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
Beckett, E M; Astapova, O; Steckler, T L et al. (2014) Developmental programing: impact of testosterone on placental differentiation. Reproduction 148:199-209
Veiga-Lopez, A; Wurst, A K; Steckler, T L et al. (2014) Developmental programming: postnatal estradiol amplifies ovarian follicular defects induced by fetal exposure to excess testosterone and dihydrotestosterone in sheep. Reprod Sci 21:444-55
Padmanabhan, V; Veiga-Lopez, A (2014) Reproduction Symposium: developmental programming of reproductive and metabolic health. J Anim Sci 92:3199-210
Delaney, Angela; Padmanabhan, Vasantha; Rezvani, Geoffrey et al. (2014) Evolutionary conservation and modulation of a juvenile growth-regulating genetic program. J Mol Endocrinol 52:269-77
Sliwowska, Joanna H; Fergani, Chrysanthi; Gawa?ek, Monika et al. (2014) Insulin: its role in the central control of reproduction. Physiol Behav 133:197-206
Padmanabhan, Vasantha; Salvetti, Natalia R; Matiller, Valentina et al. (2014) Developmental programming: prenatal steroid excess disrupts key members of intraovarian steroidogenic pathway in sheep. Endocrinology 155:3649-60
Jackson, Leslie M; Mytinger, Andrea; Roberts, Eila K et al. (2013) Developmental programming: postnatal steroids complete prenatal steroid actions to differentially organize the GnRH surge mechanism and reproductive behavior in female sheep. Endocrinology 154:1612-23
Padmanabhan, Vasantha; Veiga-Lopez, Almudena (2013) Animal models of the polycystic ovary syndrome phenotype. Steroids 78:734-40
Veiga-Lopez, A; Moeller, J; Patel, D et al. (2013) Developmental programming: impact of prenatal testosterone excess on insulin sensitivity, adiposity, and free fatty acid profile in postpubertal female sheep. Endocrinology 154:1731-42
Veiga-Lopez, Almudena; Ye, Wen; Padmanabhan, Vasantha (2012) Developmental programming: prenatal testosterone excess disrupts anti-Mullerian hormone expression in preantral and antral follicles. Fertil Steril 97:748-56

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