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）：雌激素是一种极其重要的激素，可指导哺乳动物正常获得结构和功能能力，对包括生殖系统在内的多个器官系统的生长和分化有影响。目前，相当多的注意力集中在几种异生化学物质（例如甲氧滴滴涕和 2,3,7,8 四氯二苯并-对二恶英）对正常雌激素功能的潜在破坏上。据推测，这些化学物质会通过干扰正常内分泌功能的共同机制，对野生动物和人类造成不孕和癌症等影响。这项研究的总体目标是了解发育过程中破坏雌激素功能的长期后果。该提案中的研究提出了这样的假设：在胎儿发育的关键时期接触内分泌干扰物会导致靶细胞中激素反应系统的“重新编程”，从而导致晚年对内源性激素或外源性雌激素样异生素的异常反应。为了检验这一假设，将完成以下具体目标：1）表征阴道、子宫和卵巢上雌激素反应系统的特定时间产前破坏所产生的生理后果；2）测试雌激素反应系统的产前破坏是否会改变阴道、子宫和卵巢对异生素（即甲氧滴滴涕和 2,3,7,8 四氯二苯并-对二恶英）的反应产后生活。总的来说，这项研究将确定产前雌激素破坏是否会对阴道、子宫和卵巢的形态和功能产生长期影响，并在以后的生活中显现出来。此外，拟议的研究将产生一种新型转基因动物模型的特征，该模型对未来的研究有价值：内分泌干扰对受雌激素指导、调节或影响的其他发育终点（例如，大脑、乳腺、骨骼和心血管系统）、ERα 在女性生殖系统中的生理作用，以及与 ERα 相互作用的异生素对女性生殖系统的影响。