Journal Article

Human Embryonic Stem Cell Derived Hepatocyte-Like Cells as a Tool for <i>In Vitro</i> Hazard Assessment of Chemical Carcinogenicity

Reha Yildirimman, Gabriella Brolén, Mireia Vilardell, Gustav Eriksson, Jane Synnergren, Hans Gmuender, Atanas Kamburov, Magnus Ingelman-Sundberg, José Castell, Agustin Lahoz, Jos Kleinjans, Joost van Delft, Petter Björquist and Ralf Herwig

in Toxicological Sciences

Volume 124, issue 2, pages 278-290
Published in print December 2011 | ISSN: 1096-6080
Published online August 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr225

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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.

Keywords: carcinogenicity; systems toxicology; risk assessment; toxicogenomics; computational biology

Journal Article.  6658 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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