Effects Of Perinatal Hypothyroidism Research Articles

Perinatal Propylthiouracil-Induced Hypothyroidism Impaired Motor Coordination in Adult Female Offspring

Thyroid hormone (TH) play crucial roles in the growth and development of brain. Efficiency of TH during the perinatal period results in severe mental and physical retardation, known as cretinism in humans. Animal models have largely focused on mild and severe hypothyroidism associated with deficits in body weight, developmental delays, and cognitive deficits. Although various behavioral analyses have been reported, the effect of perinatal hypothyroidism in adult female mice has not been clarified. The aim of this study was to examine whether propylthiouracil (PTU)-induced hypothyroidism could impair motor coordination in female offspring. We used C57BL/6j mice and divided them into three groups based on the dose of PTU which was applied during perinatal period (embryonic day-14 to postnatal day-14); control, 5 ppm, and 50 ppm groups. We observed motor coordination function and additional nociceptive test in female offspring. We found that motor coordination and nociceptive threshold were affected in 50 ppm groups. We concluded that the moderate hypothyroidism could impair motor coordination in adult offspring.

Hyperactive behavioral phenotypes and an altered brain monoaminergic state in male offspring mice with perinatal hypothyroidism.

Thyroid hormone (TH) is essential for normal brain development. TH insufficiency during early stages of development may increase the risk for attention deficit/hyperactivity disorder, in which malfunction of brain monoaminergic systems is likely involved. However, little is known about the effects of perinatal hypothyroidism on behaviors and brain monoaminergic systems in offspring mice. The present study examined in mice (1) whether perinatal hypothyroidism causes hyperactive behavioral phenotypes, (2) how perinatal hypothyroidism influences brain monoaminergic systems, and (3) whether hyperactive behavioral phenotypes are associated with the state of brain monoaminergic systems. When dams were exposed to propylthiouracil, offspring mice developed hypothyroidism during the perinatal period. Offspring mice with perinatal hypothyroidism exhibited hyperactive behavioral phenotypes such as hyper-ambulatory activity and an increased response rate in the two-way active avoidance test in a male-specific manner. Significant decreases in dopamine (DA) and serotonin turnover were observed in the striatum (ST), nucleus accumbens, hypothalamus, and hippocampus in male mice with perinatal hypothyroidism. A significant correlation between ambulatory activity and DA turnover in the ST and an augmented ambulatory response to the DA reuptake inhibitor bupropion suggested that DA in the ST was involved in the hyper-ambulatory activity in mice with perinatal hypothyroidism.

Effects of perinatal hypothyroidism on reference memory in the rat

Effects of perinatal hypothyroidism on reference memory in the rat

Effects of perinatal hypothyroidism on regulation of reelin and brain-derived neurotrophic factor gene expression in rat hippocampus: Role of DNA methylation and histone acetylation

Thyroid hormones have long been known to play important roles in the development and functions of the central nervous system, however, the precise molecular mechanisms that regulate thyroid hormone-responsive gene expression are not well understood. The present study investigated the role of DNA methylaion and histone acetylation in the effects of perinatal hypothyroidism on regulation of reelin and brain-derived neurotrophic factor (BDNF) gene expression in rat hippocampus. The findings indicated that the activities of DNA methyltransferase (DNMT), methylated reelin and BDNF genes were up-regulated, whereas, the activities of histone acetylases (HAT), the levels of global acetylated histone 3 (H3) and global acetylated histone 4 (H4), and acetylated H3, acetylated H4 at reelin promoter and at BDNF gene promoter for exon II were down-regulated in the hippocampus at the developmental stage of the hypothyroid animals. These results suggest that epigenetic modification of chromatin might underlie the mechanisms of hypothyroidism-induced down-regulation of reelin and BDNF gene expression in developmental rat hippocampus.

