DHEA and DHEA sulfate differentially regulate neural androgen receptor and its transcriptional activity.
The mechanism of action of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S), two interconvertable neurosteroids, has not been fully characterized in the central nervous system (CNS). Previous studies demonstrated that DHEA was intrinsically androgenic, suggesting that it may act through a genomic pathway. However, it is not known whether DHEA-S also produces androgenic effects, an important question given that the concentration of DHEA-S in brain is some 7-12 times that of DHEA. The current study compared the potential androgenic effects of DHEA-S with DHEA by examining their capacity to induce two characteristic effects of an androgenic compound. These included the ability to (1) up-regulate neural androgen receptor (AR) protein level in mouse brain and immortalized GT1-7 hypothalamic cells and (2) assess their effect on reporter gene expression through AR in CV-1 cells cotransfected with pSG5-AR and pMMTV-ARE-CAT reporter. Semi-quantitative Western blot analysis showed that DHEA treatment significantly augmented AR in mouse brain and GT1-7 cells in a dose-dependent manner and that these effects were not blocked by trilostane (TRIL), a known 3beta-hydroxysteroid dehydrogenase inhibitor. DHEA also promoted AR-mediated reporter gene expression as a function of dose and the effect was comparable with or without the addition of TRIL. In contrast, DHEA-S treatment failed to increase AR level in the mouse brain or GT1-7 cells and modestly induced AR-mediated reporter gene expression only at substantially elevated concentrations compared to DHEA. The findings demonstrate that DHEA is capable of exerting androgenic effects through AR while the androgenicity of DHEA-S is negligible. The implications of the results for models of the mechanism of action of DHEA and its sulfate ester, DHEA-S, in the brain are considered.
Mo
Qianxing
Q
Department of Biological Sciences, Lehigh University, 111 Research Drive, Bethlehem, PA 18015, USA.
Lu
Shi-Fang
SF
Hu
Shan
S
Simon
Neal G
NG
D000272:Adipates / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007031:Hypothalamus / Q000166:cytology; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection / Q000379:methods
D000272:Adipates; D011944:Receptors, Androgen; C013966:dioctyl adipate; D019314:Dehydroepiandrosterone Sulfate