The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. At risk is the fetus whose mother has been exposed to exogenous steroids for a variety of reasons: she has had failed contraception and continued exposure to contraceptive steroids, she is on anabolic steroids, or she is inadvertently being exposed to environmental compounds that have estrogenic or androgenic activity. Experimental manipulation of the prenatal steroid environment provides a powerful investigative tool for unraveling mechanisms that underlie programming of the reproductive axis. Findings from the current funding period found prenatal testosterone (T) excess disrupts the developmental trajectory of the fetus culminating in reproductive neuroendocrine, ovarian, metabolic and behavioral perturbations and implicates ovarian hyperandrogenism and hyperinsulinemia in the development of the pathology. This proposal aims to capitalize on this recently validated sheep model to test a novel, unifying hypothesis for the developmental origins of infertility disorders namely """"""""Hyperinsulinemia and functional hyperandrogenism resulting from metabolic perturbations and/or increased steroid drive to the fetal neuroendocrine-ovarian system plays a key role in prenatal T-induced reproductive dysfunctions"""""""". The specific goals of the P01 proposal are to 1) use an insulin-sensitizing agent postnatally to ameliorate hyperinsulinemia and determine if it rescues reproductive function in prenatal T-treated sheep, 2) use an anti-androgen postnatally and determine if it rescues reproductive function in prenatal T-treated sheep, 3) determine if co-treatment with T and an androgen antagonist during fetal life will prevent metabolic and reproductive pathology from developing in the adult, and 4) determine the neuroanatomical, neuroendocrine, ovarian, behavioral and metabolic mechanisms underlying restoration of function. The proposal targets key elements of strategic plans that emanated from workshops convened by the NICHD in 2000-01 """"""""From Cells to Selves"""""""" and focuses on the following areas: fetal antecedents of disease, reproductive health for the 21st Century, developmental biology and biobehavioral development.

Public Health Relevance

Unintended fetal exposure to excess steroids or steroid mimics from the environment poses serious threat to reproductive health, a major public health concern. Using a novel animal model and integrative intervention approaches these studies will identify metabolic, neuroendocrine and ovarian mechanims by which fetal exposure to excess steroids causes adult infertlity. Studies are relevant both at individual and societal level.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DSR-L (PV))
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Lamar, Charisee A
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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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
Recabarren, S E; Recabarren, M; Sandoval, D et al. (2017) Puberty arises with testicular alterations and defective AMH expression in rams prenatally exposed to testosterone. Domest Anim Endocrinol 61:100-107
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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