Bisphenol-A and Reproductive Dysfunction

双酚 A 与生殖功能障碍

• 批准号: 7579192
• 负责人: VASANTHA PADMANABHAN
• 金额: $ 34.85万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-11 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579192
• 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; 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

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）是荷尔蒙活性，合成或天然化学物质，会干扰内分泌系统正常功能，最著名的是生殖内分泌轴。对EDC的关注主要是由于研究表明EDC暴露对人类的影响，包括雌激素敏感的癌症的急剧增加，人类精子质量和数量的下降，子宫内膜异位症的显着升高以及女性早期青春期的显着增加。由于雌二醇在繁殖和其他生物过程中的普遍和关键作用，环境中的雌激素污染物特别关注。鉴于性类固醇在发育过程中在器官分化中起着至关重要的作用，因此在子宫内外暴露于外源性类固醇模仿的情况下，合理的期望可能会改变成人生殖功能障碍中胎儿的发育轨迹。我们使用绵羊作为模型的初步研究表明，在人类孕产妇和羊水中发现的与环境相关的EDC接近增塑剂双酚A（BPA），导致低出生的女性后代，早期的女性后代，早期的后体重超高质症，并表现出严重的defun依，并表现出了def. defucts ccarded defects deffects defucts。 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.此外，产前暴露于BPA会加剧产后生殖易感性对类固醇暴露的敏感性，并在生殖衰竭中达到高潮。三个具体目标将检验这些假设。在特定的目标1中，我们将确定母体循环中未结合的BPA是否达到胎儿，并且在人类胎儿所见的水平上破坏了成人的生殖功能。在特定的目标2中，我们将确定在神经内分泌或卵巢水平上是否介导了产前BPA效应，并涉及控制GNRH/LH分泌的产后神经内分泌反馈控制的机制和/或/或卵巢对促腺激素的敏感性。在特定的目标3中，我们将确定产前暴露于BPA是否加剧了生殖后雌二醇暴露的易感性，最终导致生殖衰竭。该提案针对的是NICHD在2000 - 01年召集的研讨会中发出的战略计划的关键要素，它专注于三个目标领域：胎儿疾病前因，21世纪的生殖健康以及发育生物学。这些发现将与有关不孕症的胎儿起源的研究以及当前暴露水平的雌激素环境破坏者对人类健​​康构成的研究。公共卫生相关性：内分泌干扰化合物（EDC）是荷尔蒙活性，合成或天然化学物质，会干扰内分泌系统正常功能，最著名的是生殖内分泌轴。由于雌二醇在繁殖和其他生物过程中的普遍和关键作用，环境中的雌激素EDC特别关注。该提议将确定胎儿暴露于双足A（一种环境雌激素EDC）的机制，其水平类似于与人类胎儿的暴露的水平，会破坏女性的生殖功能，并且如果这种效应被夸大而持续暴露于雌激素化合物中。这些发现将与雌激素环境破坏者在当前暴露水平上对生殖健康相关。