Prenatal Programming of Reproductive Health and Disease

描述（由申请人提供）：生殖系统对早期暴露于类固醇激素的易感性已经成为我们现代社会的一个主要问题。如果母亲由于各种原因暴露于外源性类固醇，胎儿就有风险：她避孕失败并继续暴露于避孕类固醇，她正在服用合成代谢类固醇，或者她无意中暴露于具有雌激素或雄激素活性的环境化合物。对产前类固醇环境的实验操作为揭示生殖轴编程的机制提供了一个强大的调查工具。目前的研究发现，产前睾酮(T)过量会破坏胎儿的发育轨迹，最终导致生殖神经内分泌、卵巢、代谢和行为紊乱，并可能导致卵巢高雄激素症和高胰岛素血症。本研究旨在利用最近验证的绵羊模型来验证一个新的、统一的不孕症发育起源假说，即“由代谢紊乱和/或胎儿神经内分泌-卵巢系统类固醇驱动增加引起的高胰岛素血症和功能性高雄激素症在产前t诱导的生殖功能障碍中起关键作用”。P01提案的具体目标是：1)在出生后使用胰岛素增敏剂改善高胰岛素血症，并确定它是否能挽救产前T治疗绵羊的生殖功能；2)在出生后使用抗雄激素，并确定它是否能挽救产前T治疗绵羊的生殖功能；3)确定在胎儿时期与T和雄激素拮抗剂共同治疗是否能防止成年后代谢和生殖病理的发展。4)确定功能恢复背后的神经解剖学、神经内分泌、卵巢、行为和代谢机制。该提案的目标是2000- 2001年联合国儿童健康与发展中心召开的“从细胞到自我”讲习班产生的战略计划的关键要素，并侧重于以下领域：疾病的胎儿前兆、21世纪的生殖健康、发育生物学和生物行为发展。

DESCRIPTION (provided by applicant): The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. At risk is the fetus whose mother has been exposed to exogenous steroids for a variety of reasons: she has had failed contraception and continued exposure to contraceptive steroids, she is on anabolic steroids, or she is inadvertently being exposed to environmental compounds that have estrogenic or androgenic activity. Experimental manipulation of the prenatal steroid environment provides a powerful investigative tool for unraveling mechanisms that underlie programming of the reproductive axis. Findings from the current funding period found prenatal testosterone (T) excess disrupts the developmental trajectory of the fetus culminating in reproductive neuroendocrine, ovarian, metabolic and behavioral perturbations and implicates ovarian hyperandrogenism and hyperinsulinemia in the development of the pathology. This proposal aims to capitalize on this recently validated sheep model to test a novel, unifying hypothesis for the developmental origins of infertility disorders namely "Hyperinsulinemia and functional hyperandrogenism resulting from metabolic perturbations and/or increased steroid drive to the fetal neuroendocrine-ovarian system plays a key role in prenatal T-induced reproductive dysfunctions". The specific goals of the P01 proposal are to 1) use an insulin-sensitizing agent postnatally to ameliorate hyperinsulinemia and determine if it rescues reproductive function in prenatal T-treated sheep, 2) use an anti-androgen postnatally and determine if it rescues reproductive function in prenatal T-treated sheep, 3) determine if co-treatment with T and an androgen antagonist during fetal life will prevent metabolic and reproductive pathology from developing in the adult, and 4) determine the neuroanatomical, neuroendocrine, ovarian, behavioral and metabolic mechanisms underlying restoration of function. The proposal targets key elements of strategic plans that emanated from workshops convened by the NICHD in 2000-01 "From Cells to Selves" and focuses on the following areas: fetal antecedents of disease, reproductive health for the 21st Century, developmental biology and biobehavioral development.