Demethylation of specific Wnt/β-catenin pathway genes and its upregulation in rat brain induced by prenatal valproate exposure

Anat Rec (Hoboken). 2010 Nov;293(11):1947-53. doi: 10.1002/ar.21232.


Valproate (VPA) has been used for decades in the treatment of epilepsy and migraine. However, maternal administration of VPA during pregnancy increases susceptibility to autism spectrum disorders (ASDs) in the offspring. The aim of this study was to investigate the methylation modification and its effects on the activity of Wnt/β-catenin pathway in the rat brain prenatally exposed to VPA. We exposed the rats in early pregnancy to VPA and found that the prenatal VPA exposure, in comparison with the prenatal vehicle exposure, induced demethylation in the promoter regions of wnt1 and wnt2, but not in those of Wnt inhibitory factor-1 and Dickkopf 1, in the prefrontal cortexes and hippocampi of the offspring. Consequently, both mRNA and protein expression of wnt1 and wnt2 were increased. Furthermore, the activity of Wnt/β-catenin pathway was upregulated, as indicated by the increased levels of β-catenin, hence the growing expression of its target genes. This work suggested an epigenetic action via which VPA, when administered in early pregnancy, induced dysregulation of signaling pathway, further facilitating susceptibility to ASDs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / embryology
  • Brain / metabolism*
  • DNA Methylation
  • Epigenesis, Genetic
  • Female
  • GABA Agents / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / embryology
  • Hippocampus / metabolism
  • Models, Animal
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / embryology
  • Prefrontal Cortex / metabolism
  • Pregnancy
  • Prenatal Exposure Delayed Effects / metabolism*
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Up-Regulation / drug effects*
  • Up-Regulation / physiology
  • Valproic Acid / pharmacology*
  • Wnt1 Protein / genetics*
  • Wnt1 Protein / metabolism
  • Wnt2 Protein / genetics*
  • Wnt2 Protein / metabolism
  • beta Catenin / genetics*
  • beta Catenin / metabolism


  • GABA Agents
  • Wnt1 Protein
  • Wnt1 protein, rat
  • Wnt2 Protein
  • beta Catenin
  • Valproic Acid