Developmental programming: Impact of fetal exposure to endocrine disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus

摘要

Bisphenol-A (BPA) and methoxychlor (MXC), two endocrine disrupting chemicals (EDCs) with estrogenic and anti-androgenic effects, disrupt the reproductive system. BPA has profound effects on luteinizing hormone (LH) surge amplitude and MXC on LH surge timing in sheep. The neural mechanisms involved in differential disruption of the LH surge by these two EDCs remains to be elucidated. We tested the hypothesis that differential effects of BPA and MXC on LH surge system involved changes in hypothalamic gonadotropin releasing hormone (GnRH) and estrogen receptors (ESR), ESR1 and ESR2 mRNA expression. Pregnant sheep were given daily injections of cottonseed oil (controls), MXC or BPA (5 mg/kg/day) from day 30 to 90 of gestation (term 147 d). Offspring from these animals were euthanized as adults, during the late follicular phase following synchronization of estrus with prostaglandin F2α, just prior to the expected onset of preovulatory LH surge and changes in mRNA expression of hypothalamic GnRH, ESR1, and ESR2 quantified following in situ hybridization. GnRH mRNA expression was significantly lower in both groups of EDC-treated females compared to controls. ESR1 expression was increased in prenatal BPA- but not MXC-treated females in medial preoptic area relative to controls. In contrast ESR2 expression was reduced in the medial preoptic area of both EDC-treated groups. Differences in expression of ESR1/ESR2 receptors may contribute to the differential effects of BPA and MXC on the LH surge system. These findings provide support that prenatal exposure to EDCs alters the neural developmental trajectory leading to long-term reproductive consequences in the adult female.