Bisphenol-A and Reproductive Dysfunction

描述(申请人提供)：内分泌干扰化合物(EDC)是荷尔蒙活性的、合成的或天然的化学物质，干扰内分泌系统的正常功能，最显著的是生殖内分泌轴。对EDC的担忧主要是因为有研究指出，EDC对人类可能产生的影响包括雌激素敏感型癌症的急剧增加，人类精子质量和数量的下降，子宫内膜异位症的显著增加，以及女性青春期提前。由于雌二醇在生殖和其他生物过程中起着普遍和关键的作用，环境中的雌激素污染物特别令人担忧。鉴于性激素在发育过程中对器官分化起着至关重要的作用，有理由预计在子宫内暴露于外源性类固醇可能会改变胎儿的发育轨迹，最终导致成年生殖功能障碍。我们以绵羊为模型的初步研究表明，产前暴露于增塑剂双酚A(BPA)，一种与环境相关的EDC，水平接近人类母体血液和羊水中的水平，导致出生体重低的雌性后代，出生后早期促性腺功能亢进，以及表现为严重抑制促黄体生成素激增的周期缺陷。在这项建议中，我们将测试一种假设，即产前暴露于BPA(一种类似于环境雌激素的环境雌激素)的水平与人类胎儿的暴露水平相似，将通过扰乱控制出生后GnRH/LH分泌的神经内分泌反馈控制和卵巢对促性腺激素的敏感性的机制来扰乱成年生殖功能。此外，产前暴露于双酚A将加剧出生后对类固醇暴露的生殖易感性，并最终导致生殖失败。三个具体目标将检验这些假说。在具体目标1中，我们将确定母体循环中的未结合双酚A是否到达胎儿，并在人类胎儿看到的水平上扰乱成人生殖功能。在具体目标2中，我们将确定产前BPA效应是在神经内分泌还是在卵巢水平介导的，并涉及破坏控制出生后神经内分泌反馈控制GnRH/LH分泌和/或卵巢对促性腺激素的敏感性的机制。在具体目标3中，我们将确定产前暴露于双酚A是否会加剧出生后雌激素暴露的生殖易感性，最终导致生殖失败。该提案针对NICHD在2000-2001年召开的讲习班产生的战略计划的关键要素，侧重于三个有针对性的领域：疾病的胎儿先兆、21世纪的生殖健康和发育生物学。这一发现将与不孕不育的胎儿起源以及目前暴露水平的雌激素环境干扰物对人类健康构成的威胁的研究相关。

DESCRIPTION (provided by applicant): Endocrine disrupting compounds (EDC) are hormonally active, synthetic or natural chemicals that interfere with normal functioning of the endocrine system, most notably the reproductive endocrine axis. Concern about EDC has mainly been fueled by studies that point to likely effects of EDC exposure on humans including dramatic increases in estrogen sensitive cancers, decline in human sperm quality and quantity, a notable rise in endometriosis, and early puberty in women. Because of the universal and crucial role estradiol plays in reproduction and other biologic processes, estrogenic pollutants in the environment are of particular concern. Given that sex steroids play a crucial role in organ differentiation during development, it is reasonable to expect in utero exposure to exogenous steroid mimics may alter the developmental trajectory of the fetus culminating in adult reproductive dysfunction. Our preliminary studies using sheep as a model revealed that prenatal exposure to the plasticizer bisphenol A (BPA), an environmentally relevant EDC, at levels approaching that found in human maternal blood and amniotic fluids, resulted in low birth weight female offspring, early postnatal hypergonadotropism, and cycle defects manifested as severe dampening of the LH surge. In this proposal, we will test the hypothesis that prenatal exposure to BPA, an environmental estrogen mimic, at levels similar to what human fetuses are exposed to, will disrupt adult reproductive function by disrupting the mechanisms controlling postnatal neuroendocrine feedback controls of GnRH/LH secretion and ovarian sensitivity to gonadotropins. Further, prenatal exposure to BPA will exacerbate postnatal reproductive susceptibility to steroid exposure and culminate in reproductive failure. Three Specific Aims will test these hypotheses. In Specific Aim 1, we will determine if unconjugated BPA in the maternal circulation reaches the fetus and at levels seen by the human fetus disrupt adult reproductive function. In Specific Aim 2, we will determine if prenatal BPA effect is mediated at the neuroendocrine or ovarian level and involves disruption of the mechanisms controlling postnatal neuroendocrine feedback controls of GnRH/LH secretion and/or ovarian sensitivity to gonadotropins. In Specific Aim 3, we will determine if prenatal exposure to BPA exacerbates reproductive susceptibility to postnatal estradiol exposure culminating in reproductive failure. The proposal targets key elements of strategic plans that emanated from workshops convened by the NICHD in 2000-01 by focusing on three targeted areas: fetal antecedents of disease, reproductive health for the 21st century, and developmental biology. The findings will be relevant to research on fetal origin of infertility and the threat estrogenic environmental disruptors at current exposure levels pose to human health.