propylthiouracil and Congenital-Hypothyroidism

The subject of thyroid disease in pregnancy is receiving increasing attention from many scientific disciplines. Thyroid function in pregnancy is characterised by a T4 surge at 12 weeks declining thereafter. Serum thyroid hormone concentrations fall in the second half of pregnancy but there are few data on normal reference ranges. Fetal brain development depends on T4 transport into the fetus which in turn depends on sufficient maternal iodine supply. There is current concern that adequate iodisation is not present in large parts of Europe. There is increasing evidence that thyroid autoimmunity is associated with fetal loss but the mechanism is unclear and therapy requires carefully conducted studies. While hyperthyroidism in pregnancy is uncommon, effects on both mother and child are critical if untreated. The use of propylthiouracil is recommended together with measurement of TSH receptor antibodies at 36 weeks gestation. Women receiving thyroxine therapy for hypothyroidism or as suppressive therapy should have their dose increased by up to 50% during pregnancy. There are now substantial data to show deleterious effects on child IQ resulting from low maternal T4 (or high TSH) during gestation. Major advances in molecular biology have contributed to elucidation of many genetic causes of congenital hypothyroidism. However, the aetiology of the majority of cases is still unclear and further research is required. The presence of TPO antibodies in about 10% of pregnant women in early gestation is a predictor of an increased incidence of subclinical hypothyroidism during pregnancy and also of postpartum thyroid dysfunction. The latter condition occurs in 5-9% of women and 25-30% progress to permanent hypothyroidism. This review suggests that screening for thyroid function in early pregnancy and levothyroxine intervention therapy for maternal subclinical hypothyroidism should be considered but evidence is awaited. Screening for both thyroid dysfunction and thyroid antibodies ideally at a preconception clinic but certainly in early gestation is recommended.

Topics: Antithyroid Agents; Autoantibodies; Congenital Hypothyroidism; Drug Combinations; Female; Humans; Hyperthyroidism; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Infant, Newborn; Intelligence Tests; Mass Screening; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Propylthiouracil; Receptors, Thyrotropin; Thyroid Diseases; Thyroid Function Tests; Thyrotropin; Thyroxine

Topics: Antithyroid Agents; Congenital Hypothyroidism; Female; Goiter; Graves Disease; Humans; Hypothyroidism; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Propylthiouracil

Topics: Adult; Calcium; Carbimazole; Congenital Hypothyroidism; Dihydrotachysterol; Female; Humans; Hyperparathyroidism; Hyperthyroidism; Hypoparathyroidism; Hypothyroidism; Infant, Newborn; Parathyroid Diseases; Parathyroid Glands; Pregnancy; Pregnancy Complications; Propylthiouracil; Puerperal Disorders; Thyroid Diseases; Thyroxine

Topics: Congenital Hypothyroidism; Female; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Prognosis; Propylthiouracil; Thyroid (USP); Thyroid Diseases; Thyroid Gland; Thyroxine

Topics: Abortion, Spontaneous; Congenital Hypothyroidism; Female; Fetal Death; Humans; Hyperthyroidism; Infant, Newborn; Infant, Newborn, Diseases; Intellectual Disability; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroidectomy; Triiodothyronine

Adverse neurodevelopmental consequences remain a primary concern when evaluating the effects of thyroid hormone (TH) disrupting chemicals. Though the developing brain is a known target of TH insufficiency, the relationship between THs in the serum and the central nervous system is not well characterized. To address this issue, dose response experiments were performed in pregnant rats using the goitrogen propylthiouracil (PTU) (dose range 0.1-10 ppm). THs were quantified in the serum and brain of offspring at gestational day 20 (GD20) and postnatal day 14 (PN14), two developmental stages included in OECD and EPA regulatory guideline/guidance studies. From the dose response data, the quantitative relationships between THs in the serum and brain were determined. Next, targeted gene expression analyses were performed in the fetal and neonatal cortex to test the hypothesis that TH action in the developing brain is linked to changes in TH concentrations within the tissue. Results show a significant reduction of T4/T3 in the serum and brain of the GD20 fetus in response to low doses of PTU; interestingly, very few genes were significantly different at any dose tested. In the PN14 pup significant reductions of T4/T3 in the serum and brain were also detected; however, twelve transcriptional targets were identified in the neonatal cortex that correlated well with reduced brain THs. These results show that serum T4 is a good predictor of brain THs, and offer several target genes that could serve as pragmatic readouts of T4/T3 dysfunction within the PN14 cortex.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Cerebral Cortex; Congenital Hypothyroidism; Dose-Response Relationship, Drug; Female; Fetus; Gene Expression; Maternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Long-Evans; Thyroid Hormones

