Background: Genome-wide expression profiling is increasingly being used to identify transcriptional changes induced by drugs and environmental stressors. In this context, the Toxicogenomics Project–Genomics Assisted Toxicity Evaluation system (TG-GATEs) project generated transcriptional profiles from rat liver samples and human/rat cultured primary hepatocytes exposed to more than 100 different chemicals.

Objectives: To assess the capacity of the cell culture models to recapitulate pathways induced by chemicals in vivo , we leveraged the TG-GATEs data set to compare the early transcriptional responses observed in the liver of rats treated with a large set of chemicals with those of cultured rat and human primary hepatocytes challenged with the same compounds in vitro .

Methods: We developed a new pathway-based computational pipeline that efficiently combines gene set enrichment analysis (GSEA) using pathways from the Reactome database with biclustering to identify common modules of pathways that are modulated by several chemicals in vivo and in vitro across species.

Results: We found that some chemicals induced conserved patterns of early transcriptional responses in in vitro and in vivo settings, and across human and rat genomes. These responses involved pathways of cell survival, inflammation, xenobiotic metabolism, oxidative stress, and apoptosis. Moreover, our results support the transforming growth factor beta receptor (TGF-βR) signaling pathway as a candidate biomarker associated with exposure to environmental toxicants in primary human hepatocytes.

Conclusions: Our integrative analysis of toxicogenomics data provides a comprehensive overview of biochemical perturbations affected by a large panel of chemicals. Furthermore, we show that the early toxicological response occurring in animals is recapitulated in human and rat primary hepatocyte cultures at the molecular level, indicating that these models reproduce key pathways in response to chemical stress. These findings expand our understanding and interpretation of toxicogenomics data from human hepatocytes exposed to environmental toxicants.

Citation: El-Hachem N, Grossmann P, Blanchet-Cohen A, Bateman AR, Bouchard N, Archambault J, Aerts HJ, Haibe-Kains B. 2016. Characterization of conserved toxicogenomic responses in chemically exposed hepatocytes across species and platforms. Environ Health Perspect 124:313–320; http://dx.doi.org/10.1289/ehp.1409157

*^,**These authors contributed equally to this work.

Address correspondence to B. Haibe-Kains, Princess Margaret Cancer Centre, University Health Network, 101 College St., Toronto, ON, M5G 1L7, Canada. Telephone: 1 (416) 581-7628. E-mail: bhaibeka@uhnresearch.ca , or to H.J.W.L. Aerts, Department of Radiology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA. E-mail: hugo@jimmy.harvard.edu

We thank the investigators of the Toxicogenomics Project–Genomics Assisted Toxicity Evaluation system (TG-GATEs) study who have made their invaluable data available to the scientific community.

N.E.-H. was supported by an Institut de Recherches Cliniques de Montréal (IRCM) doctoral fellowship. B.H.-K. was supported by the Gattuso Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre. H.J.W.L.A. was supported by diXa, a part of the European Union (EU) Seventh Framework Programme, under grant agreement number no. RI-283775. We also acknowledge financial support from the National Institutes of Health (NIH-USA U01CA190234).

The authors declare they have no actual or potential competing financial interests.

Received: 1 September 2014 Accepted: 9 July 2015 Advance Publication: 14 July 2015 Final Publication: 1 March 2016

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