Valproate-induced alterations in human theca cell gene expression: Clues to the association between valproate use and metabolic side effects

Jennifer R. Wood, Velen L. Nelson-Degrave, Erik Jansen, Jan M. McAllister, Sietse Mosselman, Jerome F. Strauss

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Valproic acid (VPA) is an anti-epileptic drug that has been associated with polycystic ovary syndrome (PCOS)-like symptoms, including increased ovarian androgen production. The hyperandrogenemia likely reflects the stimulatory action of VPA on theca cell androgen synthesis and has been correlated to its activity as a histone deacteylase inhibitor in these cells. To determine whether VPA induces a PCOS-like genomic phenotype, we compared the gene expression profiles of untreated (UNT) normal, VPA-treated normal, and UNT PCOS theca cells. Hierarchal cluster analysis demonstrated similarities in the gene expression profiles of VPA-treated normal and PCOS theca cells. Statistical analysis identified 1,050 transcripts that have significantly altered mRNA abundance in both VPA-treated normal and UNT PCOS theca cells compared with normal UNT theca cells. Among these 1,050 transcripts were cAMP-GEFII and TRB3, which have increased and decreased mRNA abundance, respectively. The altered abundance of these two mRNAs was correlated to increased basal and - insulin-induced phosphorylation of protein kinase B (Akt/PKB). Thus these studies indicate that VPA- and PCOS-induced changes in gene expression enhance Akt/PKB signal transduction in human theca cells. Furthermore, common changes in gene expression in PCOS and VPA-treated normal theca cells suggest a possible mechanism for the development of PCOS-like symptoms, including increased steroid synthesis and arrested follicle development in women receiving chronic VPA therapy.

Original languageEnglish (US)
Pages (from-to)233-243
Number of pages11
JournalPhysiological genomics
Volume20
DOIs
StatePublished - Apr 2005

Keywords

  • Antiepileptic drug
  • Histone deacetylase inhibitor
  • Microarray
  • Polycystic ovary syndrome

ASJC Scopus subject areas

  • Physiology
  • Genetics

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