Long-lasting effects of perinatal hypothyroidism on auditory startle responses and prepulse inhibition in weanling, adult, and elderly rats

Long-lasting effects of perinatal hypothyroidism on auditory startle responses and prepulse inhibition in weanling, adult, and elderly rats

Perinatal and chronic hypothyroidism impair behavioural development in male and female rats

A lack of thyroid hormone, i.e. hypothyroidism, during early development results in multiple morphological and functional alterations in the developing brain. In the present study, behavioural effects of perinatal and chronic hypothyroidism were assessed during development in both male and female offspring of hypothyroid rats. To induce hypothyroidism, dams and offspring were fed an iodide-poor diet and drinking water with 0.75% sodium perchlorate; dams starting 2 weeks prior to mating and pups either until the day of killing (chronic hypothyroidism) or only until weaning (perinatal hypothyroidism) to test for reversibility of the effects observed. Neuromotor competence, locomotor activity and cognitive function were monitored in the offspring until postnatal day 71 and were compared with age-matched control rats. Early neuromotor competence, as assessed in the grip test and balance beam test, was impaired by both chronic and perinatal hypothyroidism. The open field test, assessing locomotor activity, revealed hyperactive locomotor behavioural patterns in chronic hypothyroid animals only. The Morris water maze test, used to assess cognitive performance, showed that chronic hypothyroidism affected spatial memory in a negative manner. In contrast, perinatal hypothyroidism was found to impair spatial memory in female rats only. In general, the effects of chronic hypothyroidism on development were more pronounced than the effects of perinatal hypothyroidism, suggesting the early effects of hypothyroidism on functional alterations of the developing brain to be partly reversible and to depend on developmental timing of the deficiency.

Behavioral development in adolescent rats of perinatal hypothyroidism and its relations to androgen receptor gene expression in hippocampus

To investigate the behavioral development in adolescent rats of perinatal hypothyroidism and its relation to androgen receptor (AR) gene expression in the hippocampus. Perinatal hypothyroidism was induced by gavages 50 mg/d of propylthiouracil solution in 48 dams starting at embryonic day 15 through the lactation period. Twenty-four pups (M:F=1) of perinatal hypothyroidism were injected intraperitoneally with 2 microg T(4)/100 g BW daily from the day of birth to the age of 21 days (treatment group); 24 pups (M:F=1) without treatment were designated as hypothyroidism group. And 24 normal pups (M:F=1) served as the control group. The effects of perinatal hypothyroidism on the abilities to learn and retain memory traces and on behavior were observed in rats of both sexes at 60 days. Experiments were performed using models of conditioned "open" field test and passive avoidance reflexes. Hippocampus samples were collected and AR mRNA was detected by competitive RT-PCR. Perinatal hypothyroidism caused an increase of crossing number and decrease of rearing and defecation in both sexes. In treatment groups, only the crossing number in male didn't reach the normal level (P >0.05). In passive avoidance test, hypothyroidism groups showed more mistakes in both sexes and shorter latencies in males, the females performed better than males (P <0.01). The treatment groups performed significantly better than the age-matched hypothyroidism groups and reached the normal level (P >0.05). AR mRNA levels in hippocampus of hypothyroid group were lower than those of the controls in males, and the levels in treatment groups were significantly higher in comparison with the hypothyroidism groups (P <0.01). There were no significant differences among the three female groups (P >0.05). In male group, there was negative correlation between the number of crossing and AR mRNA in the hippocampus (r=-0.537, P=0.001), negative correlation between the number of mistake and AR mRNA (r=-0.532, P=0.001), and positive correlation between the latency and AR mRNA (r=0.564, P=0.000). Perinatal hypothyroidism results in hyperactivity and anti-anxiety effects on adolescent rats, the sex difference is depleted, and also causes learning and memory impairment but the degree of influence higher in male than female. The decreased level of AR mRNA expression in hippocampus contributes to the change of behavioral ability in adolescent male.

