Placental epigenetic modifications and development in valproic acid-induced teratogenesis
Valproic acid , epigenetic , teratogen
Valproic acid (VPA) is an anti-epileptic and a teratogen. In utero exposure to VPA is associated with congenital malformations and neurodevelopment disorders. VPA exerts its teratogenic effects through epigenetic dysregulation, which interferes with tissue development and function. Evidence suggests that VPA can also cause placental toxicity, which may serve as an important mechanism of VPA-induced teratogenicity. The purpose of this thesis was to investigate the effect of VPA on placental epigenetics, as well as placental growth and development, in the CD1 mouse model. We exposed pregnant mice to 600 mg/kg of VPA or saline on GD13 and collected placental tissues at 1, 3 and 24 h post-dosing, to characterize the profile of histone modifications and measure DNA methylation levels. Moreover, we exposed pregnant mice to 600 mg/kg of VPA or saline on GD9 or GD13 and collected placental and fetal tissues on GD18, to assess placental growth and development as well as fetal survival and viability. We found that exposure to VPA on GD9 significantly decreased placental weight and caused a pronounced expansion of the placental labyrinth layer following maternal exposure in CD1 mice; these results were accompanied by an increased number of resorptions, as well as exencephaly and growth restriction in VPA-exposed pups. We suspect defective placental vascularization as a possible mechanism of teratogenicity observed from VPA exposure on GD9. Exposure to VPA on GD13 significantly decreased placental weight and increased the number of resorptions but had no effect on placental tissue layer development or fetal growth. Analysis of epigenetic modifications in the GD13 placenta revealed that VPA significantly increased histone H4 acetylation and H3K4 di-methylation at 1 and 3 h post maternal dose, though had no effect on DNA methylation levels. These results demonstrate that VPA interferes with placental growth and development, and elicits histone modifications, which may a vital role in VPA-induced teratogenicity.