RV of group 2 rats than in the other groups (all P<0.05). Moreover, the numbers of alveolar sacs and lung arterioles were also reduced in group 2 than in other groups (all P<0.05), and RV systolic pressure and RV weight were increased in group 2 compared with other groups (all P<0.001).. PTU effectively attenuates complications associated with MCT-induced PAH.

Topics: Animals; Antihypertensive Agents; Arterioles; Caspase 3; Connexin 43; Disease Models, Animal; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Male; Matrix Metalloproteinase 9; Monocrotaline; Nitric Oxide Synthase Type III; Propylthiouracil; Protein Kinase C-epsilon; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Function, Right; Ventricular Pressure

There is accumulating evidence showing that ischemic preconditioning (PC) may lose its cardioprotective effect in the diseased states. The present study investigated whether PC can be effective in hypothyroidism, a clinical condition which is common and often accompanies cardiac diseases such as heart failure and myocardial infarction. Hypothyroidism was induced in rats by 3-week administration of 6n-propyl-2-thiouracil in water (0.05 %). Normal and hypothyroid hearts (HYPO) were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischemia and 45 min of reperfusion. A preconditioning protocol (PC) was also applied prior to ischemia. HYPO hearts had significantly improved post-ischemic recovery of left ventricular developed pressure, end-diastolic pressure and reduced lactate dehydrogenase release. Furthermore, phospho-JNK and p38 MAPK levels after ischemia and reperfusion were 4.0 and 3.0 fold lower in HYPO as compared to normal hearts (P<0.05). A different response to PC was observed in normal than in HYPO hearts. PC improved the post-ischemic recovery of function and reduced the extent of injury in normal hearts but had no additional effect on the hypothyroid hearts. This response, in the preconditioned normal hearts, resulted in 2.5 and 1.8 fold smaller expression of the phospho-JNK and phospho-p38 MAPK levels at the end of reperfusion, as compared to non-PC hearts (P<0.05), while in HYPO hearts, no additional reduction in the phosphorylation of these kinases was observed after PC. Hypothyroid hearts appear to be tolerant to ischemia-reperfusion injury. This response may be, at least in part, due to the down-regulation of ischemia-reperfusion induced activation of JNKs and p38 MAPK kinases. PC is not associated with further reduction in the activation of these kinases in the hypothyroid hearts and fails to confer added protection in those hearts.

Topics: Animals; Cardiac Myosins; Disease Models, Animal; Hypothyroidism; Ischemic Preconditioning, Myocardial; JNK Mitogen-Activated Protein Kinases; L-Lactate Dehydrogenase; Male; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; p38 Mitogen-Activated Protein Kinases; Perfusion; Phosphorylation; Propylthiouracil; Rats; Rats, Wistar; Recovery of Function; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Treatment Failure; Ventricular Function, Left; Ventricular Pressure

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

Adult-onset hypothyroidism is associated with neurological changes such as cognitive dysfunction and impaired learning, which may be related to alterations of synaptic plasticity. We investigate the consequence of adult-onset hypothyroidism on thyroid-mediated transcription events in striatal synaptic plasticity, and the effect of triiodothyronine (T3) replacement. We used hypothyroid mice, treated with propylthiouracil (PTU) and methimazole (MMI), with or without subsequent administration of T3. We evaluated the amount of T3 nuclear receptors (TRalpha1, TRbeta) and striatal plasticity indicators: neurogranin (RC3), Ras homolog enriched in striatum (Rhes), Ca2+/calmodulin-dependent protein kinase (CaMKII), and dopamine- and cAMP-regulated phosphoprotein (DARPP-32). In addition, we assessed hypothyroid mice motor behavior as related to striatum synaptic functions. Hypothyroid mice exhibited significantly reduced TRbeta, RC3 and Rhes expression. T3 administration reversed the expression of TRbeta, RC3, and up-regulated CaMKII levels as well as motor behavior, and decreased DARPP-32 protein phosphorylation. We suggest that thyroid hormone modulation had a major impact on striatal synaptic plasticity of adult mice which produced in turn motor behavior modifications.

Topics: Age Factors; Animals; Behavior, Animal; Biomarkers; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Corpus Striatum; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; GTP-Binding Proteins; Hypothyroidism; Male; Methimazole; Mice; Motor Activity; Movement Disorders; Neurogranin; Neuronal Plasticity; Phosphorylation; Presynaptic Terminals; Propylthiouracil; Receptors, Thyroid Hormone; Synaptic Transmission; Thyroid Gland; Triiodothyronine; Up-Regulation

Expression of all of the isoforms of the subunits of AMP-activated protein kinase (AMPK) and AMPK activity is increased in skeletal muscle of hyperthyroid rats. Activity of AMPK in skeletal muscle is regulated principally by the upstream kinase, LKB1. This experiment was designed to determine whether the increase in AMPK activity is accompanied by increased expression of the LKB1, along with binding partner proteins. LKB1, MO25, and downstream targets were determined in muscle extracts in control rats, in rats given 3 mg of thyroxine and 1 mg of triiodothyronine per kilogram chow for 4 wk, and in rats given 0.01% propylthiouracil (PTU; an inhibitor of thyroid hormone synthesis) in drinking water for 4 wk (hypothyroid group). LKB1 and MO25 increased in the soleus of thyroid hormone-treated rats vs. the controls. In other muscle types, LKB1 responses were variable, but MO25 increased in all. In soleus, MO25 mRNA increased with thyroid hormone treatment, and STRAD mRNA increased with PTU treatment. Phospho-AMPK and phospho-ACC were elevated in soleus and gastrocnemius of hyperthyroid rats. Thyroid hormone treatment also increased the amount of phospho-cAMP response element binding protein (CREB) in the soleus, heart, and red quadriceps. Four proteins having CREB response elements (CRE) in promoter regions of their genes (peroxisome proliferator-activated receptor-gamma coactivator-1alpha, uncoupling protein 3, cytochrome c, and hexokinase II) were all increased in soleus in response to thyroid hormones. These data provide evidence that thyroid hormones increase soleus muscle LKB1 and MO25 content with subsequent activation of AMPK, phosphorylation of CREB, and expression of mitochondrial protein genes having CRE in their promoters.

Topics: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Antithyroid Agents; Blotting, Western; Calcium-Binding Proteins; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Electric Stimulation; Hyperthyroidism; Hypothyroidism; Male; Mitochondrial Proteins; Multienzyme Complexes; Muscle, Skeletal; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphoprotein Phosphatases; Phosphorylation; Promoter Regions, Genetic; Propylthiouracil; Protein Phosphatase 2C; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; RNA-Binding Proteins; RNA, Messenger; Signal Transduction; Thyroxine; Transcription Factors; Triiodothyronine

Apoptosis, proliferation and histomorphometry of spleen were investigated in ovariectomized and non-ovariectomized adult Wistar rats maintained in hypothyroidism induced by daily administration of propylthiouracil (PTU) during 120 days. Two groups ovariectomized euthyroid and non-ovariectomized euthyroid were used as controls. Plasma was collected for free T4 dosage and the spleen for histomorphometry analysis, apoptosis index and the immunohistochemistry expression of caspase 3 and CDC47. Values of free T4 were lower in rats treated with PTU (p<0.05). In the hypothyroid groups there was some decrease in the spleen weight as well as the number and size of lymphoid follicles and there was some increase in the apoptotic index and the caspase 3 expression (p<0.05). However, the increase in the apoptosis index and the expression of caspase 3 in ovariectomized hypothyroid rats spleen was less accentuated than non-ovariectomized hypothyroid ones (p<0.05). The ovariectomized euthyroid group presented white pulp hyperplasia in comparison to the non-ovariectomized euthyroid group. There was no difference in the CDC47 expression between groups. It was concluded that the thyroid and ovarian hypofunction have distinct effects on the spleen and that in the hypothyroidism-hypogonadism association, the increase in the apoptosis index and in the expression of splenic caspase 3 is not as much as in isolated hypothyroidism.

