VPA-related axial skeletal defects and apoptosis: a proposed event cascade.

VPA axial malformations are related to embryonic somitic histone hyperacetylation. In cancer, histone hyperacetylation activates apoptosis. To verify if apoptosis is involved in somitic abnormalities, VPA-exposed embryos were evaluated for DNA fragmentation and for pro- (p53, acetylated p53, caspase 3) and anti-apoptotic (Sirt 1) protein expression. Pregnant mice were i.p. dosed on day 8 with VPA 400mg/kg or TSA (16 mg/kg). Embryos, collected 3, 5, 9 or 24h after treatment, were examined and processed for apoptosis or protein analysis. An event cascade has been observed at the level of somites and proposed as related to VPA-induced axial skeletal defects: increased p53 (3h), DNA fragmentation (9h), abnormalities (24h). TSA, used as alternative HDAC inhibitor, induced apoptosis and somitic abnormalities, strengthening our hypothesized link between HDAC inhibition and axial defects.