Comparative transcriptomic analyses to scrutinize the assumption that genotoxic PAHs exert effects via a common mode of action

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.

Environmentally prevalent polycyclic aromatic hydrocarbons can elicit co-carcinogenic properties in an in vitro murine lung epithelial cell model

“…We used an alveolar type II cell line from mouse as a surrogate to determine the actions of these combined PAHs in lung tissue and in the future will use mouse models as well as human cell lines to further validate these findings. Our studies together with others (Labib et al 2016 ) support the need for these additional studies to determine if re-evaluation of IARC categorization for these LMW PAHs is warranted due to the likelihood that they are co-carcinogenic or tumor promoters.…”

“…A recent paper indicated that different carcinogenic PAHs have different MOAs, via studies using transcriptomics (Labib et al 2016 ). Carcinogenic HMW PAHs had different transcript profiles and while they all induced DNA adducts, the MOAs for carcinogenicity were not the same, thus cannot be based on B[ a ]P alone.…”

Oral exposure to commercially available coal tar‐based pavement sealcoat induces murine genetic damage and mutations

“…Indeed, it has previously been demonstrated in several mouse models that the tissues examined here have constitutive or inducible levels of CYP1A1, 1A2, and/or 1B1, all of which are known to convert PAHs to DNA‐reactive metabolites [Choudhary et al, ; Nebert et al, ; Uno et al, ; Renaud et al, ; Nebert et al, ; Arlt et al, ]. Moreover, our lab group has previously demonstrated induction of CYP1A1 and 1B1 in Muta™Mouse lung and liver following an identical oral exposure regime to several individual PAHs [Labib et al, ].…”

Tissue-specific in vivo genetic toxicity of nine polycyclic aromatic hydrocarbons assessed using the Muta™Mouse transgenic rodent assay

“…Lung data were previously published in Labib et al (2012) . DBahA lacZ mutant frequency data for liver only were previously published in Malik et al (2013) , and lung lacZ and DNA adduct data for BaA, DBahA, BbF, CHRY, BkF, INDENO, and BghiP were recently published in Labib et al (2015) . These data were re-analysed in the manner stated above to permit direct comparison to the results generated specifically for this study.…”

“…The PAHs examined herein are benz( a )anthracene (BaA; IARC Group 2B), dibenz( a , h )anthracene (DBahA; IARC Group 2A), benzo( b )fluoranthene (BbF; IARC Group 2B), chrysene (CHRY; IARC Group 2B), benzo( k )fluoranthene (BkF; IARC Group 2B), indeno(1,2,3- c , d )pyrene (INDENO, IARC Group 2B), and DBalP (IARC Group 2A; also known as dibenzo( def , p )chrysene), and BghiP (IARC Group 3). The previously published results for BaP (IARC Group 1) ( Labib et al, 2012 , Lemieux et al, 2011 ), the liver lacZ mutation and DNA adduct data for DBahA ( Malik et al, 2013 ), as well as lung lacZ mutation and DNA adduct data recently published by Labib et al (2015) (for all compounds except DBalP) are also included in our analyses.…”