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Cited by 45Stress Responses and CortisolNeuroendocrine regulation and behaviorEstrogen and related hormone effects

The ERβ Ligand 5α-androstane, 3β,17β-diol (3β-diol) Regulates Hypothalamic Oxytocin (Oxt) Gene Expression

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Sharma, Dharmendra, Handa, Robert J., Uht, Rosalie M.·2012·Endocrinology
DOI 10.1210/en.2011-1002PMC PMC3339641
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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.

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  • 3β-diol treatment increases OT mRNA levels in a rat hypothalamic cell line that constitutively expresses OT.

    “Supporting this possibility, studies using a rat hypothalamic cell line that constitutively expresses OT, reported that levels of OT mRNA were significantly increased following 3β-diol treatment (Sharma, Handa, & Uht, 2012)”

    From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Sharma, Handa, & Uht, 2012

    The Results report a significant increase in Oxt mRNA after 3β-diol treatment at 30 and 60 minutes. However, the cell-characterization section identifies mHypoE-38 as derived from embryonic mouse hypothalami, not as a rat cell line. (LLM, conf=0.91)

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Authors
Sharma, D., Handa, R. J., & Uht, R. M.
Affiliations
  • University of North Texas (US)
  • University of Arizona College of Medicine- Phoenix (US)
Corresponding author
Uht, Rosalie M.
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2012-03-20
Volume
153
Issue
5
Pages
2353-2361
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/en.2011-1002
PMC
PMC3339641
OpenAlex
W2023010955
Cited by
45
References
1
Citations by year
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FWCI
2.12
Type
journal article
Language
en
Open access
Locations
  • Endocrinology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of Mental Health (R01MH082900)
  • National Institute of Neurological Disorders and Stroke (R01NS039951)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
estrogen receptor beta, 5α-androstane-3β,17β-diol, testosterone, hypothalamic paraventricular nucleus, hypothalamic-pituitary-adrenal axis, stress response, CREB, SRC-1, histone H4 acetylation, estradiol, transcriptional regulation
MeSH terms
Animals, Cell Line, Cells, Cultured, Estradiol, Hypothalamus, Neurons, Oxytocin, Promoter Regions, Genetic, Androstane-3,17-diol, Gene Expression, Mice

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