title: Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Integrative systems biology, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada.
authors.forename: Nehme
authors.initials: N
authors.lastname: El-Hachem
authors.forename: Patrick
authors.initials: P
authors.lastname: Grossmann
authors.forename: Alexis
authors.initials: A
authors.lastname: Blanchet-Cohen
authors.forename: Alain R
authors.initials: AR
authors.lastname: Bateman
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bouchard
authors.forename: Jacques
authors.initials: J
authors.lastname: Archambault
authors.forename: Hugo J W L
authors.initials: HJ
authors.lastname: Aerts
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D015870:Gene Expression; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D013045:Species Specificity; D014158:Transcription, Genetic
chemical_list: D004785:Environmental Pollutants; D018125:Receptors, Transforming Growth Factor beta