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  Human embryonic stem cell derived hepatocyte-like cells as a tool for in vitro hazard assessment of chemical carcinogenicity

Yildirimman, R., Brolen, G., Vilardell, M., Eriksson, G., Synnergren, J., Gmuender, H., et al. (2011). Human embryonic stem cell derived hepatocyte-like cells as a tool for in vitro hazard assessment of chemical carcinogenicity. Toxicological Sciences: an Official Journal of the Society of Toxicology, 124(2), 278-90. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21873647 http://toxsci.oxfordjournals.org/content/124/2/278.full.pdf.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-78B0-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-78B1-2
Genre: Journal Article

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Yildirimman, R.1, Author              
Brolen, G., Author
Vilardell, M.2, Author              
Eriksson, G., Author
Synnergren, J., Author
Gmuender, H., Author
Kamburov, A.1, Author              
Ingelman-Sundberg, M., Author
Castell, J., Author
Lahoz, A., Author
Kleinjans, J., Author
van Delft, J., Author
Bjorquist, P., Author
Herwig, R., Author
Affiliations:
1Bioinformatics (Ralf Herwig), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479648              
2Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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 Abstract: Hepatocyte-like cells derived from the differentiation of human embryonic stem cells (hES-Hep) have potential to provide a human relevant in vitro test system in which to evaluate the carcinogenic hazard of chemicals. In this study, we have investigated this potential using a panel of 15 chemicals classified as noncarcinogens, genotoxic carcinogens, and nongenotoxic carcinogens and measured whole-genome transcriptome responses with gene expression microarrays. We applied an ANOVA model that identified 592 genes highly discriminative for the panel of chemicals. Supervised classification with these genes achieved a cross-validation accuracy of > 95%. Moreover, the expression of the response genes in hES-Hep was strongly correlated with that in human primary hepatocytes cultured in vitro. In order to infer mechanistic information on the consequences of chemical exposure in hES-Hep, we developed a computational method that measures the responses of biochemical pathways to the panel of treatments and showed that these responses were discriminative for the three toxicity classes and linked to carcinogenesis through p53, mitogen-activated protein kinases, and apoptosis pathway modules. It could further be shown that the discrimination of toxicity classes was improved when analyzing the microarray data at the pathway level. In summary, our results demonstrate, for the first time, the potential of human embryonic stem cell--derived hepatic cells as an in vitro model for hazard assessment of chemical carcinogenesis, although it should be noted that more compounds are needed to test the robustness of the assay.

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 Dates: 2011
 Publication Status: Published in print
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Title: Toxicological Sciences : an Official Journal of the Society of Toxicology
Source Genre: Journal
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Pages: - Volume / Issue: 124 (2) Sequence Number: - Start / End Page: 278 - 90 Identifier: ISSN: 1096-0929 (Electronic) 1096-0929 (Linking)