Topics: Adenosine Triphosphatases; Animals; Antithyroid Agents; Apoptosis; Caspase 3; Cell Proliferation; Disease Models, Animal; DNA-Binding Proteins; Female; Hypogonadism; Hypothyroidism; Lymphoid Tissue; Minichromosome Maintenance Complex Component 7; Ovariectomy; Propylthiouracil; Rats; Rats, Wistar; Spleen; Thyroid Gland; Thyroxine

Developmental thyroid hormone (TH) deficiency leads to mental retardation and neurological deficits in humans. In this study, congenital hypothyroidism was induced in rats by adding 0.05% 6-propyl-2-thiouracil in the drinking water during gestation and suckling period. This treatment induced hyperphosphorylation of neurofilaments, the neuronal intermediate filament (IF) proteins, of heavy, medium and low molecular weight (NF-H, NF-M and NF-L, respectively) without altering the phosphorylation level of astrocyte IF proteins, glial fibrillary acidic protein (GFAP) and vimentin in cerebral cortex of rats. NF-H was hyperphosphorylated on KSP repeats in the carboxy-terminal tail domain. Furthermore, the immunocontent of GFAP and NF subunits was down-regulated, while vimentin was unaltered both in tissue homogenate and in cytoskeletal fraction of hypothyroid animals. Moreover, we verified the immunocontent of astrocyte glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) as well as activation of mitogen-activated protein kinases (MAPKs) in hypothyroid rats. Results showed that hypothyroidism is associated with decreased GLAST and GLT-1 immunocontent. Additionally, we demonstrated increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation without altering Jun N-terminal kinase (JNK) and p38(MAPK) phosphorylation. However, total JNK levels were down-regulated. Taken together, these results suggest that the thyroid status could modulate the integrity of neuronal cytoskeleton acting on the endogenous NF-associated phosphorylating system and that such effect could be related to glutamate-induced excitotoxicity, as well as ERK1/2 and JNK modulation. These events could be somehow related to the neurological dysfunction described in hypothyroidism.

Topics: Amino Acid Transport System X-AG; Analysis of Variance; Animals; Animals, Newborn; Brain; Cerebral Cortex; Congenital Hypothyroidism; Disease Models, Animal; Down-Regulation; Female; Gene Expression Regulation, Developmental; In Vitro Techniques; Intermediate Filaments; Male; Mitogen-Activated Protein Kinase Kinases; Phosphates; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Protein Binding; Radioligand Assay; Rats; Rats, Wistar

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

Topics: Aging; Animals; Disease Models, Animal; DNA, Intergenic; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Heart Ventricles; Hypothyroidism; Myocardium; Myosin Heavy Chains; Promoter Regions, Genetic; Propylthiouracil; Rats; RNA, Antisense; RNA, Messenger; Time Factors; Transcription Initiation Site; Transcription, Genetic; Triiodothyronine; Ventricular Myosins

Differentiation of adult Leydig cells (ALC) in the prepubertal rat testis is stimulated by thyroid hormone (Thy) and inhibited by the Anti-Mullerian Hormone (AMH) produced by the immature Sertoli cell (SC). As Thy induces SC maturation in the prepubertal rat testis, we hypothesized that Thy stimulation of ALC differentiation is mediated via inhibition of AMH production by the SC with their maturation. If this hypothesis is true, AMH production by the prepubertal Sertoli cells in hypothyroid rats should not decline immediately after birth as in euthyroid rats, but should be maintained throughout the hypothyroid period at a similar or higher level to that of day 1 rats. This concept was tested using control rats of postnatal days (pd) 1, 7 and 14 and hypothyroid (fed 0.1% propyl thiouracil/PTU to lactating mothers) rats of pd7 and pd14. Presence of AMH in SC was examined by immunocytochemistry for AMH. Results demonstrated that testes of pd1 rats had intense AMH positive labeling exclusively in cytoplasm of SC. In testes of pd7 and pd14 control and PTU rats, a positive but weak labeling was also observed in cytoplasm of some SC; Germ cells and testicular interstitial cells were negative for AMH at all tested ages in both experimental groups. These findings suggest that AMH production by the prepubertal SC is independent of Sertoli cell maturation and not regulated by Thy. Therefore, Thy regulation of ALC differentiation in the prepubertal rat testis is unlikely to be mediated via inhibition of AMH produced by the SC with their maturation.

Topics: Animals; Animals, Newborn; Animals, Suckling; Anti-Mullerian Hormone; Antithyroid Agents; Cell Differentiation; Cytoplasm; Disease Models, Animal; Female; Hypothyroidism; Immunohistochemistry; Lactation; Leydig Cells; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sertoli Cells; Sexual Maturation; Testis

It has been known that an intact thyroid hormone is obligatory for the attainment of the normal masticatory function at the time of weaning. Following induced maternal thyroid hypo-function, the development of masseter motoneurons was determined at postnatal days 1, 7, 15 and 23 (weaning time), using retrograde transport of horseradish peroxidase (HRP) in the normal and hypothyroid pups. Based on the HRP labeling profile (strong and weak), the soma area of the masseteric labeled motoneurons was measured in each group. No significant morphological differences were observed at the end of the first week of life. On day 15, hypothyroid masseteric labeled motoneurons consisted of 76% small and 24% medium-sized neurons compared to 58% and 42% in normal pups, respectively. At the time of weaning (i.e., day 23) the number of large masseter motoneurons reached to 1/3 of normal value with few, short and disoriented dendrites in the hypothyroid pup. There was no statistically significant difference in the uptake of HRP from the neuromuscular junction. These results suggest that neonatal thyroid hormone deficiency considerably postponed the development of feeding behavior from sucking to chewing and biting.

Topics: Animals; Animals, Newborn; Cell Enlargement; Cell Shape; Cell Size; Congenital Hypothyroidism; Dendrites; Disease Models, Animal; Feeding Behavior; Horseradish Peroxidase; Male; Mandibular Nerve; Masseter Muscle; Mastication; Motor Neurons; Neuromuscular Junction; Pons; Propylthiouracil; Rats; Rats, Sprague-Dawley; Stomatognathic System; Thyroid Gland; Thyroid Hormones; Trigeminal Nerve Diseases

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

Similar to cretinism in human children, absence or deficiency of thyroid hormones in rats and mice during early postnatal development results in marked retardation of brain development along with behavioral and cognitive deficits. Less is known about brain recovery from postnatal hypothyroidism. [Farahvar, A., Meisami, E., 2007. Novel two-dimensional morphometric maps and quantitative analysis reveal marked growth and structural recovery of the rat hippocampal regions from early hypothyroid retardation. Experimental Neurology.] found, by means of morphometric maps, that surface areas of hippocampal cortex and its CA1-CA4 regions which were significantly reduced in developing hypothyroid rats, show nearly complete growth recovery upon restoration of thyroid function. Here we explore the ability of hippocampal synapse-rich neuronal fiber layers to show recovery from early hypothyroid growth retardation. Rat pups were made hypothyroid from birth to day 25 (weaning) or up to young adulthood (day 90) by a treatment with the reversible goitrogen, PTU (n-propylthiouracil), in the drinking water. Recovery was induced by withdrawal of PTU at weaning and analysis of cytochrome oxidase (CytOx)-stained serial sections of the hippocampus and dentate gyrus at the ages of 25 and 90 days. CytOx stains the synapse-rich fiber layers of the hippocampal formation (HCF). Volumetric growth of molecular layer, stratum oriens and radiatum and dentate hilar region showed complete or nearly complete recovery from marked and significant growth retardation induced by early postnatal hypothyroidism. Also the reduced CytOx staining intensity in the hypothyroid rat HCF layers showed marked recovery following hormonal restoration. Results indicate remarkable growth plasticity of the HCF and ability of the synapse-rich fiber layers to show complete recovery of metabolic and functional neural activity from deleterious effects of early hypothyroidism. Mitochondrial CytOx is highly localized to the synapse-rich fiber layers of the HCF and its activity and histochemical staining intensity correlates positively with functional metabolic activity of neural tissue. Thus hippocampus and dentate gyrus neuronal fiber layers and their oxidative activity show remarkable ability to recover from the postnatal hypothyroid growth retardation. The results indicate that some brain regions are less vulnerable to early developmental insults and can recover.

