Bisphenol A and Ovotoxicity

描述（由申请人提供）：双酚A （BPA）是一种内分泌干扰化学物质，广泛用于聚碳酸酯塑料，如食品包装产品、牛奶容器、婴儿奶瓶、食品罐头衬垫和牙科材料。BPA的广泛使用引起了人们的关注，因为在发育和出生后暴露于BPA与多种物种的女性不育有关。虽然BPA暴露会导致多种物种不孕，但BPA导致不孕的原因尚不清楚。初步数据表明，BPA可能通过抑制卵巢卵泡生长和诱导死亡（闭锁）而导致不孕。此外，初步数据表明BPA可能通过抑制卵巢产生雌二醇（E2）而导致不孕。关于双酚a对卵巢功能影响的其他信息很少。这项由国家毒理学研究中心/食品和药物管理局（NCTR/FDA）计划的研究为检验双酚a对卵巢的影响提供了一个绝佳的机会。NCTR/FDA的设计可以很容易地扩展到测量BPA对卵巢卵泡生长、闭锁、卵泡数量、E2水平、不孕症和卵巢早衰的影响。具体来说，拟议的工作将通过测试BPA暴露抑制卵泡生长和诱导闭锁的假设来扩展NCTR/FDA的研究，从而导致E2水平降低，随后导致不孕和/或卵巢早衰。为了验证这一假设，将完成以下具体目标：1)确定BPA暴露是否通过抑制卵泡生长和/或诱导卵巢闭锁来减少卵泡数量；2)确定BPA暴露是否通过抑制E2合成和/或增加E2在大鼠卵巢中的代谢来降低E2水平；3)确定BPA暴露是否会导致成年大鼠不孕和卵巢早衰。拟议的工作将增加我们对双酚a引起卵巢毒性的机制的理解。了解BPA损害卵巢的机制是很重要的，因为这可能会导致新的靶点的发展，以治疗低E2水平，不孕症，以及由BPA引起的卵巢早衰。

DESCRIPTION (provided by applicant): Bisphenol A (BPA) is an endocrine disrupting chemical that is widely used in polycarbonate plastics such as food packaging products, milk containers, baby bottles, liners for food cans, and dental materials. The widespread use of BPA raises concerns because developmental and postnatal exposures to BPA have been linked to female infertility in a variety of species. While BPA exposure causes infertility in a variety of species, the reasons for BPA-induced infertility are unknown. Preliminary data suggest that BPA may cause infertility by inhibiting growth and inducing death (atresia) of ovarian follicles. Further, preliminary data indicate that BPA may cause infertility by inhibiting the production of estradiol (E2) by the ovary. Little other information is available on the effects of BPA on ovarian function. The study planned by the National Center for Toxicologic Research/Food and Drug Administration (NCTR/FDA) offers a perfect opportunity to examine the effects of BPA on the ovary. The NCTR/FDA design can easily be expanded to measure the effects of BPA on ovarian follicle growth, atresia, follicle numbers, E2 levels, infertility, and premature ovarian failure. Specifically, the proposed work will expand the NCTR/FDA study by testing the hypothesis that BPA exposure inhibits follicle growth and induces atresia, leading to low E2 levels followed by infertility and/or premature ovarian failure. To test this hypothesis, the following specific aims will be completed: 1) determine if BPA exposure reduces follicle numbers by inhibiting follicle growth and/or inducing atresia in rat ovaries, 2) determine if BPA exposure reduces E2 levels by inhibiting E2 synthesis and/or by increasing E2 metabolism in rat ovaries, and 3) determine the ability of BPA exposure to cause infertility and premature ovarian failure in the adult rat. The proposed work will increase our understanding of the mechanisms by which BPA causes ovotoxicity. It is important to understand the mechanisms by which BPA damages the ovary because this may lead to the development of novel targets for the treatment of low E2 levels, infertility, and premature ovarian failure induced by BPA.