Investigating The Role Of The Maternal Androgen Milieu On Placental Function: A Potential Mechanism For Programming Of Fetal Growth Restriction And Cardiometabolic Dysregulation In Adulthood

项目摘要 早期产前暴露于子宫内的性类固醇已被证明会改变胎儿的发育 在成年期的轨迹和诱导心脏代谢病理学。几项临床前研究已经 显示母体雄激素暴露与胎儿生长和发育减少有关， 成年后代的心脏代谢紊乱。在怀孕期间，胎盘是主要器官， 从母体到胎儿提供营养氧气和激素事实上，不良的胎儿结局和 已知长期健康风险的规划起源于胎盘。考虑到雄性激素 受体在人胎盘中表达，已经提出雄激素可以改变正常的 胎盘功能因此，这些观察结果强调了胎盘损害的可能性， 妊娠暴露于过量的雄激素，这可能是胎儿编程的一种机制。 成年期生长受限和随后的心脏代谢失调 本研究将探讨妊娠期母体雄激素与 胎盘功能的病理标志物，并确定其对预测心脏代谢的影响。 新英格兰参与者中的成年期疾病 围产期项目（1959-1966年）。考虑到胎盘解剖和生长的性别差异， 了解胎盘功能的变化如何影响男性和女性 后代对产前雄激素暴露的反应。因此，本建议还将调查性别 产前雄激素对胎盘影响的差异， 在以前的研究中。了解产前雄激素对胎盘的影响 系统可能导致新的性别特异性治疗方法，以靶向胎盘功能障碍， 怀孕和改善母亲及其后代的健康在整个生命周期。 博士Grace Huang（PI）是布里格姆妇女医院的医学助理教授 还有哈佛医学院她的K 08研究已经提供了纵向证据， 妊娠期雄激素环境的改变可能具有终身编程的人类模型 对后代代谢健康的影响是性别依赖的。R 03项目将 在这些发现的基础上，研究产前雄激素对胎儿发育的性别依赖性影响， 胎盘，作为一个潜在的机制，长期规划成人心脏代谢疾病。 这些将是PI可以访问和熟悉的已收集数据的二次分析 分析。总之，这些研究的结果将提供强有力的初步数据， R 01应用于进一步研究雄激素介导的机制和表观遗传标记 参与成人CVD的早期编程及其在整个生命周期中的潜在性别差异。

Project Summary Early prenatal exposure to sex steroids in utero has been shown to alter fetal developmental trajectory and induce cardiometabolic pathologies in adulthood. Several preclinical studies have shown that maternal androgen exposure is associated with reduced fetal growth and development of cardiometabolic disorders in the adult offspring. During pregnancy, the placenta is the main organ supplying nutrients, oxygen, and hormones from mother to fetus. Indeed, adverse fetal outcomes and programming of long-term health risks are known to have placental origins. Given that androgen receptors are expressed in human placenta, it has been proposed that androgens can modify normal placental function. Thus, these observations highlight the plausibility of placental compromise in pregnancies exposed to excess androgens, which may be a mechanism for programming of fetal growth restriction and subsequent cardiometabolic dysregulation in adult life This research proposal will investigate the relationship of maternal androgens during pregnancy with pathologic markers of placental function and determine their impact on predicting cardiometabolic diseases in adulthood among mother-offspring New England participants of the historic Collaborative Perinatal Project (1959-1966). Given the sex differences in the anatomy and growth of the placenta, it is also imperative to understand how changes in placental function impacts male versus female offspring in response to prenatal androgen exposure. Thus, this proposal will also investigate the sex differences in the effects of prenatal androgens on the placenta which has not be adequately addressed in previous studies. Understanding the influence of prenatal androgens on the placental system could lead to new sex-specific therapeutic approaches to target placental dysfunctions during pregnancy and improve the health of mothers and their offspring across the lifespan. Dr. Grace Huang (the PI) is an Assistant Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School. Her K08 studies have already provided longitudinal evidence in a human model that alterations in the gestational androgen milieu can have life-long programming effects on the metabolic health of the offspring that is sex-dependent. The proposed R03 project will build upon these findings and examine the sex-dependent impact of prenatal androgens on the placenta, as a potential mechanism for long-term programming of adult cardiometabolic diseases. These will be secondary analyses of data already collected that the PI has access to and familiarity with analyzing. Together, the results of these studies will provide strong preliminary data supporting an R01 application to further investigate the androgen-mediated mechanisms and epigenetic markers involved in early programming of adult CVD and their underlying sex differences across the lifespan.