Perinatal hypothyroidism effects on step-through passive avoidance task in rats

Previous studies have documented a decrease in the ability of neonatal hypothyroid animals to learn and habituate to maze tests, and an increase in spontaneous activity. However, there is little information about the effects of perinatal (i.e., prenatal and postnatal) hypothyroidism on behaviour. The present study was designed to assess whether perinatal hypothyroidism in rats induces alteration on acquisition and/or short- and long-term retention of a learned response in male Wistar rats. Perinatal hypothyroidism was induced by prolonged (E9-P21) exposure of pregnant and lactating dams to methimazole (administered orally in drinking water, 0.2 mg/ml). Cognitive function was tested at 50 days by means of a step-through passive avoidance task. The effects of perinatal hypothyroidism on the retention of the passive avoidance response are long lasting being, however, highly dependent on the retention after the original training. Our results showed that methimazole-treated rats performed more poorly when retention was tested at long-term (24 h and 7 days) retention interval. Instead, methimazole-treated rats showed longer retrieval latencies than the control ones did when retention was tested at short term (1 h).

Effect of perinatal hypothyroidism on expression of cytochrome c oxidase subunit I gene, which is cloned by differential plaque screening from the cerebellum of newborn rat.

Early development of the central nervous system is influenced by several hormones including thyroid hormone. This study was designed to clone the gene whose expression is changed in association with perinatal hypothyroidism in the rat cerebellum. Rats were sacrificed at 15 day-old postnatal age (P15) and their cerebella were removed. Poly (A)+ RNA was extracted to construct a cDNA library using lambda gt 10 cloning vector. Differential plaque screening was then performed using 32P-labeled antisense cDNA synthesized from poly (A)+ RNA of the methimazole-treated (hypothyroid) P15 rat cerebellum (hypothyroid probe), and of the euthyroid P15 rat cerebellum (euthyroid probe). The clones, which hybridized strongly to the euthyroid probe and weakly or not at all to the hypothyroid probe, were isolated. Sequence analysis of these clones revealed that all isolated clones encode cytochrome c oxidase subunit I (COX I), which is located in the mitochondrial DNA. The decrease in COX I gene expression was not seen in the animals, which received methimazole treatment and daily replacement of thyroid hormone. In situ hybridization detection showed not only overall decrease in COX I gene expression but also change in distribution of hybridization signal in the cerebellar cortex of hypothyroid rat. Such change was not observed in the T4-replaced animals. Based on the evidence that thyroid hormone greatly influences brain development, the results of the present study indicate that the terminal enzyme of mitochondrial respiratory chain, COX I is one of the important target molecules regulated by thyroid hormone in the newborn rat cerebellum.

Effect of perinatal hypothyroidism on the developmental regulation of rat pituitary growth hormone and thyrotropin genes

We studied the effects of thyroid hormone (T3) on GH, TSH, and T3 receptor (TR) gene expression as well as deiodinase activities during rat pituitary development. By reverse transcriptase-polymerase chain reaction, GH and TSH beta transcripts were detectable on fetal day 15. Although with certain differences, the expression of both GH and TSH beta genes was under T3 control during fetal and neonatal life. Differences in plasma, but not pituitary, TSH concentrations were observed between control and hypothyroid animals throughout the period studied. Both TR alpha and TR beta genes were expressed in the fetal pituitary. TR alpha 1, TR beta 2, and c-erbA alpha 2 transcripts displayed a developmental profile different from that of TR beta 1. Thyroid hormone repressed TR alpha 1, TR beta 2, and c-erbA alpha 2 and stimulated TR beta 1. Type I and type II deiodinase activities (5'DI and 5'DII, respectively) had different ontogenic patterns; 5'D-II was the predominant activity in fetuses, with levels similar to those in adults, whereas the level of 5'D-I was low and increased with age. T3 stimulated 5'D-I and decreases 5'D-II. These results demonstrate that in somatotroph and thyrotroph cells, the mechanisms responsible for T3 action are mature and active very early in development and suggest an involvement of this hormone in the establishment and/or maintenance of the somatotroph and thyrotroph phenotype.

Effect of perinatal hypothyroidism on the developmental regulation of rat pituitary growth hormone and thyrotropin genes.

