The ERβ ligand 5α-androstane, 3β,17β-diol (3β-diol) regulates hypothalamic oxytocin (Oxt) gene expression

Dharmendra Sharma, Robert J Handa, Rosalie M. Uht

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

The endocrine component of the stress response is regulated by glucocorticoids and sex steroids. Testosterone down-regulates hypothalamic-pituitary-adrenal (HPA) axis activity; however, the mechanisms by which it does so are poorly understood. A candidate testosterone target is the oxytocin gene (Oxt), given that it too inhibits HPA activity. Within the paraventricular nucleus of the hypothalamus, oxytocinergic neurons involved in regulating the stress response do not express androgen receptors but do express estrogen receptor-β(ERβ), which binds the dihydrotestosterone metabolite 3β,17β-diol (3β-diol). Testosterone regulation of the HPA axis thus appears to involve the conversion to the ERβ-selective ligand 5α-androstane, 3β-diol. To study mechanisms by which 3β-diol could regulate Oxt expression, we used a hypothalamic neuronal cell line derived from embryonic mice that expresses Oxt constitutively and compared 3β-diol with estradiol (E2) effects. E2 and 3β-diol elicited a phasic response in Oxt mRNA levels. In the presence of either ligand, Oxt mRNA levels were increased for at least 60 min and returned to baseline by 2 h. ERβ occupancy preceded an increase in Oxt mRNA levels in the presence of 3β-diol but not E2. In tandem with ERβ occupancy, 3β-diol increased occupancy of the Oxt promoter by cAMP response element-binding protein and steroid receptor coactivator-1 at 30 min. At the same time, 3β-diol led to the increased acetylation of histone H4 but not H3. Taken together, the data suggest that in the presence of 3β-diol, ERβ associates with cAMP response element-binding protein and steroid receptor coactivator-1 to form a functional complex that drives Oxt gene expression.

Original languageEnglish (US)
Pages (from-to)2353-2361
Number of pages9
JournalEndocrinology
Volume153
Issue number5
DOIs
StatePublished - May 2012

Fingerprint

Androstane-3,17-diol
Oxytocin
Ligands
Gene Expression
Nuclear Receptor Coactivator 1
Testosterone
Cyclic AMP Response Element-Binding Protein
Messenger RNA
Paraventricular Hypothalamic Nucleus
Dihydrotestosterone
Androgen Receptors
Acetylation
Estrogen Receptors
Histones
Glucocorticoids
Hypothalamus
Estradiol

ASJC Scopus subject areas

  • Endocrinology

Cite this

The ERβ ligand 5α-androstane, 3β,17β-diol (3β-diol) regulates hypothalamic oxytocin (Oxt) gene expression. / Sharma, Dharmendra; Handa, Robert J; Uht, Rosalie M.

In: Endocrinology, Vol. 153, No. 5, 05.2012, p. 2353-2361.

Research output: Contribution to journalArticle

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