Multigenerational Effects of Gestational Testosterone Excess

项目摘要 胎儿意外暴露于过量的类固醇或类固醇模拟物会对生殖和代谢造成风险 人类的健康。处于危险中的是母亲体内内源性或外源性激素水平升高的后代。 类固醇在怀孕期间的各种原因，包括疾病状态和暴露于环境 具有类固醇生成活性的化合物。对胎儿类固醇环境的实验操作提供了一个 这一有力的工具不仅可以揭示生殖功能障碍发展的潜在机制， 不孕症，而且还制定干预战略，以改善生殖和防止传播 不受欢迎的特性给后代。我们以绵羊为动物模型的研究表明， 从怀孕第30-90天产前暴露于过量的睾酮导致生殖神经内分泌， 卵巢和代谢紊乱的女性后代，重演那些在妇女与 多囊卵巢综合征（PCOS）这些扰动包括少排卵，多卵泡卵巢 形态学、功能性高雄激素血症和胰岛素抵抗。此外，产后体重增加过多 加剧了产前暴露于睾酮过量的母羊的这种功能障碍的严重性。与 越来越多的证据支持，发展程序化的特征是通过多种途径传播的。 世代，阐明生殖和代谢功能障碍传递给 下一代PCOS绵羊模型可能有助于制定干预策略， 多代人的影响，并改善后代的健康。利用妊娠60至90天的 睾丸激素暴露模型，允许自然交配（女性后代不像30-90天的男性化 暴露模型），该建议测试新的假设，即：1）产前睾酮过量促进 生殖和代谢系统多个水平的表观遗传、分子和功能改变 这将传递给后代，从而有助于疾病特征的垂直传播; 和2）通过饮食干预改变生活方式将大大减轻这些不良反应的表达， 事件，并将保护第二代（F2）后代从遗传几个生殖和代谢 由于产前睾丸激素过多而产生的缺陷，并因肥胖增加而加重。研究 在本申请中提出的靶向成体疾病的发育起源并集中于大型动物 翻译相关性模型，表现出与人类相似的发展轨迹。因为 由于母体疾病和/或环境因素导致的妊娠期暴露于过量类固醇损害生育能力， 这些研究的结果将为改善人类的生殖能力提供重要的生物学信息。 几代人，并将在满足NIH的科学任务的相关性。

PROJECT SUMMARY Inadvertent fetal exposure to excess steroids or steroid mimics poses risks to reproductive and metabolic health in humans. At risk is the offspring whose mother has elevated levels of endogenous or exogenous steroids during pregnancy for a variety of reasons, including disease states and exposure to environmental compounds with steroidogenic activity. Experimental manipulation of the fetal steroid environment provides a powerful tool not only to unravel the mechanisms underlying the development of reproductive dysfunction and infertility, but also to develop intervention strategies to improve reproduction and prevent transmission of undesirable traits to subsequent generations. Our studies using sheep as the animal model demonstrated that prenatal exposure to excess testosterone from days 30-90 of pregnancy leads to reproductive neuroendocrine, ovarian and metabolic perturbations in the female offspring that recapitulate those seen in women with polycystic ovary syndrome (PCOS). These perturbations include oligo-anovulation, multifollicular ovarian morphology, functional hyperandrogenism, and insulin resistance. Furthermore, excess postnatal weight gain exacerbated the severity of such dysfunctions in female sheep prenatally exposed to testosterone excess. With mounting evidence supporting that developmentally-programmed traits are transmitted across multiple generations, elucidating the mechanisms by which reproductive and metabolic dysfunctions are passed on to the next generation in the sheep model of PCOS may help develop intervention strategies to alleviate adverse multigenerational effects and improve the health of subsequent generations. Using the day 60 to 90 gestational testosterone exposure model that allows natural mating (female offspring are not virilized like the 30-90 day exposure model), this proposal tests the novel hypotheses that: 1) prenatal testosterone excess promotes epigenetic, molecular, and functional alterations at multiple levels of the reproductive and metabolic systems that will carry over to subsequent generations, thus contributing to the vertical transmission of disease traits; and 2) lifestyle modifications via dietary intervention will considerably mitigate expression of these adverse events and will protect the second-generation (F2) offspring from inheriting several reproductive and metabolic defects programmed by prenatal testosterone excess and aggravated by increased adiposity. The studies proposed in this application target the developmental origins of adult disease and focus on a large animal model of translational relevance that exhibits a developmental trajectory that parallels that of humans. Because gestational exposure to excess steroids due to maternal disease and/or environmental factors impairs fertility, the findings from these studies will provide crucial biological information for improving reproduction across generations and will be of relevance in meeting the scientific missions of NIH.