Low thyroid hormone (TH) conditions caused by a variety of prenatal and perinatal problems have been shown to alter postnatal regulatory thyrotropin (TSH) responsiveness to TH in humans and rodents. The mechanisms underlying this pituitary TH resistance remain unknown. Here we use the evolutionarily conserved zebrafish model to examine the effects of low TH on thyrotrope development and function. Zebrafish were exposed to the goitrogen 6-propyl-2-thiouracil (PTU) to block TH synthesis, and this led to an approximately 50% increase in thyrotrope numbers and an 8- to 10-fold increase in tshb mRNA abundance in 2-week-old larvae and 1-month-old juveniles. Thyrotrope numbers returned to normal 3 weeks after cessation of PTU treatment, demonstrating that these effects were reversible and revealing substantial plasticity in pituitary-thyroid axis regulation. Using a T4 challenge assay, we found that development under low-TH conditions did not affect the ability of T4 to suppress tshb mRNA levels despite the thyrotrope hyperplasia that resulted from temporary low-TH conditions. Together, these studies show that low developmental TH levels can lead to changes in thyrotrope number and function, providing a possible cellular mechanism underlying elevated TSH levels seen in neonates with either permanent or transient congenital hypothyroidism.

Topics: Animals; Animals, Genetically Modified; Cell Count; Cell Differentiation; Congenital Hypothyroidism; Embryo, Nonmammalian; Gene Expression Regulation, Developmental; Organogenesis; Pituitary Gland; Propylthiouracil; Receptors, Thyroid Hormone; Thyroid Hormones; Thyrotrophs; Thyrotropin, beta Subunit; Zebrafish

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

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

Thyroid hormones (TH) are one of the key factors for normal prenatal development in mammals. Previously, we showed that subclinical maternal hypothyroidism leads to premature atresia of ovarian follicles in female rat offspring in the pre-pubertal and pubertal periods. The influence of decreased concentration of TH on primordial follicles pool formation during neonatal and early infantile period of rat pups was not investigated previously. Maternal hypothyroidism during pregnancy has irreversible negative influence on primordial follicles pool formation and population of resting oocytes in female rat offspring. The study was done on neonatal and early infantile control (n-10) and hypothyroid (n-10) female rat pups derived from control (n-6) and propylthiouracil (PTU) treated pregnant dams (n-6), respectively. Ovaries of all pups were removed and processed for light and transmission electron microscopy (TEM). Number of nests, oogonia and oocytes per nest, primordial, primary, secondary and preantral follicles were determined. Screening for overall calcium presence in ovarian tissue was done using Alizarin red staining. Morphology and volume density of nucleus, mitochondria and smooth endoplasmic reticulum (sER) in the oocytes in primordial follicles was also assessed. Caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), both markers for apoptosis, and proliferating cell nuclear antigen (PCNA) for proliferation were determined in oocytes and granulosa cells in different type of follicles. In neonatal period, ovaries of hypothyroid pups had a decreased number of oogonia, oocytes and nests, an increased number of primordial follicles and a decreased number of primary and secondary follicles, while in early infantile period, increased number of primary, secondary and preantral follicles were found. Alizarin red staining was intense in hypothyroid neonatal rats that also had the highest content of dilated sER. Number of mitochondria with altered morphology in both groups of hypothyroid pups was increased. Apoptosis markers have not shown significant difference between groups but PCNA had an increased expression in the oocytes and granulosa cells in primordial follicles of hypothyroid rats. Light and electron microscopy analysis indicate that previously detected premature ovarian follicular atresia in pre-pubertal and pubertal hypothyroid rats is preceded with premature formation of primordial follicles followed by slight changes

Topics: Animals; Animals, Newborn; Apoptosis; Caspase 3; Congenital Hypothyroidism; Endoplasmic Reticulum, Smooth; Female; Hypothyroidism; In Situ Nick-End Labeling; Microscopy; Microscopy, Electron, Transmission; Mitochondria; Oocytes; Ovarian Follicle; Ovary; Pregnancy; Pregnancy Complications; Proliferating Cell Nuclear Antigen; Propylthiouracil; Rats

