title: The extreme variety of genotoxic response to benzo[a]pyrene in three different human cell lines from three different organs.
abstract: Polycyclic aromatic hydrocarbons (PAHs) are associated with occupational exposure and urban atmospheric pollution. Determination of the genotoxic properties of these compounds is thus of outmost importance. For this purpose a variety of cellular models have been widely used. Reliable results can however only be obtained with models reflecting the specific sensitivity of different organs towards PAHs. In this work, we compared the response to benzo[a]pyrene in cell lines from human lungs (A549) and bladder (T24); two important target organs for PAHs-induced cancer. Human hepatocytes (HepG2) were used as a reference, although liver is not a concern for PAHs carcinogenesis. Adducts arising from the ultimate diol-epoxide metabolite of B[a]P, BPDE, were found to be produced in a dose-dependent manner in HepG2. BPDE DNA adducts were not detected in T24 and in A549 their formation was found to be most efficient at the lowest concentration studied (0.2 µM). These results are probably explained by differences in induction and activity of phase I metabolization enzymes, as well as by proteins eliminating the B[a]P epoxide in A549. In addition to BPDE adducts, oxidative DNA damage, namely strand breaks and oxidized purines were measured and found to be produced only in minute amounts in all three cell lines. In summary, our results emphasize the large differences in the response of cells originating from different organs. Our data also point out the importance of carefully selecting the doses used in in vitro toxicological experiments. The example of A549 shows that working at high doses may lead to an underestimation of the risk. Finally, the choice of method for evaluating genotoxicity appears to be of crucial importance. The comet assay does not seem to be the best method for a compound like B[a]P which induces stable adducts causing limited oxidative damage.
authors.affiliation: Laboratoire « Lésions des Acides Nucléiques », Université Joseph Fourier - Grenoble 1/CEA/Institut Nanoscience et Cryogénie/SCIB, Grenoble, France ; Equipe EPSP Environnement et Prédiction de la Santé des Populations - laboratoire TIMC (UMR CNRS 5525), CHU de Grenoble, Université Joseph Fourier, UFR de médecine, Domaine de la Merci, La Tronche, France ; Agence de l'environnement et de la Maîtrise de l'Energie 20, Angers, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Genies
authors.forename: Anne
authors.initials: A
authors.lastname: Maître
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lefèbvre
authors.forename: Amandine
authors.initials: A
authors.lastname: Jullien
authors.forename: Marianne
authors.initials: M
authors.lastname: Chopard-Lallier
authors.forename: Thierry
authors.initials: T
authors.lastname: Douki
mesh_terms: D000395:Air Pollutants, Occupational / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D056945:Hep G2 Cells; D006801:Humans; D016273:Occupational Exposure / Q000009:adverse effects*; D009928:Organ Specificity; D010084:Oxidation-Reduction
chemical_list: D000395:Air Pollutants, Occupational; D018736:DNA Adducts; D001564:Benzo(a)pyrene