Valproic acid-induced skeletal malformations : associated gene expression cascades

Objectives: Valproic acid (VPA) is a widely used anticonvulsant medication with well-known teratogenic effects in both humans and in exptl. animal model systems. The most commonly obsd. malformations induced by VPA in exptl. animals include neural and skeletal defects. In this study the potential alterations in somitic tissue gene expression relative to the development of obsd. axial skeletal defects were examd. Methods: SWV mice were treated at 8.5 days post coitum (d.p.c.) with 1.36 mmol/kg or 2.72 mmol/kg VPA by i.p. injection. At 18.5 d.p.c., animals were killed and stained for morphol. and skeletal examn. Cervical malformations consisting of vertebral fusions and cervical ribs were consistently obsd. Phenotypic anal. confirmed the presence of dose-dependent axial skeletal malformations induced by in-utero VPA-exposure. Using antisense RNA amplification and cDNA microarrays, we examd. the expression of approx. 5700 genes in the first six postotic somites of control and treated embryos at 6, 12, 18 and 24 h after the 8.5 d.p.c. VPA treatment. Results: Anal. indicated that several ontol. groups (e.g. histone deacetylase complex, guanosine triphosphatases, cell proliferation and cytoskeletal) have significantly enriched gene expression changes in response to the teratogenic insult. The RNA from 6 h post-treatment was also subjected to a microarray cross-platform validation, and genes identified on both platforms are presented. Conclusion: These data were then used to deduce candidate cellular pathways that may be responsible for the VPA-induced teratogenic skeletal phenotypes.