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.

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 #
8324908
Study Section
Special Emphasis Panel (ZHD1-DSR-L (PV))
Program Officer
Lamar, Charisee A
Project Start
2009-09-30
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$1,443,749
Indirect Cost
$442,774
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
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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