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.
1Integrative systems biology, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada; 2Department of Medicine, University of Montreal, Montréal, Quebec, Canada; 3Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; 4Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 5Bioinformatics, Institut de Recherches Cliniques de Montréal, Montreal, Canada; 6Department of Human Genetics, McGill University, Montreal, Quebec, Canada; 7Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, Montreal, Canada; 8Laboratory of Molecular Virology, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada; 9Department of Radiology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 10Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; 11Medical Biophysics Department, University of Toronto, Toronto, Ontario, Canada
Recommended Citation:
Nehme El-Hachem,1,2* Patrick Grossmann,et al. Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms[J]. Environmental Health Perspectives,2016-01-01,Volume 124(Issue 3):313