Early Bpa Exposure Alters The Serum Thyroid Hormone Levels In Neonatal And Adult Rats Via Estrogen Receptors In Hypothalamus And Pituitary

Bisphenol A(BPA) is one of the most common environmental endocrine disruptors. It has been shown that perinatal BPA exposure is casually linked to neonatal thyroid dysfunction. However, the underlying mechanisms remain largely elusive. Here, we found that both perinatal and postnatal BPA exposure decreased serum thyroxine(T4) but increased serum triiodothyronine(T3) on postnatal day 21(PND21) and PND180 in male but not female rats. On the other hand, the serum TSH level was observed to experience a decline in male rats on PND180. As serum thyroid hormone level is under extensive regulation of the hypothalamus- pituitary-thyroid(HPT) axis, we next investigated whether BPA mediated these effects through disrupting the function of HPT axis. To this end, we examined the potential effect of postnatal BPA exposure on the nuclear expression of thyroid hormone receptor(THR)in developing hypothalamus and pituitary. The results showed that in PND14 and PND21, there was no difference between BPA-treated rats and control group in both genders, suggesting that the THR in the hypothalamus-pituitary may not be the factor mediating the effects of early BPA exposure. Somewhat surprisingly, BPA exposure had a bidirectional influence on its classical target, the estrogen receptor(ER) in the hypothalamus-pituitary of male pups. Compared to the control rats, the nuclear ER expression is markedly increased in BPA-exposed ones on PND14 but greatly increased on PND21. On the contrary, no difference was observed in control and BPA-exposed female rats. In order to further examine whether the ER in developing hypothalamus-pituitary was involved in BPA induced serum thyroid hormone level alteration in male rats, we used low dose of ICI 182,780(ICI), an ER antagonist to block the binding of ER with BPA. The results revealed that the treatment with low dose of ICI not only reversed the altered hypothalamus-pituitary nuclear ER expression in neonatal male rats, but also rescued the altered thyroid hormone levels in the adult male rats. We further found the effects of BPA on the hypothalamus nuclear ER expression also accounted for the hypothalamus related copulatory behavioral deficits, indicating that ER may be the critical factor which mediates hypothalamus dysfunction subsequent to early BPA exposure.