Bisphenol-A and the Reproductive Dysfunction

摘要 内分泌干扰化合物(EDC)是一种荷尔蒙活性的、合成的或天然的化学物质，可以干扰 内分泌系统的正常运作，最显著的是生殖内分泌轴。令人担忧的 EDC的主要推动力是研究指出EDC对人类可能产生的影响，包括 雌激素敏感型癌症急剧增加，人类精子质量和数量下降，显著上升 子宫内膜异位症，以及女性的青春期提前。因为雌激素在人体内起着普遍而关键的作用 在生殖和其他生物过程中，环境中的雌激素污染物尤其令人关注。 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，因此有理由 预计在宫内暴露于外源性类固醇可能会改变胎儿的发育轨迹 最终导致成人生殖功能障碍。我们以绵羊为模型的初步研究表明， 产前接触增塑剂双酚A(BPA)，一种与环境有关的EDC，水平接近 在人类母血和羊水中发现的这种物质，会导致早产低出生体重的女性后代。 出生后促性腺功能亢进和周期缺陷表现为严重抑制促黄体生成素峰值。在这 提案中，我们将检验产前暴露于双酚A的假设，双酚A是一种环境雌激素模拟物，在 水平与人类胎儿接触的水平相似，将通过扰乱 促性腺激素释放激素/促黄体生成素分泌和卵巢的神经内分泌反馈调控机制 对促性腺激素敏感。此外，产前暴露于双酚A会加剧出生后的生殖。 对类固醇易感性，并最终导致生殖失败。三个具体的目标将检验这些 假设。特定目标1将确定母体循环中的未结合双酚A是否到达胎儿 而人类胎儿看到的水平会扰乱成人的生殖功能。具体目标2将决定是否 产前的双酚A效应是在神经内分泌或卵巢水平上介导的，涉及到干扰 促性腺激素释放激素/促黄体生成素分泌和/或卵巢的神经内分泌反馈控制机制 对促性腺激素敏感。具体目标3将确定产前暴露于双酚A是否会加剧 出生后对雌二醇暴露的生殖易感性，最终导致生殖失败。这项建议 目标是2000-2001年日内瓦排雷中心召开的讲习班产生的战略计划的关键要素 重点关注三个目标领域：胎儿疾病前兆、21世纪的生殖健康和 发育生物学。这些发现将与不孕症的胎儿起源及其威胁的研究相关。 在目前的暴露水平下，雌激素环境干扰物对人类健康构成威胁。

SUMMARY 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. Specific Aim 1 will determine if unconjugated BPA in the maternal circulation reaches the fetus and at levels seen by the human fetus disrupt adult reproductive function. Specific Aim 2 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. Specific Aim 3 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.