Multigenerational Effects of Gestational Testosterone Excess

项目总结 胎儿无意中暴露在过量类固醇或类固醇类似物中会对生殖和代谢造成风险 人类的健康。处于危险之中的是母亲内源性或外源性水平升高的后代 怀孕期间因各种原因服用类固醇，包括疾病状态和暴露在环境中 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种 一种强有力的工具，不仅可以揭开生殖功能障碍发展的潜在机制， 不孕不育，但也制定干预策略，以改善生殖和防止传播 遗传给后代的不良特征。我们用绵羊作为动物模型的研究表明， 怀孕30天至90天的产前暴露于过量的睾丸素会导致生殖神经内分泌， 女性后代的卵巢和新陈代谢紊乱，概括了女性 多囊卵巢综合征(PCOS)。这些扰动包括少无排卵、多卵泡卵巢 形态、功能性高雄激素血症和胰岛素抵抗。此外，过多的出生后体重增加 加剧了产前暴露于睾丸激素过剩的雌性绵羊的这种功能障碍的严重程度。使用 越来越多的证据支持发育程序性特征通过多个 世代，阐明生殖和代谢功能障碍传递给 多囊卵巢综合征绵羊模型的下一代可能有助于制定干预策略，以减轻不利的影响 对多代人产生影响，改善后代的健康。使用怀孕60至90天 允许自然交配的睾丸激素暴露模型(雌性后代不像30-90天那样男性化 暴露模型)，这项提议检验了新的假设：1)产前过量的睾丸素促进 生殖和代谢系统多层次的表观遗传、分子和功能改变 这将传递给后代，从而促进疾病特征的垂直传播； 2)通过饮食干预改变生活方式将大大减轻这些不利因素的表达 并将保护第二代(F2)后代不会继承几个生殖和新陈代谢 由于出生前睾丸激素过多而导致的程序性缺陷，并因肥胖增加而加重。这些研究 在这项应用中提出的目标是成人疾病的发育起源，并关注一种大型动物 翻译关联性模型，呈现出与人类相似的发展轨迹。因为 孕期因产妇疾病和/或环境因素而暴露于过量类固醇会损害生育能力， 这些研究的发现将为改善整个生殖系统提供重要的生物学信息。 并将在满足美国国立卫生研究院的科学任务方面发挥重要作用。

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.