We studied the effects of thyroid hormone (T3) on GH, TSH, and T3 receptor (TR) gene expression as well as deiodinase activities during rat pituitary development. By reverse transcriptase-polymerase chain reaction, GH and TSH beta transcripts were detectable on fetal day 15. Although with certain differences, the expression of both GH and TSH beta genes was under T3 control during fetal and neonatal life. Differences in plasma, but not pituitary, TSH concentrations were observed between control and hypothyroid animals throughout the period studied. Both TR alpha and TR beta genes were expressed in the fetal pituitary. TR alpha 1, TR beta 2, and c-erbA alpha 2 transcripts displayed a developmental profile different from that of TR beta 1. Thyroid hormone repressed TR alpha 1, TR beta 2, and c-erbA alpha 2 and stimulated TR beta 1. Type I and type II deiodinase activities (5'DI and 5'DII, respectively) had different ontogenic patterns; 5'D-II was the predominant activity in fetuses, with levels similar to those in adults, whereas the level of 5'D-I was low and increased with age. T3 stimulated 5'D-I and decreases 5'D-II. These results demonstrate that in somatotroph and thyrotroph cells, the mechanisms responsible for T3 action are mature and active very early in development and suggest an involvement of this hormone in the establishment and/or maintenance of the somatotroph and thyrotroph phenotype.

Perinatal Hypothyroidism Decreases Hippocampal Mossy Fiber Zinc Density in Rats

The effect of perinatal hypothyroidism on hippocampal mossy fiber zinc density was examined in rats. Timed pregnant Sprague-Dawley rat dams were given water containing either 0.02% propylthiouracil (PTU) or vehicle from gestational day 18 until their litters were weaned on postnatal day 31. Hippocampal mossy fiber zinc density was reduced by 75% in both the dorsal and ventral hippocampal formation CA3 stratum lucidum region of 31-day-old PTU-treated rats compared to untreated controls. Perinatal hypothyroidism did not alter hippocampal tissue zinc concentration, indicating that the PTU-induced reduction in mossy fiber zinc was not a consequence of reduced hippocampal zinc concentration. At 120 days of age, 3 months after discontinuation of PTU treatment, hippocampal mossy fiber zinc density remained significantly reduced by 33-45% in PTU-treated rats compared to control. These data indicate that perinatal hypothyroidism causes a long-lasting reduction in hippocampal mossy fiber zinc density.

Effects of perinatal hypothyroidism in the carbohydrate composition of cochlear tectorial membrane

The presence of carbohydrates in the cochlear tectorial membrane (TM) of normal and hypothyroid rats was analyzed using fluorescent lectin probes. SBA and WGA lectins exhibited a similar reactivity in both normal and hypothyroid TMs. DBA, RCA1, UEA1 and Con A lectins were also reactive, although they showed a different distribution pattern between normal and hypothyroid TMs. Lastly, one of the lectins, PNA, was only labeled in hypothyroid TMs. These findings suggest that carbohydrate chains containing residues of N- acetyl- d- galactosamine (Ga1NAc) and N- acetyl- d- glucosamine , are similarly distributed in normal and hypothyroid TMs. Other carbohydrate residues as Ga1Nacα1,3 Ga1NAc, d-galactose (Gal), l-fucose and d-mannose, are present, but are abnormally distributed in hypothyroid TMs. The Galβ1,3Ga1NAc residues, recognized by PNA, could be present only in the hypothyroid TMs. Alterations in glycosilation of the glycoproteins in the hypothyroid TM could be responsible for the abnormal distribution pattern of carbohydrate residues here described, and for the distorted shape of the hypothyroid TM.

