Bisphenol-A and the Reproductive Dysfunction

双酚A与生殖功能障碍

• 批准号: 7595341
• 负责人: VASANTHA PADMANABHAN
• 金额: $ 14.04万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-09 至 2009-02-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595341
• 关键词: Adult; Agriculture; Amniotic Fluid; Area; Attention; Blood; Blood Circulation; Chemicals; Coin; Complex; Data; Defect; Development; Developmental Biology; Disease; Disruption; Educational workshop; Elements; Endocrine; Endocrine Disruptors; Endocrine system; Environment; Environmental Estrogen; Environmental Pollutants; 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; Numbers; 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; pollutant; postnatal; prenatal; prenatal exposure; programs; reproductive; reproductive function; sperm quality; trend

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.

总结 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， 内分泌系统的正常功能，尤其是生殖内分泌轴。关切 EDC主要受到研究的推动，这些研究指出了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， 子宫内膜异位症和女性早熟。由于雌二醇在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特别令人关注。 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， 预期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以绵羊为模型的初步研究显示， 产前暴露于增塑剂双酚A（BPA），一种与环境相关的EDC， 在人类母亲的血液和羊水中发现的，导致低出生体重的女性后代， 产后高促性腺激素症和表现为LH峰严重抑制的周期缺陷。在这 我们将检验产前暴露于BPA（一种环境雌激素模拟物）的假设， 类似于人类胎儿所接触的水平，将通过破坏成年人的生殖功能， 控制出生后GnRH/LH分泌和卵巢的神经内分泌反馈控制的机制 对促性腺激素敏感此外，产前暴露于BPA会加剧产后生殖 容易受到类固醇的影响，最终导致生殖失败。三个具体目标将测试这些 假设具体目标1将确定母体循环中的未结合BPA是否到达胎儿 达到人类胎儿的水平会破坏成年人的生殖功能。具体目标2将确定是否 产前BPA效应是在神经内分泌或卵巢水平介导的， 控制产后神经内分泌反馈控制GnRH/LH分泌和/或卵巢的机制 对促性腺激素敏感具体目标3将确定产前暴露于BPA是否会加剧 生殖对产后雌二醇暴露的敏感性，最终导致生殖失败。该提案 针对2000- 2001年NICHD召开的研讨会产生的战略计划的关键要素， 重点关注三个目标领域：胎儿疾病前因，21世纪的生殖健康， 发育生物学这一发现将有助于研究不孕症的胎儿起源和威胁 目前暴露水平的雌激素环境干扰物对人类健康的危害。