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

Arch Toxicol. 2016 Oct;90(10):2461-80. doi: 10.1007/s00204-015-1595-5. Epub 2015 Sep 16.

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.

Keywords: Benzo(a)pyrene; Complex mixtures; Mode of action; Polycyclic aromatic hydrocarbons; Toxicogenomics.

MeSH terms

  • Animals
  • Benzo(a)pyrene / toxicity
  • Carcinogens, Environmental / toxicity*
  • Cluster Analysis
  • DNA Adducts / toxicity*
  • Gastric Mucosa / metabolism
  • Lac Operon / genetics
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice, Transgenic
  • Mutagens / toxicity*
  • Polycyclic Aromatic Hydrocarbons / toxicity*
  • Stomach / drug effects
  • Stomach / pathology
  • Toxicogenetics
  • Transcriptome / drug effects*

Substances

  • Carcinogens, Environmental
  • DNA Adducts
  • Mutagens
  • Polycyclic Aromatic Hydrocarbons
  • polycyclic aromatic hydrocarbons-DNA adduct
  • Benzo(a)pyrene