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 #
5P01HD044232-09
Application #
8382078
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
$421,800
Indirect Cost
$126,991
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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