Potent genotoxic activity of benzo[a]pyrene coated onto hematite measured by unscheduled DNA synthesis in vivo in the rat

Since epidemiological studies have firmly implicated co-exposure to iron oxides and polycyclic aromatic hydrocarbons as a potential etiological factor involved in the excess mortality due to lung cancer in miners, experimental studies have been performed to investigate the role of iron particles in benzo[a]pyrene (B[a]P)-induced lung pathogenesis. In a previous study using the Comet assay in vivo in the rat, we demonstrated that iron particles enhanced B[a]P genotoxicity. To determine whether co-exposure (B[a]P/iron oxides) induces a real genotoxic activity or is only due to inhibition of DNA repair, the unscheduled DNA synthesis (UDS) assay was implemented in vivo in the rat. The UDS assay was used to measure DNA repair in two cell types (lung cells and hepatocytes) of OFA Sprague-Dawley rats, 24 h after endotracheal administration of a single dose of an iron oxide (hematite, Fe2O3) (0.75 mg), of B[a]P (0.75 mg) or of B[a]P (0.75 mg) coated on hematite particles (0.75 mg). No difference in UDS was observed in the two organs investigated in rats treated with iron oxide alone compared with control animals, while a significant increase in UDS was observed in lungs and liver of rats treated with B[a]P alone compared with control animals. The main finding was a significant increase in UDS observed in both lung and liver cells of rats treated with B[a]P coated on hematite when compared with those treated with B[a]P alone. The current study demonstrates (i) that iron particles did not inhibit UDS in lung cells and hepatocytes of OFA Sprague-Dawley treated rats with B[a]P coated on hematite and (ii) a potent genotoxic activity of co-exposure to B[a]P coated on hematite. Therefore, our data may contribute to explaining the excess mortality due to lung cancer in epidemiological studies and overall why exposure to B[a]P coated on Fe2O3 particles resulted in a higher tumor incidence in rodents compared with exposure to B[a]P alone.