Molecular Mechanisms of Adrenarche

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DESCRIPTION (provided by applicant): Adrenarche denotes the marked increase in DHEA and DHEA-S production from the adrenal zona reticularis that normally occurs at around 6 years of age. The phenotypic result of adrenarche is pubarche or the development of axillary and pubic hair that occurs in both girls and boys at about age 8. Premature or exaggerated adrenarche may be a harbinger of diseases that manifest in adulthood, thus increasing its clinical relevance. While the exact trigger that induces adrenarche remains poorly understood, the biochemical alterations in adrenal androgen production clearly reflect changes in the expression of key enzymes and cofactors in the adrenal zona reticularis. In this proposal, we focus on the mechanisms that regulate the expression of these key enzymes and cofactors during adrenarche. In Specific Aim 1, we will use microarray analyses to compare the transcription profiles of the zona reticularis at the site where DHEA-S is produced and the zona fasciculata, where cortisol is made. The increase in DHEA-S production seen at adrenarche at least partly reflects an increase in the C17-20 lyase activity of steroid 17a-hydroxylase (CYP17), presumably secondary to increased expression of the electron donor cytochrome b5, and an increase in DHEA-sulfotransferase (SULT2A1). Preliminary data already have identified differences in certain key transcription factors that may modify the expression pattern of the DHEA-S producing enzymes. Studies proposed in Specific Aim 2 will focus on the roles of these transcription factors to up-regulate cytochrome b5 and SULT2A1, as well as other genes identified in our microarray studies as key components of zona reticularis function. The noncytochrome P450 enzyme 3b-hydroxysteroid dehydrogenase (HSD3B2) has the unique ability to remove precursors from the pathway leading to DHEA-S thereby inhibiting adrenal androgen biosynthesis. HSD3B2 is expressed at high levels in cortisol-producing cells of the zona fasciculata but is absent in the reticularis once adrenarche is initiated. In Specific Aim 3, we will define the molecular mechanisms that block HSD3B2 expression in the zona reticularis. Collectively, the proposed studies will provide a detailed picture of the molecular alterations that occur in the adrenal cortex during adrenarche and should also elucidate the intra-adrenal mechanisms regulating adrenal androgen production.