Neurodevelopment is known to be particularly susceptible to thyroid hormone insufficiency and can result in extensive structural and functional deficits within the central nervous system (CNS), subsequently leading to the establishment of cognitive impairment and neuropsychiatric symptomatology. The current study evaluated the effects of gestational and/or lactational maternal exposure to propylthiouracil (PTU)-induced hypothyroidism (as a suggestive multilevel experimental approach to the study of hypothyroidism-induced changes that has been developed and characterized by the authors) on crucial brain enzyme activities of 21-day-old Wistar rat offspring in a CNS region-specific manner. The activities of acetylcholinesterase (AChE), Na(+),K(+)-ATPase and Mg(2+)-ATPase in the offspring hypothalamus, cerebellum and pons were assessed. The study demonstrated that maternal exposure to PTU (0.05% w/v in the drinking water) during the critical periods of neurodevelopment can result in an inhibition of hypothalamic, pontine and cerebellar Na(+),K(+)-ATPase; a major marker of neuronal excitability and metabolic energy production as well as an important regulator of important systems of neurotransmission. On the other hand, no significant changes in the activities of the herein offspring CNS regions' AChE and Mg(2+)-ATPase were recorded. The observed Na(+),K(+)-ATPase inhibition: (i) is region-specific (and non-detectable in whole brain homogenetes), (ii) could constitute a central event in the pathophysiology of clinically-relevant hypothyroidism-associated developmental neurotoxicity, (iii) occurs under all examined experimental schemes, and (iv) certainly deserves further clarification at a molecular and histopathological level. As these findings are analyzed and compared to the available literature, they also underline the need for the adoption and further study of Na(+),K(+)-ATPase activity as a consistent neurochemical marker within the context of a systematic comparative study of existing (and novel) simulation approaches to congenital and early age hypothyroidism.

Topics: Acetylcholinesterase; Animals; Brain; Ca(2+) Mg(2+)-ATPase; Cerebellum; Congenital Hypothyroidism; Female; Hypothalamus; Hypothyroidism; Lactation; Male; Pons; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase

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

Reduced nitric oxide availability and a heterogeneous pattern of nitric oxide synthase activity in some tissues have been reported in hypothyroidism. This study aimed at determining the effects of oral nitrate and L-arginine administration on serum, heart, and aorta nitric oxide metabolite concentrations in fetal hypothyroid rats. In an experimental study, pregnant Wistar rats were administrated tap water or 0.02 % of 6-propyl-2-thiouracil in drinking water during pregnancy and their male pups were followed (n = 8/group). In adult progeny, serum, heart, and aorta nitric oxide metabolite concentrations were measured by the Griess method after 1-week administration of sodium nitrate (500 mg/L) or L-arginine (2 %) in drinking water. Serum thyroid hormone and thyroid-stimulating hormone levels were also measured. Compared to controls, fetal hypothyroid progeny had significantly lower nitric oxide metabolite concentrations in heart (0.32 ± 0.07 vs. 0.90 ± 0.14 nmol/mg protein, p = 0.004) and aorta (2.98±0.56 vs. 6.15±0.74 nmol/mg protein, p = 0.011) tissues. Nitrate therapy restored heart nitric oxide metabolite levels decreased by fetal hypothyroidism, while L-arginine administration further decreased aorta nitric oxide metabolite levels. Sodium nitrate increased and L-arginine decreased serum nitric oxide metabolite levels in both control and fetal hypothyroid animals. In conclusion, nitrate therapy restores decreased heart nitric oxide metabolite levels, whereas L-arginine decreases aorta nitric oxide metabolite levels even further in fetal hypothyroid rats, findings relevant to the cardiovascular consequences of congenital hypothyroidism in adulthood.

Topics: Animals; Antithyroid Agents; Aorta; Arginine; Congenital Hypothyroidism; Female; Fetus; Heart; Male; Nitrates; Nitric Oxide; Pregnancy; Propylthiouracil; Rats; Rats, Wistar; Thyrotropin; Thyroxine; Triiodothyronine

To determine whether developmental hypothyroidism causes permanent disruption of neuronal development, we first performed a global gene expression profiling study targeting hippocampal CA1 neurons in male rats at the end of maternal exposure to anti-thyroid agents on weaning (postnatal day 20). As a result, genes associated with nervous system development, zinc ion binding, apoptosis and cell adhesion were commonly up- or down-regulated. Genes related to calcium ion binding were up-regulated and those for myelination were often down-regulated. We, then, examined immunohistochemical cellular distribution of Ephrin type A receptor 5 (EphA5) and Tachykinin receptor (Tacr)-3, those selected based on the gene expression profiles, in the hippocampal formation at the adult stage (11-week-old) as well as at the end of exposure. At weaning, both EphA5- and Tacr3-immunoreactive cells with strong intensities appeared in the pyramidal cell layer or stratum oriens of the hippocampal CA1 region. Although the magnitude of the change was decreased at the adult stage, Tacr3 in the CA1 region showed a sustained increase in expressing cells until the adult stage after developmental hypothyroidism. On the other hand, EphA5-expressing cells did not show sustained increase at the adult stage. The results suggest that developmental hypothyroidism caused sustained neuronal expression of Tacr3 in the hippocampal CA1 region, probably reflecting a neuroprotective mechanism for mismigration.