Topics: Age Factors; Animals; Animals, Newborn; Diagnostic Imaging; Disease Models, Animal; Electron Transport Complex IV; Female; Gene Expression Regulation, Developmental; Hippocampus; Hypothyroidism; Male; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Recovery of Function; Thyroid Gland; Thyroid Hormones

The effects of sarcomere length (SL) on sarcomeric loaded shortening velocity, power output and rates of force development were examined in rat skinned cardiac myocytes that contained either alpha-myosin heavy chain (alpha-MyHC) or beta-MyHC at 12 +/- 1 degrees C. When SL was decreased from 2.3 microm to 2.0 microm submaximal isometric force decreased approximately 40% in both alpha-MyHC and beta-MyHC myocytes while peak absolute power output decreased 55% in alpha-MyHC myocytes and 70% in beta-MyHC myocytes. After normalization for the fall in force, peak power output decreased about twice as much in beta-MyHC as in alpha-MyHC myocytes (41% versus 20%). To determine whether the fall in normalized power was due to the lower force levels, [Ca(2+)] was increased at short SL to match force at long SL. Surprisingly, this led to a 32% greater peak normalized power output at short SL compared to long SL in alpha-MyHC myocytes, whereas in beta-MyHC myocytes peak normalized power output remained depressed at short SL. The role that interfilament spacing plays in determining SL dependence of power was tested by myocyte compression at short SL. Addition of 2% dextran at short SL decreased myocyte width and increased force to levels obtained at long SL, and increased peak normalized power output to values greater than at long SL in both alpha-MyHC and beta-MyHC myocytes. The rate constant of force development (k(tr)) was also measured and was not different between long and short SL at the same [Ca(2+)] in alpha-MyHC myocytes but was greater at short SL in beta-MyHC myocytes. At short SL with matched force by either dextran or [Ca(2+)], k(tr) was greater than at long SL in both alpha-MyHC and beta-MyHC myocytes. Overall, these results are consistent with the idea that an intrinsic length component increases loaded crossbridge cycling rates at short SL and beta-MyHC myocytes exhibit a greater sarcomere length dependence of power output.

Topics: Animals; Calcium; Cell Size; Dextrans; Disease Models, Animal; Hypothyroidism; Isometric Contraction; Male; Muscle Strength; Myocardial Contraction; Myocytes, Cardiac; Myofibrils; Myosin Heavy Chains; Osmosis; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sarcomeres; Thyroidectomy

1. Hypothyroidism is accompanied by hyperlipidaemia and oxidative stress and is associated with several complications, such as atherosclerosis. Paraoxonase activity has been reported to decrease in several situations associated with atherosclerosis and oxidative stress. In the present study, the effects of different doses of taurine on serum paraoxonase and arylesterase activities, as well as on the serum lipid profile, were investigated in hypothyroid rats. 2. Forty male Sprague-Dawley rats were randomly divided into five groups as follows: Group 1, rats received normal rat chow and tap water; Group 2, rats received standard rat chow + 0.05% propylthiouracil (PTU) in the drinking water; and Groups 3-5, taurine-supplemented PTU groups (standard rat chow + 0.5, 2 or 3% taurine in the drinking water, respectively, in addition to PTU). Paraoxon or phenylacetate were used as substrates to measure paraoxonase and arylesterase activity, respectively. Plasma and tissue malondialdehyde (MDA) levels, indicators of lipid peroxidation, were determined using the thiobarbituric-acid reactive substances method. Serum triglyceride, total cholesterol and high-density lipoprotein-cholesterol (following precipitation with dextran sulphate-magnesium chloride) were determined using enzymatic methods. 3. Serum paraoxonase and arylesterase activities were increased and plasma and tissue MDA levels and serum triglyceride levels were reduced in a dose-dependent manner in taurine-treated hypothyroid rats. Taurine concentrations were positively correlated with enzyme activities and negatively correlated with MDA and triglyceride levels. 4. Further studies are needed to investigate the role of taurine supplementation in hypothyroidism in human subjects.

Topics: Animals; Antioxidants; Aryldialkylphosphatase; Carboxylic Ester Hydrolases; Cholesterol; Cholesterol, HDL; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Hypothyroidism; Lipid Peroxidation; Male; Malondialdehyde; Paraoxon; Phenylacetates; Propylthiouracil; Rats; Rats, Sprague-Dawley; Taurine; Triglycerides; Up-Regulation

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Autoimmunity; Disease Models, Animal; Graves Disease; Humans; Male; Middle Aged; Peroxidase; Propylthiouracil; Vasculitis

The aim of this study was to evaluate in vivo the antiproliferative effect of an inhibitor of isoprenoids metabolism, lovastatin, in an experimental model of propylthiouracil-induced goiter. In thyroid cells, thyrotropin (TSH)-induced proliferation requires active isoprenoid synthesis, and the HMG-CoA reductase inhibitors have antiproliferative effects in vitro. Propylthiouracil treatment (PTU) of rats led to thyroid hypertrophy and hyperplasia by TSH-induced activation of the mitogen-activated protein kinase (MAPK) pathway. Immunohistochemistry showed an increased number of proliferating cell nuclear antigen (PCNA)-positive cells in the thyroid gland of PTU-treated rats. Moreover, the phosphorylation of ERK1 and ERK2 was increased in the extract from goiter tissue as compared with the thyroid tissue of untreated rats. To determine whether the inhibition of selected pro-survival pathways (i.e., p21ras-MAPK) was sufficient to affect goitrogenesis, thyroids from 12 PTU-treated rats were injected in vivo with an adenovirus transducing a dominant-negative ras gene (Rad-L61.S186) and another set of 12 rats were injected with a pharmacological inhibitor of MAPK (PD98059). Both Rad-L61.S186 and PD98059 were able to inhibit the PTU-induced goiter. It is interesting to note that lovastatin, when administered in drinking water, significantly prevented the thyroid gland enlargement. Therefore, lovastatin-treated thyroid glands were significantly smaller than those treated with PTU alone. In addition, the lovastatin-treated glands also showed a decreased expression of phosphorylated ERK1/2 and a number of PCNA-positive cells. Our data suggest that lovastatin is an efficient inhibitor of goitrogenesis and provide a rationale for innovative therapeutic strategies employing statins in the treatment of nodular goiter in humans.

Topics: Animals; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Gene Transfer Techniques; Goiter; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperplasia; Hypertrophy; Lovastatin; Male; MAP Kinase Signaling System; Phosphorylation; Proliferating Cell Nuclear Antigen; Propylthiouracil; Protein Kinase Inhibitors; Protein Prenylation; ras Proteins; Rats; Rats, Wistar; Terpenes; Thyroid Gland; Thyrotropin

The most important goal in the treatment of cryptorchidism is to preserve the potential for fertility. This experimental study was performed to investigate the effect of propylthiouracil (PTU) on the undescended testes (UTs) of newborn rats.. The experimental cryptorchidism model in newborn male rats consisted of 4 groups. The groups A (control) and B (PTU) underwent no surgical intervention, whereas in groups C (UT only) and D (treatment) UTs were produced by dissecting and suturing the future right scrotal area. In groups D and B, 0.1% (w/v) PTU was added to the drinking water of mother rats between 2 and 24 days. At the end of the 90th day rat body weights, testicular weights, Johnsen tubular biopsy scores (JTBSs), seminiferous tubule diameters (STDs), testosterone, and thyroid hormone levels were measured. Mann-Whitney U test was used for statistical analysis.. Mean testicular weight was similar between groups A, B and D, and statistically lowest in group C. Mean body weight was statistically higher in groups A and C compared with groups B and D. Mean testosterone levels showed no statistical difference between the groups. Mean JTBSs were statistically higher in groups A and B compared with groups C and D. The value in treatment group D was statistically higher compared to group C (p<0.05). Mean STDs were statistically lowest in group C compared to other groups (p<0.05). No difference was found between groups A, B, and D (p>0.05). Both the mean free triiodothyronine and free thyroxine values between groups A and C and between groups B and D were similar. The values in groups A and C were statistically higher than those of groups B and D (p<0.05).. PTU-induced transient hypothyroidism in the newborn rat UT model shows protective effects on testicular growth parameters.

