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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD044232-09
Application #
8382080
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$456,639
Indirect Cost
$145,727
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Veiga-Lopez, A; Moeller, J; Abbott, D H et al. (2016) Developmental programming: rescuing disruptions in preovulatory follicle growth and steroidogenesis from prenatal testosterone disruption. J Ovarian Res 9:39
Cernea, Maria; Phillips, Rebecca; Padmanabhan, Vasantha et al. (2016) Prenatal testosterone exposure decreases colocalization of insulin receptors in kisspeptin/neurokinin B/dynorphin and agouti-related peptide neurons of the adult ewe. Eur J Neurosci 44:2557-2568
Padmanabhan, Vasantha; Cardoso, Rodolfo C; Puttabyatappa, Muraly (2016) Developmental Programming, a Pathway to Disease. Endocrinology 157:1328-40
Puttabyatappa, Muraly; Cardoso, Rodolfo C; Padmanabhan, Vasantha (2016) Effect of maternal PCOS and PCOS-like phenotype on the offspring's health. Mol Cell Endocrinol 435:29-39
Cardoso, Rodolfo C; Burns, Ashleigh; Moeller, Jacob et al. (2016) Developmental Programming: Insulin Sensitizer Prevents the GnRH-Stimulated LH Hypersecretion in a Sheep Model of PCOS. Endocrinology 157:4641-4653
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
Puttabyatappa, Muraly; Cardoso, Rodolfo C; Herkimer, Carol et al. (2016) Developmental programming: postnatal estradiol modulation of prenatally organized reproductive neuroendocrine function in sheep. Reproduction 152:139-50
Vyas, Arpita K; Hoang, Vanessa; Padmanabhan, Vasantha et al. (2016) Prenatal programming: adverse cardiac programming by gestational testosterone excess. Sci Rep 6:28335
Padmanabhan, Vasantha; Veiga-Lopez, Almudena; Herkimer, Carol et al. (2015) Developmental Programming: Prenatal and Postnatal Androgen Antagonist and Insulin Sensitizer Interventions Prevent Advancement of Puberty and Improve LH Surge Dynamics in Prenatal Testosterone-Treated Sheep. Endocrinology 156:2678-92

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