Topics: Animals; CA1 Region, Hippocampal; Congenital Hypothyroidism; Female; Gene Expression Profiling; Immunohistochemistry; Male; Maternal Exposure; Methimazole; Oligonucleotide Array Sequence Analysis; Pregnancy; Propylthiouracil; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, EphA5; Receptors, Tachykinin; Statistics, Nonparametric

Topics: Adult; Antithyroid Agents; Autoantibodies; Congenital Hypothyroidism; Female; Graves Disease; Humans; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Propylthiouracil; Receptors, Thyrotropin; 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

Thyroid hormones are major regulators of postnatal brain development. Thyroid hormones act through nuclear receptors to modulate the expression of specific genes in the brain. We have used microarray analysis to identify novel responsive genes in 14-day-old hypothyroid rat brains, and discovered that synaptosomal-associated protein of 25 kDa (SNAP-25) was one of the thyroid hormone-responsive genes. SNAP-25 is a presynaptic plasma membrane protein and an integral component of the vesicle docking and fusion machinery mediating secretion of neurotransmitters and is required for neuritic outgrowth and synaptogenesis. Using microarray analysis we have shown that SNAP-25 was down-regulated in the hypothyroid rat brain compared with the age-matched controls. Real-time RT-PCR and western blotting analysis confirmed that SNAP-25 mRNA and protein levels decreased significantly in the developing hypothyroid rat brain. Our data suggest that in the developing rat brain, SNAP-25 expression is regulated by thyroid hormone, and thyroid hormone deficiency can cause decreased expression of SNAP-25 and this may on some level account for the impaired brain development seen in hypothyroidism.

Topics: Animals; Animals, Newborn; Brain; Congenital Hypothyroidism; Gene Expression Profiling; Gene Expression Regulation, Developmental; Oligonucleotide Array Sequence Analysis; Propylthiouracil; Rats; Rats, Sprague-Dawley; Synaptosomal-Associated Protein 25; Thyroid Hormones

Thyroid hormone is an important factor for proper development of the mammalian brain. Perinatal hypothyroidism leads to long-term behavior and neuromotor competence alterations in humans and animals. Our study aimed to investigate the effects of perinatal hypothyroidism on behavior changes of rat pups and its relation with the apoptosis of hippocampus neurons. Behavior tests were taken to evaluate the effects caused by perinatal hypothyroidism. TUNEL staining was used to analyze the apoptosis of neurons on CA3 region of hippocampus. The study suggested that perinatal hypothyroidism affects behavior development, as well as leading to the decrease in spatial learning and memory capability. This condition can be improved with hormone substitute treatment. Furthermore, the changes of learning and memory capability are closely related to the increasing number of apoptotic neurons in the hippocampus.

Topics: Animals; Animals, Newborn; Apoptosis; Behavior, Animal; Congenital Hypothyroidism; Emotions; Female; Hippocampus; Male; Maze Learning; Memory; Motor Activity; Neurons; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Hormones

Congenital hypothyroidism was induced in rats by adding 0.05% 6-propyl-2-thiouracil in the drinking water from day 9 of gestation, and continually up to postnatal day 15. Structural alterations observed by light microscopy of seminiferous tubules and by transmission electron microscopy of Sertoli cells of treated animals were consistent with hypothyroid condition. Hypothyroidism was also associated with high phospho-p38 mitogen-activated protein kinase and decreased phospho-extracellular signal-regulated kinase 1/2 levels. Furthermore, the phosphorylation and the immunoreactivity of cytoskeletal-associated vimentin were increased without altering vimentin expression, suggesting an accumulation of insoluble and phosphorylated vimentin. These alterations in intermediate filament dynamics could result in loss of Sertoli cell cytoskeletal integrity and be somewhat related to the deleterious effects of hypothyroidism in testis. In addition, the mitochondrial alterations observed could also be related to defective cytoskeletal dynamics implying in cell damage. Moreover, we observed decreased oxygen consumption and unaltered lipid peroxidation in hypothyroid testis. However, we demonstrated decreased enzymatic and non-enzymatic antioxidant defenses, supporting an increased mitochondrial reactive oxygen species (ROS) generation, contributing to biochemical changes in hypothyroid testis. In addition, the changes in the testis histoarchitecture could be ascribed to cytoskeletal alterations, decreased antioxidant defenses, and increased ROS generation, leading to oxidative stress in the organ.

Topics: Animals; Antioxidants; Congenital Hypothyroidism; Cytoskeleton; Lipid Peroxidation; Male; Mitochondria; Oxygen Consumption; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Propylthiouracil; Rats; Rats, Wistar; Reactive Oxygen Species; Seminiferous Tubules; Sertoli Cells; Testis; Vimentin

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

Thyroid dysfunction is recognized in the newborns of mothers affected by Graves' disease during pregnancy. We describe the development of concurrent hyperthyroidism and hypothyroidism in the twin infants of a mother with Graves' disease diagnosed during pregnancy.

