The Effect of Benzo[a]Pyrene on the Expression of AhR-Regulated microRNA in Lungs of Female and Male Rats

Numerous clinical and epidemiological studies have shown that smoking is the main risk factor for lung cancer, mainly due to the presence of nitrosamines and polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BP) in tobacco smoke. The genotoxic effect of BP is determined by high DNA-binding ability of its metabolites, while the epigenetic effects are mediated by altered expression of genes encoding proteins or regulatory RNAs. According to results of clinical and epidemiological studies, the incidence of lung cancer in men and women varies. We have hypothesized that this may associated with gender-dependent differences in miRNA expression mediated by the cross-talk of BP and estrogen activated signaling pathways. To test this hypothesis, male and female rats were subjected to acute or chronic effects of PD. Using in silico analysis we have selected miRNAs in the promoters of genes (or host genes), which contain binding sites for aryl hydrocarbon (AhR) and estrogen (ER) receptors. Chronic exposure to BP significantly increased the levels of miRNA-22-3p, -29a-3p, -126a-3p, -193b-5p and decreased miRNA-483-3p in the lungs of male rats. In lungs of female rats exposed to the chronic effect of BP, the level of miRNA-483-3p increased, and the level of other studied miRNAs remained unchanged. Changes in miRNA expression were accompanied by changes in the expression of their target genes, such as PTEN, EMP2, IGF1, ITGA6, SLC34A2; the detected changes differed in female and male rats. Thus, our results suggest that gender-dependent epigenetic effects of BP may be based on different expression of AhR- and ER-regulated miRNAs.