Female fetuses exposed to Testosterone (T) produce variable outcomes in reproductive behavior as a function of the timing and dose of exposure. Prenatal T causes hyperinsulinemia and functional hyperandrogenism in ewes, typical of women with polycystic ovarian syndrome who develop severe metabolic and reproductive dysfunction. Prenatal T-treated sheep, exposed to T for 30 days of a critical period are phenotypically female, capable of copulation, but vary in the amount and type of sex behavior exhibited. Because all females were exposed to the same prenatal T treatment, these data suggest that postnatal life history influences behavioral outcomes, not just prenatal exposure to T. Prenatal T-treated sheep produce behavior typical of increased motivation for food intake and reward perception for foodassociated signals. This alteration in goal-directed behavior likely develops because the animals have excess insulin, leading to altered metabolism and increased salience of food cues. Animals vie for access to food, eventually establishing a social hierarchy. Higher ranking T-treated females exhibit more male-typical behavior than controls. Thus, the variation in adult sex behavior of T-treated females may be the result of an interaction between the effects of prenatal T on metabolism, which alters rewarding properties of food and variably influences social hierarchy, with the predisposition towards male-typical behavior also caused by prenatal T. We hypothesize that prenatal T exposure leads directly or indirectly to altered mesolimbic pathways responsible for goal-directed and rewarding behaviors. Proposed experiments will test whether postnatal attenuation of hyperinsulinemia or hyperandrogenism alters goal-directed behaviors associated with reproduction. We will test the hypotheses that prenatal-T treatment 1) alters motivation and reward perception of stimuli during development and in adults, 2) that postnatal treatment of androgenic and insulin sensitivity will alter motivation and reward responses for reproductive and feeding stimuli, and 3) prenatal Ttreatment affects behavior by altering gene and protein expression in the mesolimbic motivation/reward circuitry.

Public Health Relevance

Unintended exposure of developing fetuses to excess steroids or steroid mimics from the environment poses serious threat to reproductive behavior and health, and is a major public health concern. Using interventions and a novel animal model, proposed studies will identify the mechanisms by which fetal exposure to excess steroids leads to altered behavior that increases the risk of infertility.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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University of Michigan Ann Arbor
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Puttabyatappa, Muraly; Irwin, Ashleigh; Martin, Jacob D et al. (2018) Developmental Programming: Gestational Exposure to Excess Testosterone Alters Expression of Ovarian Matrix Metalloproteases and Their Target Proteins. Reprod Sci 25:882-892
Puttabyatappa, Muraly; Padmanabhan, Vasantha (2018) Ovarian and Extra-Ovarian Mediators in the Development of Polycystic Ovary Syndrome. J Mol Endocrinol 61:R161-R184
Puttabyatappa, Muraly; Lu, Chunxia; Martin, Jacob D et al. (2018) Developmental Programming: Impact of Prenatal Testosterone Excess on Steroidal Machinery and Cell Differentiation Markers in Visceral Adipocytes of Female Sheep. Reprod Sci 25:1010-1023
Puttabyatappa, Muraly; Padmanabhan, Vasantha (2018) Developmental Programming of Ovarian Functions and Dysfunctions. Vitam Horm 107:377-422
Puttabyatappa, Muraly; Andriessen, Victoria; Mesquitta, Makeda et al. (2017) Developmental Programming: Impact of Gestational Steroid and Metabolic Milieus on Mediators of Insulin Sensitivity in Prenatal Testosterone-Treated Female Sheep. Endocrinology 158:2783-2798
Puttabyatappa, Muraly; Padmanabhan, Vasantha (2017) Prenatal Testosterone Programming of Insulin Resistance in theĀ Female Sheep. Adv Exp Med Biol 1043:575-596
Hakim, Christopher; Padmanabhan, Vasantha; Vyas, Arpita K (2017) Gestational Hyperandrogenism in Developmental Programming. Endocrinology 158:199-212
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Cardoso, Rodolfo C; Veiga-Lopez, Almudena; Moeller, Jacob et al. (2016) Developmental Programming: Impact of Gestational Steroid and Metabolic Milieus on Adiposity and Insulin Sensitivity in Prenatal Testosterone-Treated Female Sheep. Endocrinology 157:522-35
Lu, Chunxia; Cardoso, Rodolfo C; Puttabyatappa, Muraly et al. (2016) Developmental Programming: Prenatal Testosterone Excess and Insulin Signaling Disruptions in Female Sheep. Biol Reprod 94:113

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