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Comparative transcriptomic analyses to scrutinize the assumption that genotoxic PAHs exert effects via a common mode of action
In this study, the accuracy of the assumption that genotoxic, carcinogenic polycyclic aromatic hydrocarbons (PAHs) act via similar mechanisms of action as benzo(a)pyrene (BaP), the reference PAH used in the human health risk assessment of PAH-containing complex mixtures, was investigated. Adult male...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043007/ https://www.ncbi.nlm.nih.gov/pubmed/26377693 http://dx.doi.org/10.1007/s00204-015-1595-5 |
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author | Labib, S. Williams, A. Guo, C. H. Leingartner, K. Arlt, V. M. Schmeiser, H. H. Yauk, C. L. White, P. A. Halappanavar, S. |
author_facet | Labib, S. Williams, A. Guo, C. H. Leingartner, K. Arlt, V. M. Schmeiser, H. H. Yauk, C. L. White, P. A. Halappanavar, S. |
author_sort | Labib, S. |
collection | PubMed |
description | In this study, the accuracy of the assumption that genotoxic, carcinogenic polycyclic aromatic hydrocarbons (PAHs) act via similar mechanisms of action as benzo(a)pyrene (BaP), the reference PAH used in the human health risk assessment of PAH-containing complex mixtures, was investigated. Adult male Muta™Mouse were gavaged for 28 days with seven individual, genotoxic PAHs. Global gene expression profiles in forestomach, liver, and lung (target tissues of exposure) were determined at 3 days post-exposure. The results are compared with our previously published results from mice exposed to BaP via the same exposure regimen. Although all PAHs showed enhanced ethoxyresorufin-O-deethylase activity, DNA adduct formation, and lacZ mutant frequency in the lungs, the unsupervised cluster analysis of differentially expressed genes revealed that the transcriptional changes are both PAH- and tissue-specific, with lung showing the most response. Further bioinformatics-/pathway-based analysis revealed that all PAHs induce expression of genes associated with carcinogenic processes, including DNA damage response, immune/inflammatory response, or cell signaling processes; however, the type of pathways and the magnitude of change varied for each PAH and were not the same as those observed for BaP. Benchmark dose modeling showed transcriptomic data closely reflected the known tumor incidence for the individual PAHs in each tissue. Collectively, the results suggest that the underlying mechanisms of PAH-induced toxicity leading to tumorigenesis are tissue-specific and not the same for all PAHs; based on the tissue type considered, use of BaP as a reference chemical may overestimate or underestimate the carcinogenic potential of PAHs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00204-015-1595-5) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5043007 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-50430072016-10-14 Comparative transcriptomic analyses to scrutinize the assumption that genotoxic PAHs exert effects via a common mode of action Labib, S. Williams, A. Guo, C. H. Leingartner, K. Arlt, V. M. Schmeiser, H. H. Yauk, C. L. White, P. A. Halappanavar, S. Arch Toxicol Molecular Toxicology In this study, the accuracy of the assumption that genotoxic, carcinogenic polycyclic aromatic hydrocarbons (PAHs) act via similar mechanisms of action as benzo(a)pyrene (BaP), the reference PAH used in the human health risk assessment of PAH-containing complex mixtures, was investigated. Adult male Muta™Mouse were gavaged for 28 days with seven individual, genotoxic PAHs. Global gene expression profiles in forestomach, liver, and lung (target tissues of exposure) were determined at 3 days post-exposure. The results are compared with our previously published results from mice exposed to BaP via the same exposure regimen. Although all PAHs showed enhanced ethoxyresorufin-O-deethylase activity, DNA adduct formation, and lacZ mutant frequency in the lungs, the unsupervised cluster analysis of differentially expressed genes revealed that the transcriptional changes are both PAH- and tissue-specific, with lung showing the most response. Further bioinformatics-/pathway-based analysis revealed that all PAHs induce expression of genes associated with carcinogenic processes, including DNA damage response, immune/inflammatory response, or cell signaling processes; however, the type of pathways and the magnitude of change varied for each PAH and were not the same as those observed for BaP. Benchmark dose modeling showed transcriptomic data closely reflected the known tumor incidence for the individual PAHs in each tissue. Collectively, the results suggest that the underlying mechanisms of PAH-induced toxicity leading to tumorigenesis are tissue-specific and not the same for all PAHs; based on the tissue type considered, use of BaP as a reference chemical may overestimate or underestimate the carcinogenic potential of PAHs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00204-015-1595-5) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2015-09-16 2016 /pmc/articles/PMC5043007/ /pubmed/26377693 http://dx.doi.org/10.1007/s00204-015-1595-5 Text en © The Author(s) 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Molecular Toxicology Labib, S. Williams, A. Guo, C. H. Leingartner, K. Arlt, V. M. Schmeiser, H. H. Yauk, C. L. White, P. A. Halappanavar, S. Comparative transcriptomic analyses to scrutinize the assumption that genotoxic PAHs exert effects via a common mode of action |
title | Comparative transcriptomic analyses to scrutinize the assumption that genotoxic PAHs exert effects via a common mode of action |
title_full | Comparative transcriptomic analyses to scrutinize the assumption that genotoxic PAHs exert effects via a common mode of action |
title_fullStr | Comparative transcriptomic analyses to scrutinize the assumption that genotoxic PAHs exert effects via a common mode of action |
title_full_unstemmed | Comparative transcriptomic analyses to scrutinize the assumption that genotoxic PAHs exert effects via a common mode of action |
title_short | Comparative transcriptomic analyses to scrutinize the assumption that genotoxic PAHs exert effects via a common mode of action |
title_sort | comparative transcriptomic analyses to scrutinize the assumption that genotoxic pahs exert effects via a common mode of action |
topic | Molecular Toxicology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043007/ https://www.ncbi.nlm.nih.gov/pubmed/26377693 http://dx.doi.org/10.1007/s00204-015-1595-5 |
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