ABSTRACT: Polycyclic aromatic hydrocarbons (PAHs) are widely distributed, carcinogenic environmental contaminants produced as a consequence of the incomplete combustion of fossil fuels. Benzo[a]pyrene (BaP) is a very extensively studied prototypical PAH. We recently reported a complete lack of change in microRNA (miRNA) expression in adult mouse liver following oral gavage with BaP despite a robust transcriptome response. We hypothesized that hepatic miRNAs may not be highly responsive to the treatment. Here, we analyse the pulmonary mRNA and miRNA response to BaP in the same mice. Adult male B6C3F1 mice were exposed to 5, 50, 150 and 300 mg/kg BaP by oral gavage for three consecutive days and sacrificed 4 or 24 hours after the last exposure. Serum clinical chemistry and DNA adduct levels in whole lung and liver tissues were analysed at both the time points for all the doses. Acute exposure to BaP resulted in modest decreases in serum inorganic phosphorous, calcium, glucose, alkaline phosphatase and lactate dehydrogenase in animals treated with 300 mg/kg BaP. 32P postlabeling of DNA revealed similar increases in BaP-DNA adducts in both lungs and livers of exposed mice in a dose dependent manner at the 4 hour time point. Using DNA microarrays, pulmonary mRNA and miRNA expression was analysed 4 hours after the final exposure. Over 1,000 genes were statistically differentially expressed (fold change > 1.5 and p < 0.05), encompassing numerous pathways including: oxidative stress, xenobiotic metabolism, cell proliferation, cell cycle, B and T-cell receptor signalling and primary immunodeficiency signalling pathways. Analysis of miRNA profiles revealed downregulation of miR-150, miR-142-5p, 142-3p and upregulation of miR-34c and miR-29b. These miRNAs are involved in various biological processes including immune response, cell proliferation and cell cycle, which are also the main pathways affected at the gene expression level. As BaP exposure does not result in hepatocarcinogenicity, but does cause lung cancer, these miRNAs may play an important role in the outcome of the exposure and be more predictive of carcinogenesis. Keywords: mRNA, miRNA, Pulmonary, non-target tissue, Toxicogenomics, Benzoapyrene
