title: Valproic acid-induced skeletal malformations: associated gene expression cascades.
abstract: OBJECTIVE
  Valproic acid (VPA) is a widely used anticonvulsant medication with well-known teratogenic effects in both humans and in experimental animal model systems. The most commonly observed malformations induced by VPA in experimental animals include neural and skeletal defects. In this study the potential alterations in somitic tissue gene expression relative to the development of observed axial skeletal defects were examined.
  
  
  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 morphological and skeletal examination. Cervical malformations consisting of vertebral fusions and cervical ribs were consistently observed. Phenotypic analysis confirmed the presence of dose-dependent axial skeletal malformations induced by in-utero VPA-exposure. Using antisense RNA amplification and cDNA microarrays, we examined the expression of approximately 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
  Analysis indicated that several ontological 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.
  
  
  CONCLUSIONS
  These data were then used to deduce candidate cellular pathways that may be responsible for the VPA-induced teratogenic skeletal phenotypes.
authors.affiliation: Department of Biology, University of Milan, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Massa
authors.forename: Robert M
authors.initials: RM
authors.lastname: Cabrera
authors.forename: Elena
authors.initials: E
authors.lastname: Menegola
authors.forename: Erminio
authors.initials: E
authors.lastname: Giavini
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000235:genetics*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000633:toxicity*; D001842:Bone and Bones / Q000002:abnormalities*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D010641:Phenotype; D011247:Pregnancy; D016372:RNA, Antisense / Q000235:genetics; D014635:Valproic Acid / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D016372:RNA, Antisense; D014635:Valproic Acid