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Bisphenol-A and Reproductive Dysfunction

双酚 A 与生殖功能障碍

基本信息

批准号：
8391728
负责人：
VASANTHA PADMANABHAN
金额：
$ 35.91万
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 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8391728
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 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.

描述（由申请人提供）：内分泌干扰化合物（EDC）是具有生殖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。对EDC的担忧主要是由于研究指出EDC暴露对人类的可能影响，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着普遍和关键的作用，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期间的器官分化中起着至关重要的作用，因此可以合理预期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，最终导致成人生殖功能障碍。我们使用绵羊作为模型的初步研究显示，产前暴露于增塑剂双酚A（BPA），一种环境相关的EDC，接近人类母体血液和羊水中发现的水平，导致低出生体重雌性后代，出生后早期促性腺激素过多，以及表现为LH激增严重抑制的周期缺陷。在这个建议中，我们将测试的假设，产前暴露于BPA，环境雌激素模拟物，在类似于人类胎儿暴露的水平，将破坏成年生殖功能的机制控制出生后的神经内分泌反馈控制的GnRH/LH分泌和卵巢的敏感性促性腺激素。此外，产前暴露于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未结合BPA是否到达胎儿，并在人类胎儿观察到的水平上破坏成人生殖功能。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，并涉及控制出生后GnRH/LH分泌和/或卵巢对促性腺激素敏感性的神经内分泌反馈控制机制的破坏。在具体目标3中，我们将确定产前暴露于BPA是否会加剧对产后雌二醇暴露的生殖易感性，最终导致生殖失败。该提案针对的是2000- 2001年NICHD召开的研讨会所产生的战略计划的关键要素，重点关注三个目标领域：胎儿疾病的先兆、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研究以及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。