Bisphenol-A and Reproductive Dysfunction

双酚 A 与生殖功能障碍

基本信息

批准号：
8077648
负责人：
VASANTHA PADMANABHAN
金额：
$ 7.68万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-11 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8077648
关键词：
Adult Agriculture Amniotic Fluid Area Attention Blood Blood Circulation Chemicals Coin Complex Data Defect Development Developmental Biology Disease Educational workshop Elements Endocrine Endocrine Disruptors Endocrine system Environment Environmental Estrogen Environmental Pollutants Epidemiology Estradiol Estrogens Exposure to Failure Feedback Female Fetus Functional disorder Gonadal Steroid Hormones Gonadotropins Health Hormonal Hormones Human Industrial Waste Infertility Low Birth Weight Infant Malignant Neoplasms Mediating Metabolic Modeling National Institute of Child Health and Human Development Neurosecretory Systems Nutritional Organ Ovarian Pathway interactions Perinatal Exposure Physiological Physiology Plasticizers Play Predisposition Pregnancy Process Puberty Reproduction Reproductive Health Research Role Sheep Steroids Strategic Planning Structure Testing Woman bisphenol A endometriosis environmental agent fetal offspring pollutant postnatal prenatal prenatal exposure programs public health relevance reproductive reproductive function sperm quality trend

项目摘要

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.

描述（由申请人提供）：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，会干扰内分泌系统的正常功能，尤其是生殖内分泌轴。对 EDC 的担忧主要是由一些研究引起的，这些研究指出 EDC 暴露对人类可能产生的影响，包括雌激素敏感癌症的急剧增加、人类精子质量和数量的下降、子宫内膜异位症的显着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发挥普遍且关键的作用，环境中的雌激素污染物特别令人关注。鉴于性类固醇在发育过程中的器官分化中发挥着至关重要的作用，因此可以合理地预期，在子宫内暴露于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)（一种与环境相关的 EDC），其含量接近人类母体血液和羊水中的含量，会导致女性后代出生体重低、产后早期促性腺激素亢进。，循环缺陷表现为 LH 激增的严重抑制。在本提案中，我们将测试以下假设：产前接触 BPA（一种环境雌激素模拟物），其水平与人类胎儿所接触的水平相似，会通过破坏控制 GnRH/LH 分泌的产后神经内分泌反馈控制的机制来破坏成年生殖功能和卵巢对促性腺激素的敏感性。此外，产前接触 BPA 会加剧产后生殖对类固醇暴露的敏感性，并最终导致生殖衰竭。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未结合的 BPA 是否会到达胎儿以及人类胎儿所见的水平是否会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介导，并涉及破坏控制 GnRH/LH 分泌和/或卵巢对促性腺激素敏感性的产后神经内分泌反馈控制的机制。在具体目标 3 中，我们将确定产前接触 BPA 是否会加剧对产后雌二醇暴露的生殖易感性，最终导致生殖障碍。该提案针对 NICHD 于 2000-01 年召开的研讨会提出的战略计划的关键要素，重点关注三个目标领域：胎儿疾病的前因、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以及当前暴露水平下的雌激素环境干扰物对人类健康造成的威胁的研究相关。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，会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发挥普遍且关键的作用，环境中的雌激素 EDC 受到特别关注。该提案将确定胎儿接触双酚 A（一种环境雌激素 EDC）的机制，其水平与人类胎儿的水平相似，会破坏女性的生殖功能，以及如果持续接触雌激素化合物，这种影响是否会加剧。这些发现将与雌激素环境干扰物在当前暴露水平下对生殖健康造成的威胁相关。