Valproate-induced alterations in human theca cell gene expression: clues to the association between valproate use and metabolic side effects.
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.
Wood
Jennifer R
JR
Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, USA.
Nelson-Degrave
Velen L
VL
Jansen
Erik
E
McAllister
Jan M
JM
Mosselman
Sietse
S
Strauss
Jerome F
JF
D000927:Anticonvulsants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011085:Polycystic Ovary Syndrome / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013799:Theca Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D017931:DNA Primers; D014635:Valproic Acid