Early transcriptional responses in mouse embryos as a basis for selection of molecular markers predictive of valproic acid teratogenicity
(English)Manuscript (preprint) (Refereed)
Cell-based in vitro assays would potentially reduce animal testing in preclinical drugdevelopment. Mouse embryos exposed to the teratogenic drug valproic acid (VPA)in utero for 1.5, 3 or 6 h on gestational day 8 were analyzed using microarrays.Significant effects on gene expression were observed as early as 1.5 h, and 85 probeswere deregulated across all time points. To find transcriptional markers of VPAinduceddevelopmental toxicity, the in vivo data were compared to previous in vitrodata on embryonal carcinoma P19 cells exposed to VPA for 1.5, 6 or 24 h. Maximalconcordance between embryos and cells was at the 6-h time points, with 163 genesshowing similar deregulation. Developmentally important Gene Ontology terms, suchas “morphogenesis” and “tube development” were overrepresented among putativeVPA target genes. The genes Gja1, Hap1, Sall2, H1f0, Cyp26a1, Fgf15, Otx2, andLin7b emerged as candidate in vitro markers of potential VPA-induced teratogenicity.
Gene ontology; in vitro toxicology; microarray; mouse embryo; neural tube defects; teratogen; toxicogenomics; valproic acid
Pharmacology and Toxicology
Research subject Toxicology
IdentifiersURN: urn:nbn:se:uu:diva-110148OAI: oai:DiVA.org:uu-110148DiVA: diva2:275579