TY - JOUR
T1 - The androgen metabolite, 5α-Androstane-3β,17β-diol (3β-Diol), activates the oxytocin promoter through an estrogen receptor-β pathway
AU - Hiroi, Ryoko
AU - Lacagnina, Anthony F.
AU - Hinds, Laura R.
AU - Carbone, David G.
AU - Uht, Rosalie M.
AU - Handa, Robert J.
PY - 2013/5/1
Y1 - 2013/5/1
N2 - Testosterone has been shown to suppress the acute stress-induced activation of the hypothalamicpituitary- 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, 5β-Androstane-3β,17β-diol (3β-diol), binds and activates estrogenreceptor- β (ER-β), the predominantERin 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-. 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.
AB - Testosterone has been shown to suppress the acute stress-induced activation of the hypothalamicpituitary- 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, 5β-Androstane-3β,17β-diol (3β-diol), binds and activates estrogenreceptor- β (ER-β), the predominantERin 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-. 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.
UR - http://www.scopus.com/inward/record.url?scp=84876761292&partnerID=8YFLogxK
U2 - 10.1210/en.2012-2253
DO - 10.1210/en.2012-2253
M3 - Article
C2 - 23515287
AN - SCOPUS:84876761292
SN - 0013-7227
VL - 154
SP - 1802
EP - 1812
JO - Endocrinology
JF - Endocrinology
IS - 5
ER -