Multigenerational Effects of Gestational Testosterone Excess

妊娠期睾酮过多对多代人的影响

• 批准号: 10413928
• 负责人: Rodolfo C. Cardoso
• 金额: $ 48.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413928
• 关键词: Adult; Adverse event; Animal Model; Animals; Barker Hypothesis; Biological; Cell physiology; Clinical; Defect; Deterioration; Development; Dietary Intervention; Disease; Environment; Environmental Risk Factor; Epigenetic Process; Evaluation; Exhibits; Exposure to; Failure; Feedback; Female; Fertility; Fetus; Functional disorder; Generations; Genetic Transcription; Goals; Health; Hormonal; Human; Hyperandrogenism; Impairment; Incidence; Infertility; Inherited; Insulin Resistance; Intervention; Investigation; Lead; Life Style Modification; Metabolic; Metabolic dysfunction; Mission; Modeling; Molecular; Morphology; Mothers; Neurosecretory Systems; Nutritional; Obesity; Outcome; Ovarian; Partner in relationship; Pathologic; Pathology; Phenotype; Polycystic Ovary Syndrome; Pregnancy; Preventive; Process; Reproduction; Research; Resources; Risk; Severities; Sheep; Steroids; System; Testing; Testosterone; Therapeutic; United States National Institutes of Health; Vertical Disease Transmission; Virilism; Weight Gain; Woman; body system; dietary restriction; disease transmission; excessive weight gain; fertility improvement; fetal; improved; intervention effect; lifestyle intervention; meetings; metabolic phenotype; next generation; novel; offspring; oligo anovulation; ovarian dysfunction; postnatal; premature; prenatal; prenatal exposure; prevent; public health relevance; reduce symptoms; relating to nervous system; reproductive; reproductive axis; reproductive development; reproductive senescence; sheep model; tool; trait; translational model; transmission process

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.

项目摘要 无意间胎儿暴露于多余类固醇或类固醇模仿的构成构成生殖和代谢的风险 人类的健康。处于危险的是后代，其母亲的内源性或外源水平升高 怀孕期间类固醇的原因有多种，包括疾病状态和暴露于环境 具有类固醇活性的化合物。胎儿类固醇环境的实验操作提供了 强大的工具不仅是为了揭示生殖功能障碍发展的基础机制和 不孕症，但也制定干预策略以改善繁殖并防止传播 后代的不良特征。我们使用绵羊作为动物模型的研究表明 从怀孕的第30-90天开始暴露于过量睾丸激素会导致生殖神经内分泌， 雌性后代的卵巢和代谢扰动，概括了那些在妇女中看到的 多囊卵巢综合征（PCOS）。这些扰动包括寡素化，多叶状卵巢 形态，功能性超雄激素和胰岛素抵抗。此外，产后体重增加过多 加剧了这种功能障碍在睾丸激素过量的雌性绵羊中的严重程度。和 越来越多的证据支持发育编程的性状在多个 一代，阐明了生殖和代谢功能障碍的机制 PCOS绵羊模型中的下一代可能有助于制定干预策略以减轻不利 多代效应并改善后代的健康。使用第60至90天的妊娠 允许天然交配的睾丸激素暴露模型（女性后代没有像30-90天那样病毒 暴露模型），该提案测试了新的假设：1）产前睾丸激素过量促进 在多个生殖和代谢系统的多个级别的表观遗传学，分子和功能改变 这将延续到随后的世代，从而导致疾病特征的垂直传播。 2）通过饮食干预修改生活方式将大大减轻这些不利的表达 事件并将保护第二代（F2）后代免受遗传的生殖和代谢 产前睾丸激素过量编程的缺陷，并因肥胖增加而加剧。研究 在本应用中提出的目标是成人疾病的发展起源，并专注于大动物 转化相关性的模型，表现出与人类相关的发展轨迹。因为 由于母体疾病和/或环境因素损害生育能力，妊娠暴露于过量类固醇， 这些研究的发现将提供至关重要的生物学信息，以改善跨越繁殖 几代人，并且将与执行NIH的科学任务有关。