Perinatal Hypothyroidism Decreases Hippocampal &lt;sup&gt;3&lt;/sup&gt;H-Vinylidene Kainic Acid Binding in Rats

The effect of perinatal hypothyroidism on the number and distribution of hippocampal kainic acid binding sites was examined in rats. Timed pregnant Sprague-Dawley rat dams were given water containing either 0.02% propylthiouracil (PTU) or untreated water from gestational day 18 until their litters were weaned at postnatal day 31. The offspring were sacrificed at 31 or 120 days of age, blood samples collected and their brains frozen. In the 31-day-old rats, serum thyroxine, serum triiodothyronine, total body weight and whole brain weight all indicated that the PTU-treated rats were hypothyroid. Hippocampal kainic acid binding was analyzed in sections of dorsal and ventral hippocampal formation by in vitro 3H-vinylidene kainic acid (VKA) autoradiography. Compared to the untreated controls, specific 3H-VKA binding was reduced by 43% in the ventral hippocampal formation stratum lucidum of 31-day-old PTU-treated rats. Specific 3H-VKA binding was not different in the dorsal hippocampal formation. Saturation of 3H-VKA binding studies indicated that the decrease-induced by PTU treatment--in ventral hippocampal 3H-VKA binding was due to a reduction in the total number of 3H-VKA binding sites. At 120 days of age, 3 months after the cessation of the PTU treatment, serum thyroid hormone levels were not different than those of controls, indicating a recovery of thyroid hormone function after the perinatal PTU treatment. However, specific 3H-VKA binding remained significantly reduced in the ventral hippocampal formation of 120-day-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of home orientation in hypothyroid and hyperthyroid rat pups.

In order to assess the effects of perinatal hypothyroidism or hyperthyroidism on the development of an integrated behavioral response, we tested hypothyroid, hyperthyroid, and control pups, as well as pups receiving thyroxine replacement therapy, for the development of the home orientation response. Hypothyroidism was induced in the pups by feeding the pregnant or lactating female a diet of .2% propylthiouracil from Day 15 of gestation to Day 22 postpartum. Pups receiving replacement therapy and pups made hyperthyroid were injected daily with thyroxine, starting at birth. The ability of the pups to initiate and maintain locomotion toward the nest was assessed between Days 4 and 22. Hyperthyroid, control, and replacement therapy pups behaved very similarly on the task, showing a peak in the percentage of pups homing between Days 12 and 16. Hypothyroid pups showed a delay in the peak percentage until Day 20, although the percentage of pups was similar to that found in other treatments. An integrated behavioral response can be delayed by hypothyroidism and still emerge apparently intact at a later age.

Effect of perinatal hypothyroidism by 6-propyl-2-thiouracil on sexual maturation in female rats

妊娠18日目から分娩後19日までPTU0.04%を含む飼料で母ラットを飼育し,甲状腺機能低下を誘起した雌子ラットの成長,性成熟について無処理の対照と比較したところ,以下の結果を得た。1. 成長は顕著に遅れた。2. 腔開口,腟垢の発情期像出現の日齢が顕著に遅れた。3. 卵巣,子宮の発育が遅れた。4. 下垂体LH含量が低下した。5. 以上の現象は生後0~19日齢までのT4処理により打ち消された。

The persistent effects of perinatal hypothyroidism on pituitary, thyroidal, and gonadal functions.

Abstract In view of the persistent consequences of neonatal hyperthyroidism, the late effects of brief perinatal hypothyroidism were studied in the rat. The administration of propylthiouracil (PTU) either during the end of pregnancy or neonatally or both resulted in a persistently enlarged thyroid gland associated with an elevated pituitary and hypothalamic thyroid-stimulating hormone (TSH) content, a diminished rate of net synthesis of TSH, and a slightly diminished serum thyroid hormone concentration. Comparable PTU treatment of both young and adult rats failed to produce persistent changes in pituitary TSH content or in the PBI. Perinatal hypothyroidism also caused a delay in puberty with prolongation of estrous cycles. Treatment with thyroxin (T 4 ) neonatally, after prenatal PTU administration, prevented the late pituitary-thyroidal changes but not the gonadal effects. The possibility that pregnant women receiving PTU during pregnancy may have children with mild late gonadal and thyroidal alterations must be considered and should be studied.