Topics: Adult; Antithyroid Agents; Congenital Hypothyroidism; Diagnosis, Differential; Drug Administration Schedule; Female; Graves Disease; Humans; Infant, Newborn; Infant, Premature; Male; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Hormones; Thyroxine; Twins

Topics: Congenital Hypothyroidism; Diseases in Twins; Female; Graves Disease; Humans; Infant, Newborn; Male; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyrotropin; Thyroxine

We experienced a case of fetal goitrous hypothyroidism in an infant delivered by a 33-year-old woman receiving 300 mg/day of propylthiouracil (PTU) for hyperthyroidism due to Graves' disease. A large fetal goiter (maximum diameter, 60 mm) was detected by magnetic resonance imaging (MRI) at 36 weeks of gestation. Initial fetal blood sampling revealed hypothyroidism with a serum thyroid-stimulating hormone (TSH) of 99 microIU/mL, free triiodothyronine (T(3)) of 1.97 pg/mL, and free thyroxine (T(4)) of 0.29 ng/dL. Consequently, a diagnosis of fetal goitrous hypothyroidism due to transplacental passage of maternal PTU was made. To reduce the risk of perinatal complications, 300 microg of levothyroxine sodium (L-T(4)) was administered into the maternal amniotic fluid twice between 37 and 38 weeks of gestation. Subsequent fetal MRI showed that the size of goiter had decreased. At 38 weeks and 5 days of gestation, a 3042-g male infant was born by cesarean section. There were no severe complications at delivery, although mild tachypnea was observed and the infant's thyroid gland was slightly enlarged. He was treated with L-T(4) for two weeks. At present, his growth and neurological development are normal. This case indicates that intrauterine therapy by the intraamniotic administration of L-T(4) can be effective in treating fetal goitrous hypothyroidism even during late gestation.

Topics: Adult; Amniotic Fluid; Antithyroid Agents; Congenital Hypothyroidism; Female; Fetal Diseases; Fetal Therapies; Gestational Age; Goiter; Graves Disease; Humans; Hyperthyroidism; Infant, Newborn; Male; Maternal-Fetal Exchange; Pregnancy; Pregnancy Trimester, Third; Propylthiouracil; Thyroxine; Treatment Outcome

Despite the recognized importance of thyroid hormones for normal brain development, little is known about the critical molecular events underlying this role. We investigated the molecular basis of thyroid hormone action on the developing brain by comparing genome-wide gene expression patterns in the cerebellum between euthyroid and hypothyroid juvenile mice using microarrays. Pregnant dams were treated with 0.1% or 0.04% 6-propyl-2-thiouracil (PTU) in drinking water continuously from day 13 post conception until weaning to produce hypothyroid pups. Cerebella were collected from vehicle and 0.1% PTU treated pups at post-natal day (PND) 15, and mRNA from these was subjected to microarray analysis using Agilent high-density oligonucleotide chips. Statistical analysis (MAANOVA) revealed significant differential expression in 2940 genes including 1357 up- and 1583 down-regulated genes. Further analysis (combined MAANOVA and ANOVA) identified 204 significantly altered genes. Hypothyroidism had a greater effect on gene expression in male than in female pups. Transcriptional changes in several genes [Syt12 (Synaptotagmin 12), Rcor (RE1-silencing transcription factor co-repressor), Bag3 (Bcl-associated athanogene 3), p21, cyclin D, Bax (Bcl2-associated X protein), and Pcp2 (Purkinje cell protein 2)] were confirmed using real-time (RT) PCR analysis. Significantly altered expression of Bag3 in cerebella from PND 15 and PND 60 pups exposed to PTU suggests permanent functional alterations in the hypothyroid brain. The thyroid hormone negative regulation of Rcor expression was confirmed in vitro using HepG2 cells. In addition to Rcor, expression of several other genes that code for critical components of the REST (RE1-silencing transcription factor) pathway was shown to be altered in hypothyroid animals. These results suggest that modification of this pathway may have a significant role in causing impaired development in the hypothyroid brain.

