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.
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.