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

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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.