Topics: Animals; Animals, Newborn; Cell Line, Tumor; Cerebellum; Co-Repressor Proteins; Congenital Hypothyroidism; DNA-Binding Proteins; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Histone Deacetylases; Hypothyroidism; Male; Mice; Mice, Inbred C57BL; Microarray Analysis; Nerve Tissue Proteins; Pregnancy; Pregnancy Complications; Propylthiouracil; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sex Factors; Thyroid Hormones; Tumor Cells, Cultured

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

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

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

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

Topics: Abdomen; Antithyroid Agents; Congenital Hypothyroidism; Female; Graves Disease; Humans; Hypothyroidism; Infant, Newborn; Male; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Propylthiouracil

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

Mental retardation associated with hypothyroidism may be caused by impairment of brain ketone body-metabolizing enzymes during the suckling period. However, much evidence suggests that, immediately after delivery, lactate, instead of ketone bodies or glucose, may be the best substrate for the brain. In this work, we have studied the effect of experimentally induced congenital hypothyroidism on the rate of lactate, glucose, and 3-hydroxybutyrate utilization in early neonatal brain slices. Methimazole (MMI) administration to the mothers caused a 5.4- and 1.7-fold decrease in neonatal plasma concentrations of L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3), respectively. Propylthiouracil (PTU) administration to the mothers caused a 7.3- and > 2-fold decrease in plasma T4 and T3 concentrations, respectively. MMI-induced hypothyroidism did not significantly modify the rate of lactate, glucose, or 3-hydroxybutyrate oxidation to CO2 and their incorporation into lipids by the neonatal brain. However, PTU-induced hypothyroidism decreased the rate of lactate and glucose oxidation to CO2 and their incorporation into lipids by 17% (p < 0.05). 3-Hydroxybutyrate utilization was not modified by this treatment. Separation by HPLC of the lipids revealed that PTU-mediated inhibition of lipid synthesis from lactate and glucose may be accounted for by specific inhibition of the rate of sterol synthesis (15%, p < 0.05), whereas the rate of phospholipid synthesis was unaffected. These results suggest that the early newborn may develop mechanisms aimed at avoiding the possible brain damage caused by the inhibition of lipid synthesis brought about by mild neonatal hypothyroidism.

Topics: 3-Hydroxybutyric Acid; Animals; Animals, Newborn; Antithyroid Agents; Brain; Congenital Hypothyroidism; Energy Metabolism; Female; Glucose; Hydroxybutyrates; Hypothyroidism; In Vitro Techniques; Lactic Acid; Methimazole; Phospholipids; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormones

The abundances of G protein alpha-subunits (Gi1 alpha, Gi2 alpha, G0 alpha and Gq/ll alpha) were measured in synaptosomal membranes isolated from forebrain and hindbrain regions of euthyroid and hypothyroid neonatal rats at 10, 15, 20 and 25 days post-partum. The findings show that hypothyroidism causes a distinct perturbation of the normal developmental profile of these signalling components. It is suggested that these changes may contribute to some of the neurological deficits arising from hypothyroidism in early development.

Topics: Animals; Animals, Newborn; Brain; Congenital Hypothyroidism; Female; GTP-Binding Proteins; Hypothyroidism; Iodine; Nerve Tissue Proteins; Organ Size; Pregnancy; Pregnancy Complications; Propylthiouracil; Rats; Rats, Sprague-Dawley; Signal Transduction; Synaptosomes

The effect of congenital hypothyroidism on the visual system of Wistar rats was studied by determining neuron density in the retinal ganglion cell layer. Retinae of adult rats from mothers treated with propylthiouracil, 50 mg/day, starting on the 15th day of pregnancy (PTU group), and of adult rats from untreated mothers (control group) were examined. Retinae were prepared, and the neurons in the nasotemporal region located above the optic disc were counted. Hypothyroid rats showed a significant reduction in the retinal area (about 6.8%), when compared to controls. The cell density in the retinal ganglion cell layer was significantly decreased in 6 PTU-treated compared to 5 control retinae in total (2,793 +/- 330 vs 3,704 +/- 662 neurons/mm2), nasal (3,031 +/- 580 vs 3,853 +/- 699 neurons/mm2) and temporal (2,555 +/- 155 vs 3,555 +/- 827 neurons/mm2) regions. These alterations in a region considered to be one of the most specialized in the visual process suggest a structural deficiency induced by congenital hypothyroidism, with a possible decrease in the visual acuity of the rat.

