The human fetal adrenal undergoes a unique pattern of cortical zone-specific growth and development which is essential for normal postnatal maturation and homeostasis, but the regulation of this process is unclear. Using the baboon as a nonhuman primate translational model, and the aromatase inhibitor letrozole to suppress placental estrogen levels during the second half of pregnancy, we have shown that estrogen represses fetal zone growth and production of the androgens dehydroepiandrosterone (DHA)/DHA sulfate (DHAS), although fetal ACTH levels were unaltered. Preliminary studies show that offspring delivered from estrogen-deprived baboon pregnancies exhibit glucose intolerance/insulin resistance. We propose, therefore, that estrogen represses responsivity of the fetal cortical zone to ACTH, thereby maintaining fetal adrenal androgen and thus placental estrogen synthesis at physiological levels to ensure homeostasis after birth. The underlying mechanism(s), however, are unknown. ACTH receptor (R) binds to melanocortin 2 receptor accessory protein (MRAP) which controls ACTHR trafficking and activation. ACTH stimulates fetal adrenal expression of insulin-like growth factor (IGF)-II which promotes fetal adrenal growth.
Aim 1 will test the hypothesis that estrogen represses expression/interaction of ACTHR and MRAP and consequently expression of: (a) IGF-II/IGFR and the cyclins required for growth of and (b) adenylate cyclase and the low density lipoprotein (LDL)R and enzymes required for DHA/DHAS synthesis by the fetal zone of the baboon fetal adrenal cortex. To accomplish Aim 1, components of the ACTHR signaling, IGF-II/cell cycle and steroidogenesis pathways will be assessed in fetal adrenals obtained at midgestion and near term in untreated baboons and near term in baboons treated throughout the second half of gestation with letrozole ? estradiol to suppress/restore estrogen. In vitro studies with baboon fetal adrenals will elucidate mechanisms underlying estrogen action. Finally, since estrogen stimulates and androgens inhibit insulin sensitivity/glucose metabolism, Aim 2 will test the hypothesis that the elevated levels of placental estrogen during the second half of gestation directly, and/or by restraining fetal adrenocortical zone androgen secretion, developmentally program components of the insulin receptor signaling pathway within insulin target tissues, i.e. skeletal muscle, of the fetus leadin to insulin sensitivity/glucose homeostasis after birth. To accomplish Aim 2, offspring from estrogen-replete or estrogen-deprived baboon pregnancies will be reared to adulthood and insulin sensitivity and components of the insulin receptor signaling pathway determined to elucidate underlying mechanisms. The knowledge gained from this study is expected to translate to the human and make the following novel conceptual advances in perinatal and developmental endocrinology: (a) estrogen regulates fetal adrenocortical growth and development and (b) estrogen directly, and/or by controlling fetal adrenocortical development, programs insulin sensitivity and consequently glucose homeostasis after birth.

Public Health Relevance

The present study will significantly advance knowledge of fetal adrenocortical development essential for perinatal homeostasis and demonstrate the consequences of improper estrogen production/levels or action during pregnancy, e.g. with premature birth or exposure to endocrine disruptors, in increasing the risk of developing type 2 diabetes in offspring after birth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK093950-01A1
Application #
8502094
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Sato, Sheryl M
Project Start
2013-04-01
Project End
2017-02-28
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$595,924
Indirect Cost
$137,401
Name
University of Maryland Baltimore
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Bonagura, Thomas W; Babischkin, Jeffery S; Pepe, Gerald J et al. (2016) Assessment of Protein Expression by Proximity Ligation Assay in the Nonhuman Primate Endometrium, Placenta, and Fetal Adrenal in Response to Estrogen. Methods Mol Biol 1366:149-61
Maniu, Adina; Aberdeen, Graham W; Lynch, Terrie J et al. (2016) Estrogen deprivation in primate pregnancy leads to insulin resistance in offspring. J Endocrinol 230:171-83
Pepe, Gerald J; Maniu, Adina; Aberdeen, Graham et al. (2016) Estrogen Regulation of Fetal Adrenal Cortical Zone-Specific Development in the Nonhuman Primate Impacts Adrenal Production of Androgen and Cortisol and Response to ACTH in Females in Adulthood. Endocrinology 157:1905-13
Babischkin, Jeffery S; Aberdeen, Graham W; Pepe, Gerald J et al. (2016) Estrogen Suppresses Interaction of Melanocortin 2 Receptor and Its Accessory Protein in the Primate Fetal Adrenal Cortex. Endocrinology 157:4588-4601
Dumitrescu, Adina; Aberdeen, Graham W; Pepe, Gerald J et al. (2014) Placental estrogen suppresses cyclin D1 expression in the nonhuman primate fetal adrenal cortex. Endocrinology 155:4774-84
Pepe, Gerald J; Lynch, Terrie J; Albrecht, Eugene D (2013) Regulation of baboon fetal ovarian development by placental estrogen: onset of puberty is delayed in offspring deprived of estrogen in utero. Biol Reprod 89:132