Effects Of Perinatal Hypothyroidism On Androgen Receptor Gene Expression In The Neonatal Rat Brain And Behavioral Development In Puberty

IntroductionIt has long been known that thyroid hormones play an important role in the regulation of the maturation of the nervous system. Nevertheless, the casual relationship between a thyroid hormone deficiency during the fetal and neonatal period and the irreversible brain damage caused by congenital hypothyroidism was not accepted until the second half of 20th century when the first "cretin" rats were produced experimentally. Differential gene expression is one of the mechanisms guiding mammalian brain development. Thyroid hormone exerts specific effects on brain development by regulating gene expression. Previous studies revealed relatively high levels of AR in the rat hippocampus, which shows that there may be some relationship between androgen receptors and cognitive aspects. Previous studies on behavioral evaluation in hypothyroid rats often used male animals only, with little or no regard to sex differences. Therefore, this study was conducted to assess the perinatal effects of the thyroid hormones deficiency on the expression of androgen receptor (AR) mRNA in the developing rat cerebral cortex and hippocampus, while we also investigated gender-related sexual differences in the effects of perinatal hypothyroidism on adolescent rat behavior.Methods1. Perinatal hypothyroidism was induced by the administration of propylthiouracil (PTU) solution to the dams by gavages (50mg/d) beginning on embryonic day 15 and continuing throughout the lactational period. A group of pups were injected intraperitoneally with levothroxine (L-T4) 2μg /100g BW daily, starting from the day of birth. Cerebral cortex and hippocampus specimen were collected from controls, hypothyroid and T4-injected hypothyroid rats on postnatal day 1,5, 10, 15 and 20. Quantification of ARmRNA in the cerebral cortex and hippocampus of developing rat were performed with competitive RT-PCR using internal and external standardization.2. The effects of perinatal hypothyroidism on the abilities to learn and retain memory traces and on behavior were studied in rats of both sexes at around 60 days. Experiments were performed using models of conditioned passive avoidance reflexes and the "open" field test. Hippocampus specimen tissues of all groups were collected to analyze ARmRNA expression using competitive RT-PCR.Results1. An age-related increases and sex difference in ARmRNA levels was observed in neonatal rats (with significantly higher levels for male animals). Evidence also suggests that AR expression is higher in the hippocampus than in the cerebral cortex. ARmRNA levels in the hypothyroid pups were lower than in the age-matched controls. The mRNA levels in the T4-injected hypothyroid pups were significantly higher, in comparison with the age-matched hypothyroid pups, but some hippocampus groups did not reach the normal level(male: 10, 20 days; female: 15, 20 days).2. In the open-field test, the amount of locomotor activity and the level of anxiety,measured by the total number of crossings and of defecation, indicated a gender difference with less activity and more defecation in normal male animals. Normal male rats performed better than females in passive avoidance reflexes. Perinatal hypothyroidism caused an increase of locomotor activity and decreased anxiety-related behavior in both sexes without a gender difference. In the passive avoidance test, hypothyroid rats performed poorly, but females changed a little and performed better than males. T4-injected hypothyroid rats performed significantly better in the tests than age-matched hypothyroid rats, and almost all groups reached the normal level except the number of crossing of male rats in open field. ARmRNA levels in hypothyroid hippocampus of adolescent male rats were lower than that in the controls, and the levels among the T4-injected hypothyroid pups reached the normal level. There was no significant difference among the three adolescent female groups.Conclusions1. The expression of ARmRNA decreases in the developing rat brain with perinatal hypothyroidism. Treatment with...