Topics: Animals; Cell Count; Congenital Hypothyroidism; Female; Hypothyroidism; Male; Pregnancy; Propylthiouracil; Rats; Rats, Wistar; Retina; Retinal Ganglion Cells; Thyroid Hormones; Visual Acuity

Topics: Acoustic Stimulation; Animals; Choline O-Acetyltransferase; Congenital Hypothyroidism; Evoked Potentials, Auditory, Brain Stem; Female; Glutamate Decarboxylase; Hypothyroidism; Nystagmus, Pathologic; Pregnancy; Propylthiouracil; Rats; Reflex, Vestibulo-Ocular; Thyroxine; Vestibule, Labyrinth

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

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

The effects of propylthiouracil (PTU) treatment on the plasma vasopressin level, on the number of hepatic (V1) or renal (V2) vasopressin receptors and on the hormone-sensitive adenylate cyclase activity in the kidney of developing rats were studied in parallel. In addition, we investigated the corrective effects of thyroxine therapy on the plasma vasopressin level and parameters related to the liver, and the effects of vasopressin therapy on the parameters related to the kidney. As already reported in the case of the number of V2 receptors and adenylate cyclase activity in the kidney, the deficient plasma vasopressin level in hypothyroid rats was completely corrected by two daily physiological doses of thyroxine given from birth to the age of sacrifice (1 month). Unlike the V1 receptors, the V2 receptors are known to be highly dependent on their specific circulating ligand. Since, first of all, the deficit was similar in the numbers of V1 and V2 receptors in hypothyroid rats, and, secondly, the treatment of hypothyroid rats by two daily physiological doses of long lasting vasopressin was found ineffective to recover the deficit in the number of V2 receptors, it can be concluded that thyroid deficiency directly alters vasopressin receptor biosynthesis in both liver and kidney, instead of acting via the depressed plasma vasopressin level.

Topics: Animals; Congenital Hypothyroidism; Hypothyroidism; Kidney; Liver; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Angiotensin; Receptors, Vasopressin; Thyroxine; Vasopressins

Thyroid hormone effects on the developing rat brain were analyzed regarding the nucleic acid contents and the rate of protein synthesis using PTU induced neonatal hypothyroid rat as a model for human congenital hypothyroidism. Significantly reduced amount of total DNA contents per brain and protein/DNA ratio were demonstrated in both cerebrum and cerebellum of the hypothyroid rat after 14 days, suggesting the disturbed cell formation and cell growth in the hypothyroid rat brain. And the maturation of the cerebellum extended later into postnatal life than does that of the cerebrum. Additional evidence by the reduced rate of protein synthesis in the hypothyroids would correlate with these altered morphogenesis. Postmitochondrial supernatant (PMS) obtained from both control and hypothyroid brain homogenate, which was used for the experiment of protein synthesis, contained the same amount of the RNA contents. Therefore the defective protein synthesis might be attributed to the disturbed translational process of the genetic message in protein.

Topics: Animals; Brain; Congenital Hypothyroidism; DNA; Female; Hypothyroidism; Maternal-Fetal Exchange; Nerve Tissue Proteins; Pregnancy; Propylthiouracil; Rats

The effect of congenital thyroid deficiency upon the postnatal development of the rat kidney has been studied by measuring the nucleic acid, protein and lipid contents, and the area and thickness of the different regions in the organ, i.e. cortex, outer and inner medulla. Thyroid deficiency, induced by daily propylthiouracil treatment, strongly affects the development of the renal cortex. The medulla, and still more its inner part which develops early and partly before the onset of thyroid function, is relatively preserved. These effects are completely corrected by daily thyroxine therapy, excluding a possible toxic effect of the antithyroid drug. Moreover, they are partly reversible after cessation of propylthiouracil treatment.

Topics: Aging; Animals; Congenital Hypothyroidism; DNA; Female; Hypothyroidism; Kidney; Kidney Cortex; Kidney Medulla; Lipid Metabolism; Male; Organ Size; Propylthiouracil; Proteins; Rats; Rats, Inbred Strains; RNA

Rats were treated with a goitrogen, propylthiouracil (PTU), from 3 days before delivery up to different ages postnatally. Peripheral auditory function was evaluated with the auditory brain-stem response (ABR) technique performed at 200 days of age. All groups of rats exposed consecutively pre- and postnatally to PTU displayed permanent auditory impairment for each stimulus modality used, as revealed by significantly prolonged wave I latencies and elevated thresholds, and the severity of these abnormalities was directly related to the duration of PTU treatment. The only congenitally hypothyroid animals not affected were those treated from 3 days before parturition up to birth and those treated for 10 days beginning at 35 days of age. These data underline the susceptibility of the developing auditory system since, while very brief perinatal PTU exposure resulted in permanent evoked response abnormalities, longer exposure in later life had no effect.

Topics: Animals; Congenital Hypothyroidism; Evoked Potentials, Auditory; Female; Hypothyroidism; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains

In order to study the corrective effects of thyroxine (T4) on functional abnormalities induced by congenital hypothyroidism, small doses of T4 were injected to propylthiouracil-treated (PTU-treated) rat pups for 2 consecutive days on selected periods of development (days 3 and 4, 6 and 7, 9 and 10, 12 and 13, 18 and 19). Some animals also received thyroid replacement therapy from days 12 to 17. The animals were tested electrophysiologically on day 30, by recording the compound action potential and the cochlear microphonic from the round window after click and tone burst stimulation. PTU-treated animals given T4 for 2 consecutive days demonstrated both AP and CM threshold shifts. On the contrary, PTU-treated animals given T4 from days 12 to 17 demonstrated a normal CM output of the cochlea, but still showed elevated AP thresholds. These results are discussed with previous data concerning the corrective effects of T4 on cochlear structures in PTU-treated rats previously described.

