Abstract
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 materialThe online version of this article (doi:10.1007/s00204-015-1595-5) contains supplementary material, which is available to authorized users.
Highlights
Many regulatory agencies recommend the use of a reference chemical approach to assess the hazards posed by chemical mixtures in complex environmental matrices (EFSA 2008; Health Canada 2010; Health Protection Agency 2010; USEPA 2010)
The transcriptomic profiles derived from the present study were compared with the profiles of mice exposed to BaP to investigate whether BaP, as a reference polycyclic aromatic hydrocarbons (PAHs), accurately represents the toxicity posed by other individual PAHs
The present study explored the validity of the assumption that BaP is an acceptable reference PAH for genotoxic, carcinogenic PAHs by examining the global gene expression changes in three separate tissues
Summary
Many regulatory agencies recommend the use of a reference chemical approach to assess the hazards posed by chemical mixtures in complex environmental matrices (EFSA 2008; Health Canada 2010; Health Protection Agency 2010; USEPA 2010). This in turn leads to the production of reactive intermediates (e.g., diol epoxides) that covalently bind DNA and form bulky DNA adducts When left unrepaired, these DNA adducts can result in mutations in tumor-suppressor genes or oncogenes, which can eventually lead to carcinogenesis, implying a genotoxic mode of action in cancer. Measurement of DNA adducts and DNA mutations have long been taken as measurable markers of the genotoxic mode of action of PAHs. the existing toxicological database (showing evidence for carcinogenicity and the details pertinent to the underlying mechanisms of carcinogenicity) for the individual PAHs is incomplete and lacks experimental support for the use of the reference chemical method (Bostrom et al 2002). In order to strengthen the application of the reference chemical approach, the USEPA (USEPA 2010) has outlined certain considerations that are important for PAH mixture cancer risk assessment, which includes a detailed characterization of toxicological responses elicited by individual PAHs in the mixture
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