Topics: Animals; Animals, Newborn; Antimetabolites; Biopsy; Cryptorchidism; Disease Models, Animal; Follow-Up Studies; Male; Propylthiouracil; Rats; Rats, Wistar; Testosterone; Treatment Outcome

Literature has reported a controversy concerning the effects of the environmental pollutant perchlorate on pertinent physiological systems. However, no research to date has evaluated the effect of concomitant consumption of perchlorate and an additional environmental contaminant on physiological systems. The present preliminary investigation served to assess the effects of oral consumption of perchlorate, alone and in combination with ethanol, on thyroid hormone and brain catecholamine concentrations in female rats of gestational age. Forty, female Myers' high ethanol-preferring rats were randomly assigned to 1 of 7 groups that received: (1) deionized water, both bottles (2) deionized water and 10% ethanol (v/v), two separate bottles (3) 300 microg/l perchlorate solution in deionized water, both bottles (4) 300 microg/l perchlorate in deionized water and in 10% ethanol (v/v), two separate bottles (5) 3000 microg/l perchlorate solution in deionized water, both bottles (6) 3000 microg/l perchlorate in deionized water and in 10% ethanol (v/v), two separate bottles (7) 0.01% propylthiouracil solution in deionized water, both bottles. At cessation of the treatment period, plasma triiodothyronine (T3) and thyroxine (T4) levels were measured by radioimmunoassay and brain area concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and norepinephrine were measured by high performance liquid chromatography. Perchlorate consumption, alone and/or in combination with ethanol consumption, failed to produce significant alterations from control values for triiodothyronine, thyroxine, dopamine, DOPAC, or norepinephrine. The data suggest that the no-observed effect level of perchlorate consumption on thyroid hormone and brain catecholamine concentrations is above the 3000 microg/l concentration in the adult female rat.

Topics: Alcohol-Induced Disorders, Nervous System; Animals; Animals, Outbred Strains; Brain; Brain Chemistry; Catecholamines; Chromatography, High Pressure Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Environmental Pollutants; Ethanol; Female; Perchlorates; Propylthiouracil; Rats; Thyroid Hormones

This work aimed at verifying the influence of propyl-thiouracil (PTU)-induced thyroid hormone deficiency on gingival mucosa of young male rats, measuring total protein concentration, collagen content and DNA concentration as indices of cellular population. Fifty Sprague-Dawley rats were used. The animals were grouped in: PTU-treated (i.p. 10 mg/d) and control rats (C). The experience was maintained for a period of 10 weeks. Total protein content of gingival mucosa tissue was determined by the Lowry method; hydroxyprolin rate, as prototype amino acid of collagen, was determined using the Newman method, and DNA concentration was measured by Burton's methodology. The results showed decreased amounts of PTU-treated rats gingival total protein content (PTU= 41.23 +/- 24.05 vs. C= 63.36 +/- 18.05); no alterations were seen in hydroxyprolin concentration neither in DNA content of PTU treated rats, respectively (PTU= 2.18 +/- 1.48 vs. C= 2.29 +/- 1.51) and (PTU= 0.33 +/- 0.19 vs. C= 0.46 +/- 0.41). Thus, PTU treatment promotes a decrease in total protein content of rat gingival mucosa that may be interpreted as a decrease in protein synthesis induced by the hypothyroid condition, but with no alteration either in collagen or nucleic acid rates.

Topics: Animals; Antithyroid Agents; Collagen; Colorimetry; Disease Models, Animal; DNA; Gingiva; Hydroxyproline; Hypothyroidism; Male; Propylthiouracil; Proteins; Rats; Rats, Sprague-Dawley; Spectrophotometry; Thyroxine; Triiodothyronine

We have previously reported that thyroid capsular inflammation induced by sulfadimethoxine (SDM), a goitrogen, might play a role in development of invasive follicular cell adenocarcinomas in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). The present study was designed to examine the role of cyclooxygenase (COX)-2, widely known to be up-regulated in inflammatory states, during chemically induced rat thyroid carcinogenesis. Male F344 rats received a subcutaneous DHPN (2800 mg/kg) injection, and 1 week later were allowed free access to drinking water containing antithyroidal propylthiouracil (PTU, 0.003%) or SDM (0.1%) for 4 or 10 weeks. Control groups receiving goitrogen alone and no treatment were also included. At week 4, diffuse follicular cell hyperplasia was induced in all PTU- and SDM-treated groups, along with fibrous capsular thickening and capsular thickening with inflammation, respectively. Additionally, multiple focal follicular cell hyperplasias and adenomas were observed in the DHPN + PTU and DHPN + SDM cases. At week 10, adenocarcinomas invasive to the capsule and restricted to the capsular adjacent region, were frequent in the DHPN + SDM group, but not observed in the animals given DHPN + PTU. Western blots and immunohistochemistry revealed constitutive COX-2 expression in non-neoplastic follicular cells of the control and all of the PTU- and SDM-treated rats. However, COX-2 reactivity was significantly reduced or negative in the preneoplastic/neoplastic lesions in the DHPN-treated groups. In fibrous or inflamed thickened capsules, only a few component cells with inflammatory elements were positive for COX-2, and there was no significant difference in this regard between the PTU and SDM treatments. The present results suggest that capsular inflammation could play a role in development of invasive carcinomas, but COX-2 expression does not make a major contribution.

Topics: Adenocarcinoma, Follicular; Animals; Anti-Infective Agents; Antithyroid Agents; Blotting, Western; Carcinogens; Cyclooxygenase 2; Disease Models, Animal; Enzyme Inhibitors; Immunohistochemistry; Inflammation; Iodide Peroxidase; Male; Nitrosamines; Propylthiouracil; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; Sulfadimethoxine; Thyroid Neoplasms

Thyroid hormones are critical for the development and maturation of the central nervous system. Insufficiency of thyroid hormones during development impairs performance on tasks of learning and memory that rely upon the hippocampus and impairs synaptic function in young hypothyroid animals. The present study was designed to determine if perturbations in synaptic function persist in adult euthyroid animals exposed developmentally to insufficient levels of hormone. Pre- and postnatal thyroid hormone insufficiency was induced by administration of 3 or 10 ppm propylthiouracil (PTU) to pregnant and lactating dams via the drinking water from gestation day (GD) 6 until postnatal day (PN) 30. This regimen produced a graded level of hormonal insufficiency in the dam and the offspring. Population spike and population excitatory postsynaptic potentials (EPSP) were recorded at the pyramidal cell layer and the stratum radiatum, respectively, in area CA1 of hippocampal slices from adult male offspring. PTU exposure increased baseline synaptic transmission, reduced paired-pulse facilitation, and increased the magnitude of the population spike long-term potentiation (LTP). Phosphorylation of the extracellular signal-regulated kinases (ERK1 and ERK2) was increased as a function of LTP stimulation in slices from PTU-exposed adult animals. On the other hand, no differences in the basal levels of synaptic proteins implicated in synaptic plasticity (total ERK, synapsin, growth-associated protein-43, and neurogranin) were detected. These results reinforce previous findings of persistent changes in synaptic function and, importantly extend these observations to moderate levels of thyroid hormone insufficiency that do not induce significant toxicity to the dams or the offspring. Such alterations in hippocampal synaptic function may contribute to persistent behavioral deficits associated with developmental hypothyroidism.

Topics: Animals; Antithyroid Agents; Blotting, Western; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Female; Hippocampus; Hypothyroidism; Lactation; Long-Term Potentiation; Nerve Tissue Proteins; Phosphorylation; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Long-Evans; Synaptic Transmission; Thyroid Hormones

Thyroid hormone is essential for the proper development of the mammalian central nervous system (CNS). In the present study, we examined behavioural alterations caused by transient perinatal hypothyroidism induced by an anti-thyroid drug, propylthiouracil (PTU). This drug produces perinatal disruption of the thyroid system and subsequent behavioural changes, which we investigated using a series of behavioural tests and focusing particularly on attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In the open field test, both male and female rats that had experienced perinatal hypothyroidism (HT rats) showed an increased percent of locomotion behaviour and reduced grooming behaviour, suggesting that HT rats may be hyperactive and show fewer anxiety characteristics. Neither male nor female HT rats showed retention in the passive avoidance test. Male HT rats showed a significantly lower rate of correct avoidance responses than control rats in earlier sessions in the active avoidance test. In addition, we observed significant increases in the number of times that rats crossed the partition during inter-trial intervals and the percent of failure of avoidance during 5 s electrical stimuli in HT rats, suggesting that HT rats are restless, have a shortened attention span and panic easily. In measuring spontaneous motor activity during a period of darkness, male HT rats appeared to plunge into active phase with short, quick steps, while male control rats showed only long active phases during a stress-free period of darkness. These abnormal behavioural characteristics in HT rats might coincide with those found in some cases of ADHD.

