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.
Università di Milano, Department of Biology, Via Celoria 26, Milan, Italy.
Francesca
F
Di Renzo
Maria Luisa
ML
Broccia
Erminio
E
Giavini
Elena
E
Menegola
D000014:Abnormalities, Drug-Induced / Q000196:embryology* / Q000209:etiology; D000107:Acetylation; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D001842:Bone and Bones / Q000002:abnormalities* / Q000196:embryology*; D053148:Caspase 3 / Q000032:analysis; D053938:DNA Fragmentation; D004622:Embryo, Mammalian / Q000737:chemistry; D047108:Embryonic Development; D005260:Female; D005865:Gestational Age; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D011247:Pregnancy; D056564:Sirtuin 1 / Q000032:analysis; D019170:Somites / Q000002:abnormalities / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D014635:Valproic Acid / Q000008:administration & dosage / Q000633:toxicity*
D000927:Anticonvulsants; D006657:Histones; D016159:Tumor Suppressor Protein p53; D014635:Valproic Acid; D053148:Caspase 3; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1