Abnormal hormonal, nutritional, metabolic or environmental conditions during pregnancy alter the developmental trajectory of the fetus culminating in adult diseases. Exposure of sheep to excess testosterone (T) during fetal life leads to neuroendocrine, ovarian and metabolic defects that parallel the reproductive and metabolic phenotype of women with polycystic ovary syndrome, with postnatal obesity amplifying these defects. Ovarian defects involve increased follicular recruitment and follicular persistence. Ovarian disruptions are evident during fetal life and include increased androgen receptor expression, imbalance in the ratio of estrogen receptor alpha and beta, and altered insulin signaling. Metabolic defects, mediated by androgenic actions ofT, are also evident eariy in fetal life culminating in insulin resistance. Postpubertal treatment with an insulin sensitizer improves insulin sensitivity and prevents further deterioration of reproductive axis implicating a role for insulin. Our recent findings suggest that gestational co-treatment with an androgen antagonist overcomes disruptive effects of prenatal T at the neuroendocrine and ovarian level. Proposed studies will determine the contributing role of prenatal androgen in the programming of prenatal T-induced reproductive pathology and delineate the relative role of postnatal hyperinsulinemia and functional ovarian hyperandrogenism in facilitating the expression of cyclic ovarian disruptions. Specifically, studies will address if attenuation of hyperinsulinemic status beginning before puberty with insulin sensitizers or ovarian hyperandrogenism with an androgen antagonist would overcome follicular persistence and rescue cyclic function in prenatal T-treated sheep and if prevention of androgen action by co-treatment with androgen antagonist during fetal life would prevent programming of metabolic and reproductive pathologies. Ovaries from these interventional studies will be used to 1) address the role of intraovarian steroid and insulin receptor signaling, 2) identify protein clusters mediating prenatal T-induced ovarian dysfunction;and 3) delineate the role of epigenetic modifications in mediating differential protein expressions. Findings from these studies would be of translational relevance to human infertility disorders.

Public Health Relevance

Unintended exposure of developing fetuses to excess steroids or steroid mimics from the environment poses serious threat to reproductive health and is a major public health concern. Using interventions and a novel animal model, proposed studies will identify the ovarian mechanisms by which fetal exposure to excess steroids leads to infertility. Findings are of relevance from both individual health and societal perspectives.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD044232-07
Application #
8142936
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2010-08-01
Project End
2014-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
7
Fiscal Year
2010
Total Cost
$447,299
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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; 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; 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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