Topics: Animals; Attention; Attention Deficit Disorder with Hyperactivity; Avoidance Learning; Disease Models, Animal; Exploratory Behavior; Female; Hypothyroidism; Male; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats

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

To evaluate the effect of a hypothyroid state, induced by chronic propylthiouracil administration, on splanchnic and systemic hemodynamic parameters in rats with portal hypertension due to portal vein ligation.. Portal hypertension was induced by surgical stenosis of the portal vein. Cardiac index and portal blood flow were measured using radioactive microspheres. Measurements were performed after treatment with propylthiouracil (1 mg/ml in drinking water) for 5 days.. Propylthiouracil-treated portal hypertensive rats had a lower portal pressure (12.4 +/- 1.9 versus 16.3 +/- 0.7 mmHg; p < 0.05) and portal blood flow (11.6 +/- 0.7 versus 13.2 +/- 1.3 ml/min/100 g; p < 0.05) than non-treated animals. Splanchnic vasoconstriction in treated animals was associated with a higher peripheral vascular resistance (2.3 +/- 0.4 versus 1.8 +/- 0.3 mmHg/ml/min/100 g; p < 0.05) than controls.. These results suggest that portal pressure can be lowered by inducing a hypothyroid state by chronic administration of propylthiouracil.

Topics: Animals; Antithyroid Agents; Disease Models, Animal; Hemodynamics; Hypertension, Portal; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Splanchnic Circulation; Vasoconstriction

There exists a need for better diagnostic tests to characterise thyroid disease in horses. Currently available diagnostic tests fail to differentiate between thyroid gland disorders and thyroid abnormalities resulting from pituitary or hypothalamic problems.. To evaluate the effects of treatment with propylthiouracil (PTU) and bromocryptine (BROM) on serum concentrations of triiodothyronine (T3), thyroxine (T4), reverse T3 (rT3) and equine thyroid-stimulating hormone (e-TSH, thyrotrophin) in mature horses.. Healthy mature horses were treated using either PTU or BROM for 28 days. The effect of treatment on the thyroid axis was assessed by measuring T3, T4, rT3 and e-TSH before and at +14 and +28 days. The effect of PTU and BROM on the response of T3, T4, rT3 and e-TSH to thyrotrophin-release hormone (TRH) administration was also assessed before and at +14 and +28 days of treatment.. Treatment with PTU led to a significant reduction in serum concentrations of T3, T4 and rT3 on Day 28 and increase of e-TSH on Day 28 (P < 0.05). Treatment with BROM did not cause any measurable effect on serum concentrations of T3, T4, rT3 or e-TSH. The percentage increment by which serum concentration of T4, T3 and e-TSH increased following stimulation with TRH was decreased by treatment with PTU for 28 days (P < 0.05) but were not affected by treatment with BROM for 28 days.. These results suggest that 1) treatment with PTU may be used in horses as a model of primary hypothyroidism; 2) the use of BROM as a model of secondary hypothyroidism in horses is not supported; and 3) e-TSH assay deserves further investigation for the clinical diagnosis of thyroid axis dysfunction in horses.. Propylthiouracil effectively causes primary hypothyroidism. There is substantial variability between horses with respect to their sensitivity to this substance when administered orally. Further studies pertaining to the characterisation of equine thyroid disorders are warranted and the use of both PTU for the experimental induction of primary hypothyroidism and e-TSH for the diagnostic characterisation of thyroid disorders in horses should be considered.

Topics: Animals; Antithyroid Agents; Bromocriptine; Disease Models, Animal; Female; Hormone Antagonists; Horse Diseases; Horses; Hypothyroidism; Propylthiouracil; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine

Hypothyroidism is associated with impaired blood flow to skeletal muscle under whole body exercise conditions. It is unclear whether poor cardiac and/or vascular function account for blunted muscle blood flow. Our experiment isolated a small group of hindlimb muscles and simulated exercise via tetanic contractions. We hypothesized that muscle blood flow would be attenuated in hypothyroid rats (HYPO) compared with euthyroid rats (EUT). Rats were made hypothyroid by mixing propylthiouracil in their drinking water (2.35 x 10-3 mol/l). Treatment efficacy was evidenced by lower serum T3 concentrations and resting heart rates in HYPO (both P<0.05). In the experimental preparation, isometric contractions of the lower right hindlimb muscles at a rate of 30 tetani/min were induced via sciatic nerve stimulation. Regional blood flows were determined by the radiolabelled microsphere method at three time points: rest, 2 min of contractions and 10 min of contractions. Muscle blood flow generally increased from rest ( approximately 5-10 ml/min per 100 g) through contractions for both groups. Further, blood flow during contractions did not differ between groups for any muscle (eg. red section of gastrocnemius muscle; EUT, 59.9 +/- 14.1; HYPO, 61.1 +/- 15.0; NS between groups). These findings indicate that hypothyroidism does not significantly impair skeletal muscle blood flow when only a small muscle mass is contracting. Our findings suggest that impaired blood flow under whole body exercise is accounted for by inadequate cardiac function rather than abnormal vascular function.

Topics: Animals; Disease Models, Animal; Heart Rate; Hindlimb; Hypothyroidism; Male; Microspheres; Muscle Contraction; Muscle, Skeletal; Physical Exertion; Propylthiouracil; Random Allocation; Rats; Rats, Sprague-Dawley; Regional Blood Flow

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

Thyroid status is crucial in energy homeostasis, but despite extensive studies the actual mechanism by which it regulates mitochondrial respiration and ATP synthesis is still unclear. We studied oxidative phosphorylation in both intact liver cells and isolated mitochondria from in vivo models of severe not life threatening hyper- and hypothyroidism. Thyroid status correlated with cellular and mitochondrial oxygen consumption rates as well as with maximal mitochondrial ATP production. Addition of a protonophoric uncoupler, 2,4-dinitrophenol, to hepatocytes did not mimic the cellular energetic change linked to hyperthyroidism. Mitochondrial content of cytochrome oxidase, ATP synthase, phosphate and adenine nucleotide carriers were increased in hyperthyroidism and decreased in hypothyroidism as compared to controls. As a result of these complex changes, the maximal rate of ATP synthesis increased in hyperthyroidism despite a decrease in ATP/O ratio, while in hypothyroidism ATP/O ratio increased but did not compensate for the flux limitation of oxidative phosphorylation. We conclude that energy homeostasis depends on a compromise between rate and efficiency, which is mainly regulated by thyroid hormones.

Topics: Adenosine Triphosphate; Animals; Disease Models, Animal; Electron Transport Complex IV; Hepatocytes; Hyperthyroidism; Hypothyroidism; Mitochondria, Liver; Oxidative Phosphorylation; Oxygen Consumption; Propylthiouracil; Proton Pumps; Rats; Rats, Wistar; Thyroid Gland

Several anecdotal reports indicate that cancer may occasionally remain in a dormant state for prolonged periods in patients with hypothyroidism. Once the hypothyroid state is recognized and supplementation therapy with thyroid hormones is initiated, disease progression occurs. In this experiment, 6-n-propyl-2-thiouracil (PTU) was added to the water of athymic nude mice. The animals were subsequently inoculated with cells from a human prostate cancer cell line.. The growth rate of subcutaneously implanted prostate xenografts was significantly slower in mice treated with PTU compared with mice that did not receive PTU. In a separate experiment, tritiated thymidine incorporation assays were performed in DU145 and PC3 human prostate cancer cells with and without PTU. No significant differences were observed, indicating that PTU did not exert any antitumor effect in vitro.. Our study demonstrates that PTU inhibits the growth of human prostate tumors in nude mice via an indirect effect. This antitumor effect may be caused by hypothyroidism. This is the first in vivo study suggesting potential therapeutic applications for thyroid hormone manipulations in human cancer of the prostate. Further studies will determine growth kinetics of xenotransplanted prostate cancer in vitro and in vivo. PTU-induced hypothyroidism may be further explored in conjunction with other antineoplastic therapy.

