Prenatal Programming of Reproductive Health and Disease

描述(由申请人提供)：强有力的流行病学证据表明，胎儿在怀孕期间暴露于的营养、代谢和激素环境永久地“规划”了其成年后生理和行为的发展和随后的表现。在哺乳动物中，生殖系统的产前编程是惊人的。例如，雌性大鼠在子宫中可以仅仅通过雄性小鼠共享相同的子宫角而雄性化。同样，在子宫中暴露于过多的雄激素会导致猴子和绵羊不育，这是有充分证据的。生殖系统对早期暴露于类固醇激素的敏感性已成为我们现代社会的一个主要问题。面临风险的是母亲因各种原因而接触到外源性类固醇的胎儿：她避孕失败，继续接触避孕类固醇；她正在服用合成类固醇；她无意中接触到了具有雌激素或雄激素活性的环境化合物。产前类固醇环境的实验操作为解开生殖轴编程的基础机制提供了一个强大的研究工具。我们在绵羊身上的研究表明，从怀孕30-90天开始，实验性暴露于过量雄激素会导致一系列成人疾病，包括：促性腺激素亢进、高胰岛素血症、多卵泡卵巢形态、卵泡闭锁增加、异常生殖行为，以及许多 卵巢周期缺陷，最终导致生殖失败。这项由多名研究人员提出的提案将检验这样一种假设：“雄激素和雌激素对生殖生理和行为进行编程。在胎儿发育的关键时期，女性胎儿暴露于增加的性类固醇会导致出生后神经内分泌和卵巢生理的变化，最终导致出生后生活中生殖和行为反应的中断。这一假说的核心是对出生后类固醇的反应改变，这些反应最终会由于对内源性和外源性类固醇作用的敏感性增加而降低生育能力。” 该提案针对NICHD在2000-2001年召开的讲习班产生的战略计划的关键要素，侧重于四个目标领域：疾病的胎儿先兆、21世纪的生殖健康、发育生物学和生物行为发展。这些发现将与成人疾病的胎儿起源、不孕不育、衰老和性别认同的研究相关。这项研究工作的结果将证明通过综合方法解决生殖和行为问题所获得的附加值。

DESCRIPTION (provided by applicant): Strong epidemiological evidence suggests that the nutritional, metabolic and hormonal environment to which the fetus is exposed during gestation permanently "programs" the development and subsequent expression of its physiology and behavior during adulthood. In mammals, prenatal programming of the reproductive system is striking. For example, female rats can be masculanized in utero by the mere presence of male littermates sharing the same uterine horn. Similarly, it is well documented that exposure to excess androgens in utero can lead to sterility in monkeys and sheep. 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; 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. Our studies in sheep reveal that experimental exposure to excess androgen from 30-90 days of gestation culminates in a suite of adult disorders that include: hypergonadotropism, hyperinsulinemia, multifollicular ovarian morphology, increased follicular atresia, aberrant reproductive behaviors, and a number of ovarian cycle defects that culminate in reproductive failure. This multi-investigator proposal will test the hypothesis that "Androgens and estrogens program the reproductive physiology and behavior. Exposure of female fetuses to increased sex steroids during critical periods of fetal development produces changes in postnatal neuroendocrine and ovarian physiology culminating in disrupted reproductive and behavioral responses in postnatal life. Central to this hypothesis is altered responses to postnatal steroids, responses that ultimately reduce fertility as a consequence of increased susceptibility to endogenous and exogenous sex steroid actions." The proposal targets key elements of strategic plans that emanated from workshops convened by the NICHD in 2000-01 by focusing on fours targeted areas: fetal antecedents of disease, reproductive health for the 21st century, developmental biology and biobehavioral development. The findings will be relevant to research on fetal origin of adult diseases, infertility, aging, and gender identity. The results of this research effort will demonstrate the added value gained by an integrative approach to solving reproductive and behavioral problems.