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 研究表明，产前早期在子宫内接触性激素会改变胎儿的发育 在成年期跟踪和诱导心脏代谢病理。一些临床前研究已经 研究表明，母亲接触雄激素与胎儿生长和发育减少有关 成年后代的心脏代谢障碍。在怀孕期间，胎盘是主要的器官 从母亲向胎儿提供营养、氧气和激素。事实上，不良的胎儿结局和 众所周知，对长期健康风险的规划源于胎盘。考虑到雄激素 受体在人胎盘中表达，已有研究表明雄激素可以改变正常 胎盘功能。因此，这些观察结果突出了胎盘妥协的合理性 妊娠暴露于过量雄激素，这可能是一种规划胎儿 成年后的生长受限和随后的心脏代谢紊乱 这项研究计划将调查怀孕期间母体雄激素与 胎盘功能的病理标志物及其对心脏代谢预测的影响 新英格兰参加历史性合作的母子成年期的疾病 围产期计划(1959-1966)。鉴于胎盘在解剖和生长方面的性别差异，它 了解胎盘功能的变化对男性和女性的影响也是非常必要的 子代对产前雄激素暴露的反应。因此，这项建议还将调查性别 产前雄激素对胎盘影响的差异 在以前的研究中解决了这些问题。了解产前雄激素对胎盘的影响 系统可以导致新的针对性别的治疗方法来针对胎盘功能障碍 怀孕和改善母亲及其子女一生的健康。 格蕾丝·黄博士是布里格姆妇女医院的医学助理教授 和哈佛医学院。她的K08研究已经提供了纵向证据 孕期雄激素环境的改变可能会有终生编程的人类模型 对性别依赖的后代的代谢健康的影响。拟议的R03项目将 在这些发现的基础上，研究产前雄激素对性别的影响 胎盘，作为成人心脏代谢性疾病长期规划的潜在机制。 这些将是对PI有权访问和熟悉的已收集数据的二次分析 通过分析。总之，这些研究的结果将提供强有力的初步数据支持 R01在进一步研究雄激素介导的机制和表观遗传标记中的应用 参与了成人心血管疾病的早期规划以及他们在整个生命周期中潜在的性别差异。

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.