Topics: Animals; Antimetabolites, Antineoplastic; Contrast Media; Disease Models, Animal; Humans; Hypothyroidism; Male; Mice; Mice, Nude; Propylthiouracil; Prostatic Neoplasms; Thymidine; Thyroid Hormones; Transplantation, Heterologous; Tumor Cells, Cultured

Congenital hypothyroidism results in deafness that is caused by changes in the auditory receptor, including scanty development of the outer hair cells and a lack of synaptogenesis between these cells and the efferent system. although the afferent population is present. The normal efferent innervation of the cochlea originates in the superior olivary complex, arising from efferent neurons belonging to the lateral or to the medial olivocochlear system. In the rat, the former is constituted by neurons located in the lateral superior olivary nucleus, that project to the inner hair cells, while the later originates in the ventral nuclei of the trapezoid body and project to the outer hair cells. The aim of this work is to study the localization, number and morphology of the olivochochlear neurons in congenital hypothyroid animals by means of the injections of the retrograde tracers, either fast blue or cholera toxin, in the cochlea. The mean total number of labeled olivocochlear neurons after injection of fast blue in hypothyroid animals was 1,016, and in control ones was 1,027. Using cholera toxin, the mean total number of labeled olivocochlear neurons was slightly lower: 863 in hypothyroid animals versus 910 in control ones. Although both tracers showed no significant differences between groups, when the somatic area of the labeled olivocochlear neurons is considered, the size of all of the three different population of cells (lateral olivocochlear neurons, medial olivocochlear neurons and shell neurons) was significantly lower in the hypothyroid rats. This is the first study of the olivocochlear neurons in hypothyroid animals. The conclusion from this work is that in hypothyroid rats the labeled olivocochlear neurons are significantly smaller but that there is not any modification in the localization and number of the labeled olivocochlear neurons, suggesting that thyroid hormones are necessary for the neuronal growth. However, most of the medial olivocochlear neurons do not make contact with their target, so their maintenance suggests that the axons are in contact with other structures of the cochlea.

Topics: Abnormalities, Drug-Induced; Afferent Pathways; Amidines; Animals; Cholera Toxin; Cochlea; Cochlear Nucleus; Congenital Hypothyroidism; Disease Models, Animal; Female; Fluorescent Dyes; Hypothyroidism; Olivary Nucleus; Pregnancy; Propylthiouracil; Rats; Rats, Wistar

In hypothyroid rats, partial hepatectomy does not induce liver regeneration until 120 h after surgical operation. when, instead, in normal rats a complete recovery of the liver mass, in this interval, is observed. In normal rats, a good efficiency of mitochondrial oxidative phosphorylation is needed as an energy source for liver regeneration (Guerrieri, F. et al., 1995); in hypothyroid rats the efficiency of mitochondrial oxidative phosphorylation is low in the 0-120 h interval after partial hepatectomy. This low efficiency of oxidative phosphorylation appears to be related to a low mitochondrial content of F0F1-ATP synthase, in liver of hypothyroid rats, which does not recover after partial hepatectomy. In the liver of hypothyroid rats, low levels of the nuclear-encoded mitochondrial catalytic betaF1 subunit and of its transcript are observed and they do not increase, as occurs in normal rats, after partial hepatectomy.

Topics: Adenosine Triphosphate; Animals; Antithyroid Agents; Disease Models, Animal; Gene Expression; Hepatectomy; Hypothyroidism; Liver; Liver Regeneration; Male; Mitochondria, Liver; Propylthiouracil; Proton-Translocating ATPases; Rats; Rats, Wistar; Time Factors

Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart compensates for myofibril degeneration, transgenic mice were created that undergo progressive loss of myofibrils after birth. Myofibril degeneration was induced by overexpression of tropomodulin, a component of the thin filament complex which determines and maintains sarcomeric actin filament length. The tropomodulin cDNA was placed under control of the alpha-myosin heavy chain gene promoter to overexpress tropomodulin specifically in the myocardium. Offspring with the most severe phenotype showed cardiomyopathic changes between 2 and 4 wk after birth. Hearts from these mice present characteristics consistent with dilated cardiomyopathy and a failed hypertrophic response. Histological analysis showed widespread loss of myofibril organization. Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and alpha-actinin reactivity at Z discs. Contractile function was compromised severely as determined by echocardiographic analyses and isolated Langendorff heart preparations. This novel experimentally induced cardiomyopathy will be useful for understanding dilated cardiomyopathy and the effect of thin filament-based myofibril degeneration upon cardiac structure and function.

Topics: Animals; Antimetabolites; Cardiomyopathy, Dilated; Carrier Proteins; Disease Models, Animal; Gene Expression; Hemodynamics; Mice; Mice, Transgenic; Microfilament Proteins; Myocardial Contraction; Myofibrils; Propylthiouracil; Tropomodulin

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

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 effect of pre and postnatal hypothyroid environment on the development of cerebellum in the rat pups was determined. Four groups of rat dams, namely control, Group I, II and III were treated with propylthiouracil (PTU) in water for different length of time during pregnancy and nursing periods. The pups born from these dam groups were subsequently named after the corresponding dam group, namely control, Group I, II and III. General quantitative results showed that pups from the treated dams had significantly lower (p < 0.05) body weights compared to control pups. Cerebella from five day old pups were taken and structural changes estimated using unbiased "design based" stereological methods, which have made it possible to investigate specific qualities in the organ. The total volumes of cerebellum and intracerebellar nuclei were estimated using Cavalieri Principle. The mean total volume of cerebellum and the mean total volume of intracerebellar nuclei were significantly lower (p < 0.05) in all the pup groups (I, II, III) from the treated dams compared to control pups from the control dams. The cerebellar volume decreased in relation to the duration of treatment. The mean ratio of the total volume of intracerebellar nuclei to volume of cerebellum was significantly increased (p < 0.05) in Group III pups compared to control and Group I pups. The mean numerical density of neurones in the intracerebellar nuclei was nearly equal in all the pup groups except in Group III pups whereby it was increased. The mean total number of neurones in Groups I and II pups was reduced, but did not reach statistical significance. The mean numerical density of neuroglia in the intracerebellar nuclei was nearly the same in all the pup groups, the mean total number of glial cells was significantly reduced (p < 0.05) in Groups I and II pups compared to control and the mean neuron/glial ratio was increased in Group III pups compared to control and other treated groups. Thus, the neuroglia appear to be more sensitive to hypothyroidism than neurons. The above results show that PTU-induced hypothyroidism causes reduction in structural parameters in developing cerebellum and confirm that growth and maturation of the foetal cerebellum is dependent on the maintenance of normal T4 and T3 levels in the pregnant dam and developing pups during pre and postnatal stages of development.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Cerebellum; Disease Models, Animal; Embryonic and Fetal Development; Female; Hypothyroidism; Male; Neurons; Organ Size; Pregnancy; Pregnancy Complications; Propylthiouracil; Rats; Rats, Wistar; Thyroxine; Triiodothyronine

Reports of the coexistence of hyperparathyroidism and thyroid disease have raised the issue of a possible etiologic relationship. The present study tests the hypothesis that chronic elevation of thyroid-stimulating hormone (TSH) is related to the development of hyperparathyroidism. Four groups of 60 female rats were treated as follows: group 1, control; group 2, propylthiouracil (PTU) 0.0025%; group 3, PTU 0.0025% plus thyroxine, 5 microg two times per week; and group 4, only thyroxine. The animals' serum calcium, phosphorus, TSH, thyroxine, and parathyroid hormone (PTH) levels were evaluated at 0, 6, 12, and 18 months. Significant elevation of TSH was sustained throughout the 18 months in groups 2 and 3. The PTH levels were also significantly elevated in both group 2 and group 3 animals (P = 0.02). The histopathologic features of the parathyroids were evaluated at 18 months. In the group 2 (PTU only) animals, which had profound hypothyroid, 44% developed parathyroid adenomas. In the group 3 (PTU plus thyroxine) animals, who had mildly elevated TSH levels, 53% developed parathyroid adenomas. These findings are consistent with the hypothesis that prolonged TSH stimulation may lead to hyperparathyroidism in the rat model.

