MON-217 Maternal Androgen Excess and Obesity Induce Cardiac Hypertrophy and Left Ventricular Dysfunction in Female Offspring

Polycystic ovary syndrome (PCOS) is suggested to increase the risk for cardiovascular disease and type 2 diabetes. We hypothesized here that prenatal exposure to dihydrotestosterone (DHT) and/or maternal obesity lead to adverse metabolic and cardiac programming in the female offspring. The maternal obese PCOS phenotype was induced in mice by prenatal DHT exposure (PNA) combined with high-fat/high-sucrose (HFHS) diet. The female offspring were subjected to metabolic and cardiac assessment during adulthood. The PNA offspring displayed cardiac hypertrophy, as indicated by increased interventricular septal and posterior wall thickness on echocardiography. These observations were not accompanied by aberrant metabolic profile. The expression of targeted genes involved in cardiac hypertrophy, fibrosis, and calcium signaling was upregulated in PNA female offspring, with limited or no impact of maternal obesity. Furthermore, we examined whether the maternal obese PCOS phenotype augmented NADPH oxidase (NOX)-derived ROS production, as a contributing source of oxidative stress. Paradoxically, NOX activity was decreased and associated with upregulated gene expression of antioxidant enzymes in the PNA offspring heart. Next, we explored for early signs of alterations in the heart of newly born PNA offspring, which could account for the long-lasting changes observed in adulthood. Neonatal PNA hearts displayed an upregulation of transcription factors involved in cardiac hypertrophic remodeling and of genes related to calcium signaling. To determine the specific role of androgens in cardiovascular function, prepubertal female mice were implanted a pellet containing DHT or vehicle and were subjected to metabolic and cardiac assessment during adulthood. Continuous exposure to DHT led to adverse left ventricular remodeling, including increased left ventricular mass and dysregulated gene expression profile. Lastly, myography studies of mesenteric arteries revealed increased vasocontractile responses in the DHT- exposed females, suggestive of hypertension. Taken together, early life exposure to androgens may program an adverse cardiovascular phenotype in female offspring, which is most likely linked to hyperandrogenism.