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Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms
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 fro...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Institute of Environmental Health Sciences
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786983/ https://www.ncbi.nlm.nih.gov/pubmed/26173225 http://dx.doi.org/10.1289/ehp.1409157 |
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author | El-Hachem, Nehme Grossmann, Patrick Blanchet-Cohen, Alexis Bateman, Alain R. Bouchard, Nicolas Archambault, Jacques Aerts, Hugo J.W.L. Haibe-Kains, Benjamin |
author_facet | El-Hachem, Nehme Grossmann, Patrick Blanchet-Cohen, Alexis Bateman, Alain R. Bouchard, Nicolas Archambault, Jacques Aerts, Hugo J.W.L. Haibe-Kains, Benjamin |
author_sort | El-Hachem, Nehme |
collection | PubMed |
description | 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 |
format | Online Article Text |
id | pubmed-4786983 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | National Institute of Environmental Health Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-47869832016-03-16 Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms El-Hachem, Nehme Grossmann, Patrick Blanchet-Cohen, Alexis Bateman, Alain R. Bouchard, Nicolas Archambault, Jacques Aerts, Hugo J.W.L. Haibe-Kains, Benjamin Environ Health Perspect Research 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 National Institute of Environmental Health Sciences 2015-07-14 2016-03 /pmc/articles/PMC4786983/ /pubmed/26173225 http://dx.doi.org/10.1289/ehp.1409157 Text en http://creativecommons.org/publicdomain/mark/1.0/ Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, “Reproduced with permission from Environmental Health Perspectives”); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright. |
spellingShingle | Research El-Hachem, Nehme Grossmann, Patrick Blanchet-Cohen, Alexis Bateman, Alain R. Bouchard, Nicolas Archambault, Jacques Aerts, Hugo J.W.L. Haibe-Kains, Benjamin Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms |
title | Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms |
title_full | Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms |
title_fullStr | Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms |
title_full_unstemmed | Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms |
title_short | Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms |
title_sort | characterization of conserved toxicogenomic responses in chemically exposed hepatocytes across species and platforms |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786983/ https://www.ncbi.nlm.nih.gov/pubmed/26173225 http://dx.doi.org/10.1289/ehp.1409157 |
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