Multigenerational Effects of Gestational Testosterone Excess

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PROJECT SUMMARY Inadvertent fetal exposure to excess steroids or steroid mimics poses risks to reproductive and metabolic health in humans. At risk is the offspring whose mother has elevated levels of endogenous or exogenous steroids during pregnancy for a variety of reasons, including disease states and exposure to environmental compounds with steroidogenic activity. Experimental manipulation of the fetal steroid environment provides a powerful tool not only to unravel the mechanisms underlying the development of reproductive dysfunction and infertility, but also to develop intervention strategies to improve reproduction and prevent transmission of undesirable traits to subsequent generations. Our studies using sheep as the animal model demonstrated that prenatal exposure to excess testosterone from days 30-90 of pregnancy leads to reproductive neuroendocrine, ovarian and metabolic perturbations in the female offspring that recapitulate those seen in women with polycystic ovary syndrome (PCOS). These perturbations include oligo-anovulation, multifollicular ovarian morphology, functional hyperandrogenism, and insulin resistance. Furthermore, excess postnatal weight gain exacerbated the severity of such dysfunctions in female sheep prenatally exposed to testosterone excess. With mounting evidence supporting that developmentally-programmed traits are transmitted across multiple generations, elucidating the mechanisms by which reproductive and metabolic dysfunctions are passed on to the next generation in the sheep model of PCOS may help develop intervention strategies to alleviate adverse multigenerational effects and improve the health of subsequent generations. Using the day 60 to 90 gestational testosterone exposure model that allows natural mating (female offspring are not virilized like the 30-90 day exposure model), this proposal tests the novel hypotheses that: 1) prenatal testosterone excess promotes epigenetic, molecular, and functional alterations at multiple levels of the reproductive and metabolic systems that will carry over to subsequent generations, thus contributing to the vertical transmission of disease traits; and 2) lifestyle modifications via dietary intervention will considerably mitigate expression of these adverse events and will protect the second-generation (F2) offspring from inheriting several reproductive and metabolic defects programmed by prenatal testosterone excess and aggravated by increased adiposity. The studies proposed in this application target the developmental origins of adult disease and focus on a large animal model of translational relevance that exhibits a developmental trajectory that parallels that of humans. Because gestational exposure to excess steroids due to maternal disease and/or environmental factors impairs fertility, the findings from these studies will provide crucial biological information for improving reproduction across generations and will be of relevance in meeting the scientific missions of NIH.