Bisphenol-A and Reproductive Dysfunction

描述（由申请人提供）：内分泌干扰化合物（EDC）是激素活性，合成或天然化学物质，干扰内分泌系统的正常功能，最明显的是生殖内分泌轴。对EDC的关注主要是由一些研究引起的，这些研究指出，接触EDC可能对人类造成的影响包括雌激素敏感性癌症的急剧增加，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受到特别关注。鉴于性类固醇在发育过程中的器官分化中起着至关重要的作用，我们有理由认为，子宫内接触外源性类固醇模拟物可能会改变胎儿的发育轨迹，最终导致成年后的生殖功能障碍。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，其水平接近人类母体血液和羊水中发现的水平，导致雌性后代出生体重低，产后早期促性腺功能异常，以及表现为LH激增严重抑制的周期缺陷。在本研究中，我们将验证一种假设，即产前暴露于与人类胎儿暴露水平相似的环境雌激素模拟物BPA，会通过破坏控制产后GnRH/LH分泌的神经内分泌反馈控制和卵巢对促性腺激素敏感性的机制来破坏成人生殖功能。此外，产前暴露于双酚a会加剧产后对类固醇暴露的生殖易感性，最终导致生殖失败。三个具体目标将检验这些假设。在具体目标1中，我们将确定母体循环中的非共轭双酚a是否会到达胎儿体内，并达到胎儿所见的水平，从而破坏成人的生殖功能。在具体目标2中，我们将确定产前BPA效应是否在神经内分泌或卵巢水平上介导，是否涉及到产后神经内分泌反馈控制GnRH/LH分泌和/或卵巢对促性腺激素敏感性的机制的破坏。在具体目标3中，我们将确定产前暴露于BPA是否会加剧生殖易感性，而产后暴露于雌二醇是否会导致生殖失败。该提案针对2000- 2001年联合国儿童健康与发展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：胎儿疾病的前兆、21世纪的生殖健康和发育生物学。这些发现将与研究不孕的胎儿来源和目前暴露水平的雌激素环境干扰物对人类健康的威胁有关。公共卫生相关性：内分泌干扰化合物（EDC）是具有激素活性的合成或天然化学物质，可干扰内分泌系统的正常功能，尤其是生殖内分泌轴。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，环境中的雌激素性EDCs受到特别关注。该提案将确定胎儿暴露于双酚a（一种环境雌激素EDC）的机制，该机制与人类胎儿暴露于双酚a的水平相似，会破坏女性的生殖功能，以及这种影响是否会随着持续暴露于雌激素化合物而被夸大。研究结果将与雌激素环境干扰物在目前暴露水平下对生殖健康构成的威胁有关。

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. PUBLIC HEALTH RELEVANCE: 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. Because of the universal and crucial role estradiol plays in reproduction and other biologic processes, estrogenic EDCs in the environment are of particular concern. This proposal will determine the mechanisms by which fetal exposure to bisphenol-A, an environmental estrogenic EDC, at levels similar to what human fetuses are exposed to will disrupt reproductive function in the female and if such effects are exaggerated with continued exposure to estrogenic compounds. The findings will be of relevance to the threat estrogenic environmental disruptors pose at current exposure levels to reproductive health.