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 journalArticle

39 Citations (Scopus)

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 1 2005

Fingerprint

Theca Cells
Valproic Acid
Polycystic Ovary Syndrome
Gene Expression
Transcriptome
Messenger RNA
Androgens
Proto-Oncogene Proteins c-akt
Histones
Cluster Analysis
Signal Transduction
Steroids
Phosphorylation
Insulin
Phenotype

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Valproate-induced alterations in human theca cell gene expression : Clues to the association between valproate use and metabolic side effects. / Wood, Jennifer R.; Nelson-Degrave, Velen L.; Jansen, Erik; McAllister, Jan M.; Mosselman, Sietse; Strauss, Jerome F.

In: Physiological genomics, Vol. 20, 01.04.2005, p. 233-243.

Research output: Contribution to journalArticle

Wood, Jennifer R. ; Nelson-Degrave, Velen L. ; Jansen, Erik ; McAllister, Jan M. ; Mosselman, Sietse ; Strauss, Jerome F. / Valproate-induced alterations in human theca cell gene expression : Clues to the association between valproate use and metabolic side effects. In: Physiological genomics. 2005 ; Vol. 20. pp. 233-243.
@article{d2f676c96f814060b2074cb3fa7df7dd,
title = "Valproate-induced alterations in human theca cell gene expression: Clues to the association between valproate use and metabolic side effects",
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.",
keywords = "Antiepileptic drug, Histone deacetylase inhibitor, Microarray, Polycystic ovary syndrome",
author = "Wood, {Jennifer R.} and Nelson-Degrave, {Velen L.} and Erik Jansen and McAllister, {Jan M.} and Sietse Mosselman and Strauss, {Jerome F.}",
year = "2005",
month = "4",
day = "1",
doi = "10.1152/physiolgenomics.00193.2004",
language = "English (US)",
volume = "20",
pages = "233--243",
journal = "Physiological Genomics",
issn = "1094-8341",
publisher = "American Physiological Society",

}

TY - JOUR

T1 - Valproate-induced alterations in human theca cell gene expression

T2 - Clues to the association between valproate use and metabolic side effects

AU - Wood, Jennifer R.

AU - Nelson-Degrave, Velen L.

AU - Jansen, Erik

AU - McAllister, Jan M.

AU - Mosselman, Sietse

AU - Strauss, Jerome F.

PY - 2005/4/1

Y1 - 2005/4/1

N2 - 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.

AB - 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.

KW - Antiepileptic drug

KW - Histone deacetylase inhibitor

KW - Microarray

KW - Polycystic ovary syndrome

UR - http://www.scopus.com/inward/record.url?scp=15244355263&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=15244355263&partnerID=8YFLogxK

U2 - 10.1152/physiolgenomics.00193.2004

DO - 10.1152/physiolgenomics.00193.2004

M3 - Article

C2 - 15598877

AN - SCOPUS:15244355263

VL - 20

SP - 233

EP - 243

JO - Physiological Genomics

JF - Physiological Genomics

SN - 1094-8341

ER -