Multigenerational Effects of Gestational Testosterone Excess

摘要 多囊卵巢综合征(PCOS)是育龄妇女最常见的内分泌疾病， 影响到美国约500万女性和全球超过1亿女性。临床和动物研究提供了强有力的证据 有证据表明，子宫内雄激素水平升高会增加后代患上 PCOS表型。新陈代谢系统特别容易受到产前的有害影响。 雄激素过多。对绵羊的研究表明，产前暴露于睾丸激素过量会导致 许多心脏代谢紊乱的出生后发展，包括胰岛素抵抗，增加 肥胖、脂肪细胞大小和分布改变，以及高血压。因此，产前雄激素过剩 影响生殖和新陈代谢系统以及生殖干扰(例如，功能性 高雄激素症)损害代谢功能，而代谢失衡(例如，胰岛素抵抗和 高胰岛素血症)会影响生殖功能，从而形成恶性循环。产后肥胖加剧 胎儿期睾丸激素过量的影响的严重程度。因此，针对多个器官的干预 可能需要系统来防止产前编程的不良结局的表现。近期 研究为表观遗传过程提供了强有力的证据，如dna。 甲基化，在多囊卵巢综合征的病因学中。因为涉及人体组织的研究不太可行， 尤其是涉及神经内分泌和代谢组织的多囊卵巢综合征的动物模型 提供有价值的组织资源来回答机械性问题。我们建议研究 弓状核转录组和表观组的产前T过剩和出生后肥胖， 肝脏和脂肪细胞组织，我们的研究将有助于促进我们对 雄激素在器官发育中的组织作用并阐明表观遗传学和 产前T细胞过剩对代谢和生殖影响的转录机制 在这个绵羊模型中保持健康。更好地理解表观遗传和转录调节因子 这种多囊卵巢综合征绵羊模型中的代谢障碍可以帮助靶向的未来发展 干预措施。

ABSTRACT Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, affecting ~5 million women in the U.S. and over 100 million globally. Clinical and animal studies provide strong evidence indicating that elevated androgen levels in utero increase the offspring’s susceptibility to develop the PCOS phenotype. The metabolic system is particularly susceptible to the deleterious effects of prenatal androgen excess. Studies in sheep demonstrate that prenatal exposure to testosterone excess results in postnatal development of numerous cardiometabolic perturbations, including insulin resistance, increased adiposity, altered adipocyte size and distribution, and hypertension. Therefore, prenatal androgen excess impacts both the reproductive and metabolic systems, and reproductive perturbations (e.g., functional hyperandrogenism) impair metabolic function, whereas metabolic imbalances (e.g., insulin resistance and hyperinsulinemia) can impact reproductive function, thus forming a vicious cycle. Postnatal adiposity enhances the severity of the impact of prenatal testosterone excess. Consequently, interventions targeting multiple organ systems may be needed to prevent the manifestation of adverse outcomes programmed prenatally. Recent research provides strong evidence for the involvement of epigenetic processes, such as DNA methylation, in the etiology of PCOS. Because studies involving human tissues are less feasible, particularly those involving neuroendocrine and metabolic tissues, animal models of PCOS phenotype provide valuable tissue resources to answer mechanistic questions. We propose to study the impact of prenatal T excess and postnatal adiposity on transcriptome and epigenome of the arcuate nucleus, liver and adipocyte tissue, Our studies will help advance our fundamental understanding of the organizational role that androgens play in organ development and elucidate the epigenetic and transcriptional mechanisms mediating the effects of prenatal T excess on metabolic and reproductive health in this sheep model. A better understanding of the epigenetic and transcriptional mediators of metabolic dysfunction in this sheep model of PCOS can aid in the future development of targeted interventions.