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 400 mg/kg or TSA (16 mg/kg). Embryos, collected 3, 5, 9 or 24 h 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 (3 h), DNA fragmentation (9 h), abnormalities (24 h). TSA, used as alternative HDAC inhibitor, induced apoptosis and somitic abnormalities, strengthening our hypothesized link between HDAC inhibition and axial defects.