Early transcriptional responses in mouse embryos as a basis for selection of molecular markers predictive of valproic acid teratogenicity.
Cell-based in vitro assays would potentially reduce animal testing in preclinical drug development. Mouse embryos exposed to the teratogenic drug valproic acid (VPA) in utero for 1.5, 3 or 6h on gestational day 8 were analyzed using microarrays. Significant effects on gene expression were observed already at 1.5h, and 85 probes were deregulated across all time points. To find transcriptional markers of VPA-induced developmental toxicity, the in vivo data were compared to previous in vitro data on embryonal carcinoma P19 cells exposed to VPA for 1.5, 6 or 24h. Maximal concordance between embryos and cells was at the 6-h time points, with 163 genes showing similar deregulation. Developmentally important Gene Ontology terms, such as "organ morphogenesis" and "tube development" were overrepresented among putative VPA target genes. The genes Gja1, Hap1, Sall2, H1f0,Cyp26a1, Fgf15, Otx2, and Lin7b emerged as candidate in vitro markers of potential VPA-induced teratogenicity.
Kultima
Kim
K
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Husargatan 3, Box 594, SE-751 24 Uppsala, Sweden.
Jergil
Måns
M
Salter
Hugh
H
Gustafson
Anne-Lee
AL
Dencker
Lennart
L
Stigson
Michael
M
D000826:Animal Testing Alternatives; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D047108:Embryonic Development / Q000187:drug effects* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011247:Pregnancy; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013723:Teratogens / Q000633:toxicity*; D014158:Transcription, Genetic / Q000187:drug effects*; D014635:Valproic Acid / Q000633:toxicity*
D015415:Biomarkers; D013723:Teratogens; D014635:Valproic Acid; D012313:RNA