title: The androgen metabolite, 5α-androstane-3β,17β-diol (3β-diol), activates the oxytocin promoter through an estrogen receptor-β pathway.
abstract: Testosterone has been shown to suppress the acute stress-induced activation of the hypothalamic-pituitary-adrenal axis; however, the mechanisms underlying this response remain unclear. The hypothalamic-pituitary-adrenal axis is regulated by a neuroendocrine subpopulation of medial parvocellular neurons in the paraventricular nucleus of the hypothalamus (PVN). These neurons are devoid of androgen receptors (ARs). Therefore, a possibility is that the PVN target neurons respond to a metabolite in the testosterone catabolic pathway via an AR-independent mechanism. The dihydrotestosterone metabolite, 5α-androstane-3β,17β-diol (3β-diol), binds and activates estrogen receptor-β (ER-β), the predominant ER in the PVN. In the PVN, ER-β is coexpressed with oxytocin (OT). Therefore, we tested the hypothesis that 3β-diol regulates OT expression through ER-β activation. Treatment of ovariectomized rats with estradiol benzoate or 3β-diol for 4 days increased OT mRNA selectively in the midcaudal, but not rostral PVN compared with vehicle-treated controls. 3β-Diol treatment also increased OT mRNA in the hypothalamic N38 cell line in vitro. The functional interactions between 3β-diol and ER-β with the human OT promoter were examined using an OT promoter-luciferase reporter construct (OT-luc). In a dose-dependent manner, 3β-diol treatment increased OT-luc activity when cells were cotransfected with ER-β, but not ER-α. The 3β-diol-induced OT-luc activity was reduced by deletion of the promoter region containing the composite hormone response element (cHRE). Point mutations of the cHRE also prevented OT-luc activation by 3β-diol. These results indicate that 3β-diol induces OT promoter activity via ER-β-cHRE interactions.
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Building ABC1, Room 422, 425 North Fifth Street, Phoenix, Arizona 85004, USA.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Hiroi
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Lacagnina
authors.forename: Laura R
authors.initials: LR
authors.lastname: Hinds
authors.forename: David G
authors.initials: DG
authors.lastname: Carbone
authors.forename: Rosalie M
authors.initials: RM
authors.lastname: Uht
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Handa
mesh_terms: D000728:Androgens / Q000378:metabolism; D015113:Androstane-3,17-diol / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D010052:Ovariectomy; D010121:Oxytocin / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics
chemical_list: D000728:Androgens; D047629:Estrogen Receptor beta; D015113:Androstane-3,17-diol; D010121:Oxytocin