Topics: Animals; Cochlea; Cochlear Microphonic Potentials; Congenital Hypothyroidism; Evoked Potentials, Auditory; Hypothyroidism; Propylthiouracil; Rats; Rats, Inbred Strains; Reaction Time; Thyroxine

In order to study the corrective effects of thyroxine on the cochlear abnormalities induced by congenital hypothyroidism, small doses of thyroxine were injected in propylthiouracil-treated rat pups for 2 consecutive days during selected periods of development (days 3 and 4, 6 and 7, 9 and 10, 12 and 13, 18 and 19). Some animals also received thyroid replacement therapy from days 12 to 17. Corrective effects of thyroxine on cochlear structures were observed using light microscopy and transmission electron microscopy. The corrective effects not only depended on the period of administration of the hormone, but also on the structure investigated within the organ of Corti. For a given structure, a period of maximal sensitivity to thyroxine exists which corresponds to the period of development during which that structure undergoes its main morphological changes (i.e. from 6 to 13 days for the inner sulcus epithelium, the first postnatal week for the tectorial membrane, from 6 to 10 days for the pillars and the tunnel of Corti, the second and probably a part of the third postnatal week for outer hair cell synaptogenesis).

Topics: Age Factors; Animals; Cochlea; Congenital Hypothyroidism; Hypothyroidism; Microscopy, Electron; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine

Rats were treated with propylthiouracil (PTU) for 10-day periods beginning at different ages. Daily injections of L-thyroxine (T4) were administered concurrently with PTU to a group of rats which served as one control group. Peripheral auditory function was evaluated by the brainstem response audiometry (BSRA) technique performed at 12, 16, 25 and 120 days of age. PTU treatment significantly increased wave I latency (cochlear nerve compound action potential) in adult rats when administered from 3 days before delivery through 6 days of age, but was without permanent effect (wave I latencies and thresholds) when administered for 10 days starting at 10 days after birth. T4 replacement during the first 10 postnatal days prevented permanent abnormalities. These data suggest that the period of greatest vulnerability to thyroid hormone depletion in the peripheral auditory system extends from at least 3 days before delivery through between 5 and 10 days of age.

Topics: Animals; Animals, Newborn; Auditory Pathways; Brain Stem; Cochlear Nerve; Congenital Hypothyroidism; Evoked Potentials, Auditory; Female; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Hormones

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

The influence of thyroid hormone on serotonin was studied in different regions of the rat brain. Surgical thyroidectomy of adult male rats led to significant increases in the level of serotonin in the hypothalamus but had no effect on this biogenic amine in the brain stem and basal ganglia. Experimental cretinism, induced by daily propylthiouracil treatment starting at birth, caused increased serotonin levels in all brain regions studied. In contrast. neonatal hyperthyroidism, produced by daily administration of L-triiodothyronine from birth, had no effect on the ontogenic patterns of serotonin. The turnover of serotonin, estimated by determining the rate of increase of the amine following administration of the monoamine oxidase inhibitor, pargyline, was decreased in the brains of 30-day-old cretinous rats when compared to their control littermates. The data suggest that thyroid hormone may exert an important regulatory influence on serotonin metabolism in the developing brain.

Topics: Animals; Animals, Newborn; Basal Ganglia; Brain; Brain Stem; Congenital Hypothyroidism; Hyperthyroidism; Hypothalamus; Hypothyroidism; Male; Pargyline; Propylthiouracil; Rats; Serotonin; Thyroid Gland; Thyroid Hormones; Thyroidectomy; Time Factors; Triiodothyronine

Topics: Antithyroid Agents; Congenital Hypothyroidism; Female; Goiter; Humans; Hyperthyroidism; Hypothyroidism; Infant; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature, Diseases; Iodine Radioisotopes; Long-Acting Thyroid Stimulator; Male; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Function Tests; Thyroid Hormones; Thyrotropin; Thyroxine; Twins

Topics: Child; Congenital Hypothyroidism; Diagnosis; Humans; Hyperthyroidism; Infant; Infant, Newborn; Propylthiouracil; Thyroid Function Tests; Thyroiditis; Thyroiditis, Autoimmune; Thyrotoxicosis; Thyroxine; Triiodothyronine