Topics: Adenoma; Animals; Antithyroid Agents; Calcium; Chronic Disease; Disease Models, Animal; Female; Hyperparathyroidism; Hyperplasia; Hypothyroidism; Parathyroid Glands; Parathyroid Hormone; Parathyroid Neoplasms; Phosphorus; Propylthiouracil; Rats; Rats, Sprague-Dawley; Survival Rate; Thyroid Gland; Thyrotropin; Thyroxine

Cats are known to develop a lupus-like syndrome similar to that observed in humans when treated with propylthiouracil. We have previously demonstrated that propylthiouracil and other drugs associated with lupus are oxidized in the presence of myeloperoxidase to reactive intermediates. We postulated that these reactive metabolites could modify myeloperoxidase resulting in anti-myeloperoxidase antibodies and possibly be responsible for the lupus-like syndrome. Five cats were treated with propylthiouracil and 2 developed the lupus-like syndrome as well as anti-myeloperoxidase antibodies. These appeared to correlate better with disease than antinuclear antibodies. The antibodies were true autoantibodies because the myeloperoxidase used to detect the antibodies did not require treatment with propylthiouracil. In a subsequent study in which the cat food contained a higher level of taurine, none of the animals developed the autoimmune syndrome. It is possible that diet also plays an important role in the development of such adverse reactions.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Autoimmune Diseases; Cats; Disease Models, Animal; Female; Lupus Erythematosus, Systemic; Male; Peroxidase; Propylthiouracil

In full-term newborn rats, propylthiouracil (PTU) treatment has been previously shown to decrease susceptibility to O2-induced lung damage and improve survival during hyperoxic exposure. However, no differences were found in lung antioxidant enzyme (AOE) activity responses to hyperoxia compared with O2-exposed untreated (control) term rats. To further explore possible pulmonary protective effects of PTU treatment in prematurely delivered animals, we administered PTU (0.015%) in drinking water to timed-pregnant rats for the final 10 d of gestation prior to delivery 1 d before term, and during lactation; control pregnant/nursing rats received untreated water. Both groups of 21-d premature rat pups were randomized to either > 95% O2 or room air exposure after birth for up to 14 d. The left lungs of 7-d exposure pups were used to quantitate the concentrations of AOE mRNA by solution hybridization; the right lungs of the same pups were assayed for AOE activities. PTU treatment resulted in survival rates of O2-exposed preterm rat pups that were consistently higher at all time periods in hyperoxia including 7 d [PTU, 67 of 82 (82%) versus control pups, 58 of 113 (51%); p < 0.001] and 14 d [PTU, 31 of 39 (79%) versus control, 15 of 66 (23%); p < 0.001]. Further evidence of increased tolerance to > 95% O2 in PTU pups included a significant decrease in the incidence of microscopic intraalveolar edema and a significant increase in lung tissue surfactant-related phospholipids compared with O2-exposed control pups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Catalase; Disease Models, Animal; Female; Glutathione Peroxidase; Hyperoxia; Lung; Male; Peroxidases; Pregnancy; Propylthiouracil; Pulmonary Surfactants; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Survival Rate

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

Subcellular changes of the atrial cardiomyocytes of rats submitted to hypothyroidism caused by administration of 1 mg/100 g of body weight of propylthiouracil showed a) swollen mitochondria and lysis of their cristae; b) myofibrils with marked heterogeneity of patterns, some exhibiting rupture and loss of continuity of their myofilaments; c) lesser concentration of atrial granules in the perinuclear area; d) abundant granular interstitial tissue and collagen separating the myofibrils.

Topics: Animals; Collagen; Connective Tissue; Disease Models, Animal; Heart; Hypothyroidism; Mitochondria, Heart; Myofibrils; Propylthiouracil; Rats; Rats, Inbred Strains

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

The injection of a retrovirus carrying the v-ras-Ki oncogene into the thyroid gland of adult Fischer rats induces thyroid carcinomas when associated with a treatment of the animals with a goitrogenic agent. More than one hundred adult Fischer rats have been treated with the goitrogen agent propylthiouracil in order to induce thyroid hyperplasia. Twenty days after treatment, rat thyroid glands, surgically prepared, were injected with the Kirsten murine sarcoma virus (KiMSV). Within three months more than 90% of the animals developed thyroid tumors. Histologically the tumors had the appearance of well differentiated carcinomas. Thirty animals had lung metastases in addition to the thyroid carcinoma. The presence of KiMSV specific transcripts and the specific transforming protein (p21) in thyroid carcinomas and in the metastases was detected by Northern blot analysis and immunoprecipitation, respectively. Only three rats, among thirty that had not received the goitrogen treatment, but only the injection with KiMSV, developed thyroid carcinomas of very small size and with a very long latency period (almost one year). The results described represent the first instance of thyroid carcinoma induction by retroviruses. This system may be regarded as a useful model to investigate the process of thyroid carcinogenesis in vivo. These results suggest that this model may also be useful for investigating the interaction between hormones and cells harboring the activated oncogene in the development of thyroid carcinoma since activated ras oncogenes have been implicated in human thyroid carcinoma.

Topics: Animals; Carcinoma; Disease Models, Animal; Genes, ras; Kirsten murine sarcoma virus; Neoplasm Metastasis; Oncogene Protein p21(ras); Oncogene Proteins, Viral; Propylthiouracil; Rats; Rats, Inbred F344; Sarcoma Viruses, Murine; Thyroid Neoplasms; Thyrotropin

Topics: Animals; Disease Models, Animal; Histological Techniques; Hypothyroidism; Liver; Male; Mice; Propylthiouracil

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

Natural killer (NK) activity of peripheral blood lymphocytes from hyperthyroxinemic patients (Graves' disease or thyroxine (T4)-treated) is severely depressed. In order to study the relationship of thyroid hormone to NK activity, a model for hyperthyroxinemia was induced in mice by addition of T4 to the drinking water. Control mice were hypothyroid (fed propylthiouracil) or normal. Serum T4 levels were elevated (within 2 wk) in mice fed thyroid hormone. Six weeks after initiation of the diets, in vitro NK activity was undetectable in the peripheral blood, spleen, or lung mononuclear cell populations harvested from hyperthyroxinemic mice. Control mice had NK activity within the normal range. Spleen cells from mice fed thyroid hormone and control mice were tested for their ability to release lytic factors (natural killer cytotoxic factors). Lymphoid cells were incubated for 20 hr with unlabeled Yac-1 cells. Supernatants were tested for their capacity to lyse 51Cr-labeled Yac-1 cells in a 20-hr chromium release assay. Unlike controls, supernatants from hyperthyroxinemic spleen cells incubated with Yac-1 targets were unable to lyse 51Cr-Yac-1 cells. The NK cells from the mice fed T4 synthesized lytic factors because nonspecific stimuli, such as 12-O-tetradecanoyl phorbol-13-acetate and the calcium ionophore A23187, induced release of lytic factors capable of lysing Yac-1 targets into the media. These data support the hypothesis that excess thyroid hormone interferes with the triggering mechanism used by NK targets to cause release of lytic molecules from NK cells.

Topics: Animals; Cytotoxicity Tests, Immunologic; Disease Models, Animal; Female; Graves Disease; Hypothyroidism; Interleukin-2; Killer Cells, Natural; Killer Factors, Yeast; Leukocyte Count; Mice; Mice, Inbred C57BL; Propylthiouracil; Proteins; T-Lymphocytes; Thyroxine

An immune-mediated disease was produced in 9 of 17 (53%) normal healthy cats by daily p.o. administration of 150 mg of 6-propylthiouracil (PTU). This disease syndrome is characterized by lethargy, weight loss, lymphadenopathy, hemolytic anemia, a positive direct antiglobulin test (DAT) and antinuclear antibodies (ANA). The duration of drug administration before the development of a positive DAT and/or ANA ranged from 3 to 8 weeks (Mean +/- S.E.M. = 4.5 +/- 0.6), whereas the duration before the onset of clinical signs ranged from 4 to 8 weeks (6.1 +/- 0.6 weeks). On cessation of PTU administration, clinical signs resolved in all cats within 2 weeks, and the DAT and test for ANA were negative within 1 to 4 weeks (1.9 +/- 0.4 weeks). During nine PTU-rechallenge periods in four cats, both the mean time to develop a positive DAT and ANA (2.5 +/- 0.8 weeks) and the mean time to develop overt clinical signs (2.6 +/- 0.7 weeks) were shorter than similar mean times in the initial PTU treatment period (P less than .01). During nine episodes of PTU-induced disease in seven cats, PTU administration was discontinued and replaced with 150 mg of 6-propyluracil (PU), a nonsulfur analog of PTU. Resolution of both clinical and serologic signs of disease occurred in seven of the nine disease episodes within 1 to 3 weeks (2.1 +/- 0.4 weeks). In the two cats whose disease did not resolve on PU, one was sacrificed after 1 week of PU administration, without clinical or serologic resolution, because of the severity of the PTU-induced disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anemia, Hemolytic, Autoimmune; Animals; Antibodies, Anti-Idiotypic; Antibodies, Antinuclear; Autoimmune Diseases; Cats; Disease Models, Animal; Methimazole; Phagocytes; Propylthiouracil; Structure-Activity Relationship

