Strong epidemiological evidence suggests that the nutritional, metabolic and hormonal environment to which the fetus is exposed during gestation permanently """"""""programs"""""""" the development and subsequent expression of its physiology and behavior during adulthood. In mammals, prenatal programming of the reproductive system is striking. For example, female rats can be masculanized in utero by the mere presence of male littermates sharing the same uterine horn. Similarly, it is well documented that exposure to excess androgens in utero can lead to sterility in monkeys and sheep. 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; 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. Our studies in sheep reveal that experimental exposure to excess androgen from 30-90 days of gestation culminates in a suite of adult disorders that include: hypergonadotropism, hyperinsulinemia, multifollicular ovarian morphology, increased follicular atresia, aberrant reproductive behaviors, and a number of ? ovarian cycle defects that culminate in reproductive failure. This multi-investigator proposal will test the hypothesis that """"""""Androgens and estrogens program the reproductive physiology and behavior. Exposure of female fetuses to increased sex steroids during critical periods of fetal development produces changes in postnatal neuroendocrine and ovarian physiology culminating in disrupted reproductive and behavioral responses in postnatal life. Central to this hypothesis is altered responses to postnatal steroids, responses that ultimately reduce fertility as a consequence of increased susceptibility to endogenous and exogenous sex steroid actions."""""""" ? ? The proposal targets key elements of strategic plans that emanated from workshops convened by the NICHD in 2000-01 by focusing on fours targeted areas: fetal antecedents of disease, reproductive health for the 21st century, developmental biology and biobehavioral development. The findings will be relevant to research on fetal origin of adult diseases, infertility, aging, and gender identity. The results of this research effort will demonstrate the added value gained by an integrative approach to solving reproductive and behavioral problems. ? ?

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-DRG-D (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
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
Vyas, Arpita K; Hoang, Vanessa; Padmanabhan, Vasantha et al. (2016) Prenatal programming: adverse cardiac programming by gestational testosterone excess. Sci Rep 6:28335

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