Association of valproate‐induced teratogenesis with histone deacetylase inhibition in vivo
- 3 May 2005
- journal article
- Published by Wiley in The FASEB Journal
- Vol. 19 (9) , 1166-1168
- https://doi.org/10.1096/fj.04-3425fje
Abstract
Chemically induced birth defects are an important public health and human problem. Here we use Xenopus and zebrafish as models to investigate the mechanism of action of a well-known teratogen, valproic acid (VPA). VPA is a drug used in treatment of epilepsy and bipolar disorder but causes spina bifida if taken during pregnancy. VPA has several biochemical activities, including inhibition of histone deacetylases (HDACs). To investigate the mechanism of action of VPA, we compared its effects in Xenopus and zebrafish embryos with those of known HDAC inhibitors and noninhibitory VPA analogs. We found that VPA and other HDAC inhibitors cause very similar and characteristic developmental defects whereas VPA analogs with poor inhibitory activity in vivo have little teratogenic effect. Unbiased microarray analysis revealed that the effects of VPA and trichostatin A (TSA), a structurally unrelated HDAC inhibitor, are strikingly concordant. The concordance is apparent both by en masse correlation of fold-changes and by detailed similarity of dose-response profiles of individual genes. Together, the results demonstrate that the teratogenic effects of VPA are very likely mediated specifically by inhibition of HDACs.Keywords
Funding Information
- National Institute of Environmental Health Sciences (R21ES11710)
- National Institute of Mental Health (RO1MH64761)
This publication has 33 references indexed in Scilit:
- Molecular Basis of Environmentally Induced Birth DefectsAnnual Review of Pharmacology and Toxicology, 2002
- Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cellsThe EMBO Journal, 2001
- Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and TeratogenJournal of Biological Chemistry, 2001
- Action of valproic acid onXenopus laevis development: Teratogenic effects on eyesTeratogenesis, Carcinogenesis, and Mutagenesis, 2001
- Valproate enhances N-cadherin production in Xenopus embryosNeurotoxicology and Teratology, 2000
- Effects of the antiepileptic drug valproic acid on the development of the axolotl(Ambystoma mexicanum): Histological investigationsTeratogenesis, Carcinogenesis, and Mutagenesis, 1996
- Effects of the anticonvulsant drug valproic acid and related substances on the early development of the zebrafish (Brachydanio rerio)Toxicology in Vitro, 1993
- Valproic acid induced abnormal development of the central nervous system of three species of amphibians: Implications for neural tube defects and alternative experimental systemsTeratogenesis, Carcinogenesis, and Mutagenesis, 1992
- Valproic Acid‐Induced Neural Tube Defects in Mouse and Human: Aspects of Chirality, Alternative Drug Development, Pharmacokinetics and Possible MechanismsBasic & Clinical Pharmacology & Toxicology, 1991
- Additive incidence of developmental malformation for Xenopus embryos exposed to a mixture of ten aliphatic carboxylic acidsTeratology, 1991