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Early transcriptional responses in mouse embryos as a basis for selection of molecular markers predictive of valproic acid teratogenicity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
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2010 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 30, no 3, 457-468 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2010. Vol. 30, no 3, 457-468 p.
Keyword [en]
Gene Ontology, In vitro toxicology, Microarray, Mouse embryo, Neural tube defects, Teratogen, Toxicogenomics, Valproic acid
National Category
Pharmaceutical Sciences Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-133495DOI: 10.1016/j.reprotox.2010.05.014ISI: 000282165000017PubMedID: 20546886OAI: oai:DiVA.org:uu-133495DiVA: diva2:369565
Available from: 2010-11-11 Created: 2010-11-11 Last updated: 2011-03-02Bibliographically approved

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Jergil, MånsDencker, LennartStigson, Michael

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