Bisphenol A and Ovotoxicity

描述(申请人提供)：双酚A(BPA)是一种内分泌干扰性化学物质，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、食品罐头衬里和牙科材料。双酚A的广泛使用引起了人们的担忧，因为在各种物种中，发育和出生后暴露于双酚A与女性不孕有关。虽然接触双酚A会导致多种物种的不孕，但双酚A导致不孕的原因尚不清楚。初步数据表明，双酚A可能通过抑制卵泡生长和诱导卵泡死亡(闭锁)而导致不孕不育。此外，初步数据表明，双酚A可能通过抑制卵巢产生雌二醇(E2)而导致不孕。关于双酚A对卵巢功能的影响，几乎没有其他信息。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完美的机会。NCTR/FDA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。具体地说，这项拟议的工作将扩大NCTR/FDA的研究范围，验证BPA暴露抑制卵泡生长并导致闭锁、导致低E2水平继而导致不孕不育和/或卵巢早衰的假设。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/或导致大鼠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/或通过增加大鼠卵巢中的E2代谢来降低E2水平，以及3)确定BPA暴露是否能够导致成年大鼠的不孕不育和卵巢早衰。这项拟议的工作将增加我们对BPA引起卵毒性的机制的理解。了解BPA损害卵巢的机制很重要，因为这可能导致开发新的靶点来治疗由BPA引起的低E2水平、不孕不育和卵巢早衰。

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.