Long-term Consequences of Fetal Endocrine Disruption

胎儿内分泌紊乱的长期后果

• 批准号: 6885415
• 负责人: Jodi A. Flaws
• 金额: $ 14.85万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6885415
• 关键词: biological models; chlorohydrocarbon insecticide; developmental disease /disorder; dioxins; disease /disorder onset; endocrine disorder; endocrine gland /system; environmental exposure; environmental toxicology; estradiol; estrogen inhibitor; female; female reproductive system disorder; genetically modified animals; hormone regulation /control mechanism; immunocytochemistry; laboratory mouse; mammalian embryology; ovary; polymerase chain reaction; postnatal growth disorder; prenatal stress; reproductive development; toxicant interaction; uterus; vagina

DESCRIPTION (provided by applicant): Estrogen is a critically important hormone that guides the normal acquisition of structural and functional competence in mammals, with effects on the growth and differentiation of multiple organ systems, including the reproductive system. Currently, considerable attention is focused on the potential for disruption of normal estrogen function by several xenobiotic chemicals such as methoxychlor and 2, 3, 7, 8 tetrachlordibenzo-p-dioxin. These chemicals are hypothesized to cause infertility and cancer, among other effects, in wildlife and humans through a common mechanism of interfering with normal endocrine function. The overall goal of this research is to develop an understanding of the long-term consequences of disrupting estrogen function during development. The studies in this proposal address the hypothesis that exposure to endocrine disruptors during critical periods of fetal development causes "reprogramming" of the hormone response system in target cells, resulting in aberrant responses to endogenous hormones or exogenous estrogen-like xenobiotics later in life. To test the hypothesis, the following specific aims will be completed: 1) characterize the physiological consequences from specifically timed prenatal disruption of the estrogen response system on the vagina, uterus, and ovary and 2) test whether prenatal disruption of the estrogen response system alters vaginal, uterine, and ovarian responsiveness to xenobiotics (i.e., methoxychlor and 2,3,7,8 tetrachlorodibenzo-p-dioxin) during postnatal life. Collectively, this research will determine whether prenatal estrogen disruption results in long-term effects on vaginal, uterine, and ovarian morphology and function that are manifest later in life. In addition, the proposed research will result in the characterization of a novel transgenic animal model that will be valuable for future studies on: the consequences of endocrine disruption on other developmental endpoints that are directed, regulated, or influenced by estrogen (e.g., brain, mammary gland, bones, and cardiovascular system), the physiological roles of ERalpha in the female reproductive system, and the effects of xenobiotics that interact with ERalpha on the female reproductive system.

描述（由申请人提供）：雌激素是一种至关重要的激素，它指导哺乳动物中的结构和功能能力的正常获得，对包括生殖系统在内的多个器官系统的生长和分化产生影响。当前，大量关注的重点是几种异种生物学化学物质（如甲氧氯）和2、3、7、8 tetrachlordibenzo-p-dioxin损害正常雌激素功能的潜力。假设这些化学物质是通过干扰正常内分泌功能的共同机制在野生动植物和人类中引起不育和癌症的。这项研究的总体目标是对破坏发育过程中破坏雌激素功能的长期后果的理解。该提案中的研究涉及以下假设：在胎儿发育的关键时期暴露于靶细胞中激素反应系统的“重编程”，导致对内源激素或外源性雌激素样的雌激素样的反应在后来的后期生活。要检验该假设，将完成以下具体目的：1）表征阴道，子宫和卵巢上雌激素反应系统的特定定时产前破坏的生理后果，以及2）测试雌激素反应的产前破坏是否会使雌激素反应系统对阴道，子宫和卵巢的反应（Xenoibiots）（Xenobics）（I. I. overiciots）（I。产后生活期间的四氯二苯甲酸）。总的来说，这项研究将确定产前雌激素破坏是否会对阴道，子宫和卵巢形态和功能产生长期影响，这些形态和功能在以后的生活中表现出来。 In addition, the proposed research will result in the characterization of a novel transgenic animal model that will be valuable for future studies on: the consequences of endocrine disruption on other developmental endpoints that are directed, regulated, or influenced by estrogen (e.g., brain, mammary gland, bones, and cardiovascular system), the physiological roles of ERalpha in the female reproductive system, and the effects of xenobiotics that在女性生殖系统上与Eralpha相互作用。