Inhabitants of many severe endemic goiter areas have low serum T4 and high circulating TSH, despite normal levels of T3. This situation may be produced experimentally chronically feeding rats a low iodine diet (LID). We fed rats a Remington-type LID and gave them 1% NaClO4 in their drinking water for 2 days. After this, the animals were divided into three groups. One group was fed LID, supplemented with 5 micrograms I/rat.day and was used as the control group. Another group was fed LID alone. The third group was fed LID and given 1% NaClO4 to drink. The latter treatment was used to induce severe hypothyroidism. Animals were killed 1, 2, 3, and 5 weeks after the onset of these treatment schedules. The following measurements were made on some or all groups of animals: body and thyroid weights; thyroidal I content; soluble labeled iodoprotein profile; thyroidal labeled iodoamino acid distribution pattern; plasma T4, T3, and TSH; pituitary GH content; and liver intramitochondrial alpha-glycerophosphate dehydrogenase and cytosolic malic enzyme activities. T4 and T3 concentrations were also measured in liver nuclei of the animals killed 5 weeks after the onset of treatment. As assessed from various indices of thyroid function, the LID rats became iodine deficient, although not as markedly as those given LID and ClO4-, The plasma T4 decreased to undetectable levels, and plasma TSH increased, whereas circulating T3 remained normal throughout in the LID rats. In rats given LID and ClO4-, plasma T4 decreased sooner than in rats given LID alone; plasma T3 levels also became undetectable, and TSH increased more markedly and sooner than in rats given LID alone. As measured at the end of 5 weeks of treatment, pituitary GH content, and liver alpha-glycerophosphate dehydrogenase and malic enzyme activities were lower in rats given LID than in the euthyroid LID- and I--treated controls. They were not, however, as markedly reduced as in the severely hypothyroid LID- and ClO4--treated rats. In spite of normal plasma T3 levels, the concentration of T3 in liver nuclei of the rats given LID alone was significantly lower than that of the LID- and I--treated controls. The results show that the thyrotrophs, somatotrophs, and livers of rats given LID alone are not like those of euthyroid rats despite normal circulating T3 levels. In iodine-deficient rats, there is a discrepancy between the measured indices of thyroid hormone action in the liver and the circulating T3 level, but no

Topics: Animals; Cell Nucleus; Disease Models, Animal; Female; Glycerolphosphate Dehydrogenase; Goiter, Endemic; Growth Hormone; Iodine; Liver; Malate Dehydrogenase; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Acetaminophen; Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Glutathione; Hypothyroidism; Liver; Male; Necrosis; Propylthiouracil; Rats; Thyroid Gland; Thyroidectomy

Adrenoceptor-mediated responses of the cardiovascular system during propylthiouracil-induced hypothyroidism were investigated. Interfering nervous reflexes could be circumvented by using pithed rats. Cardiac beta-adrenoceptor-mediated acceleration of heart rate following electrical stimulation or injection of noradrenaline and isoprenaline was markedly diminished even after 2 weeks of treatment. This loss of beta-sensitivity prevented the study of possible changes of presynaptic regulatory adrenoceptors in this test model. Taking the increase in diastolic blood pressure after application of alpha-agonists as index of the sensitivity of vascular alpha-adrenoceptors we found these to have been desensitized in the hypothyroid state. According to these results the lack of thyroid hormones exerted a similar effect on cardiac beta- and on vascular alpha-adrenoceptors.

Topics: Animals; Atropine; Blood Pressure; Bupranolol; Clonidine; Disease Models, Animal; Electric Stimulation; Heart Rate; Hypothyroidism; Isoproterenol; Male; Norepinephrine; Phenylephrine; Propylthiouracil; Rats; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Spinal Cord; Tubocurarine

Topics: Animals; Antigen-Antibody Complex; Dactinomycin; Disease Models, Animal; Female; Lupus Erythematosus, Systemic; Mice; Propylthiouracil; Rodent Diseases; Vincristine

Topics: Animals; Cholesterol, Dietary; Corneal Opacity; Dietary Fats; Disease Models, Animal; Dogs; Female; Hypercholesterolemia; Hyperlipoproteinemias; Male; Propylthiouracil; Thyroidectomy

Experimental models for hyper-beta-lipoproteinemia were established in rats and the effects of certain hypolipidemic drugs were studied with these models. In the hyperlipemia induced in rats by feeding a high cholesterol diet, Y-9738 [ethyl 2(4-chlorophenyl)-5-ethoxy-4-oxazoleacetate] produced a dose-dependent reduction of serum cholesterol: such hypolipidemic activity was estimated to be about 7 times as great as that of clofibrate. On the other hand, clofibrate induced hepatomegaly at 100 mg/kg, whereas Y-9738 did not at this dosage, which is about 10 times the effective dose. Hyperlipemia induced by high cholesterol and thiouracil was characterized by increased beta-lipoprotein (heparin-calcium and disc electrophoresis). In this model, Y-9738 showed a dose-dependent lowering effect on beta-lipoprotein cholesterol with a marked decrease in the beta/alpha lipoprotein ratio. A tendency was noted for alpha-lipoprotein to be increased. In contrast, clofibrate exerted no effect on this hyper-beta-lipoproteinemia. These results suggest that the above models may be of value in exploring hyper-beta-lipoproteinemia and that Y-9738 may be more useful than clofibrate in the therapy of hyperlipemia.

Topics: Animals; Cholesterol; Cholesterol, Dietary; Clofibrate; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins, LDL; Male; Oxazoles; Propylthiouracil; Rats; Triglycerides

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

Administration of propylthiouracil (PTU) to pregnant, third trimester sheep led to decreasing serum thyroxine and increasing serum thyroid-stimulating hormone in both mothers and fetuses. Hypothyroidism appeared more pronounced in the fetuses than in the ewes, and goiter formation was observed in all fetuses exposed to PTU. Concomitant administration of triiodothyronine failed to protect the fetuses from the effects of PTU.

Topics: Animals; Disease Models, Animal; Female; Fetal Diseases; Goiter; Hypothyroidism; Organ Size; Pregnancy; Propylthiouracil; Sheep; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Aging; Animals; Bone Development; Calcification, Physiologic; Cartilage, Articular; Disease Models, Animal; Female; Growth Hormone; Hypothyroidism; Intervertebral Disc; Iodine Radioisotopes; Lumbar Vertebrae; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Osteosclerosis; Pituitary Diseases; Prolactin; Propylthiouracil; Spinal Osteophytosis

Topics: Angiocardiography; Animals; Aorta, Thoracic; Arrhythmias, Cardiac; Autopsy; Coronary Angiography; Coronary Vessels; Death, Sudden; Diet, Atherogenic; Disease Models, Animal; Electrocardiography; Heart; Heart Conduction System; Lidocaine; Lung; Male; Myocardium; Propylthiouracil; Radiation Effects; Swine; Ventricular Fibrillation

Topics: Animals; Animals, Newborn; Cell Differentiation; Cerebellum; Disease Models, Animal; Hypothyroidism; Microscopy, Electron; Neuroglia; Nutrition Disorders; Propylthiouracil; Rats

Topics: Animals; Animals, Newborn; Cell Differentiation; Cerebellum; Dendrites; Disease Models, Animal; Fetus; Hypothyroidism; Microscopy, Electron; Neuroglia; Propylthiouracil; Purkinje Cells; Rats

Topics: Animals; Animals, Newborn; Cerebellum; Disease Models, Animal; Hypothyroidism; Neuroglia; Propylthiouracil; Rats

Topics: Abnormalities, Drug-Induced; Age Factors; Animals; Cochlea; Deafness; Disease Models, Animal; Female; Gestational Age; Goiter; Hypothyroidism; Iodine; Male; Mice; Mice, Inbred C57BL; Organ of Corti; Pregnancy; Propylthiouracil; Thyroxine

Topics: Animals; Basement Membrane; Capillaries; Disease Models, Animal; Dogs; Inclusion Bodies; Lipid Metabolism; Male; Methimazole; Microscopy, Electron; Mitochondria, Muscle; Myocardium; Myxedema; Pectoralis Muscles; Propylthiouracil

Topics: Animals; Deficiency Diseases; Diet; Disease Models, Animal; Estradiol; Hyperplasia; In Vitro Techniques; Injections, Intramuscular; Iodine; Mammary Glands, Animal; Propylthiouracil

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: Animals; Animals, Newborn; Cell Differentiation; Cerebellar Cortex; Dendrites; Disease Models, Animal; Growth Hormone; Hypothyroidism; Propylthiouracil; Purkinje Cells; Rats

Topics: Animals; Colloids; Cricetinae; Disease Models, Animal; Goiter; Hyperplasia; Iodine; Male; Microscopy, Electron; Propylthiouracil; Thyroglobulin; Thyroid Hormones; Thyrotropin