Multigenerational Effects of Gestational Testosterone Excess

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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.