title: Characteristics and modifying factors of asbestos-induced oxidative DNA damage.
abstract: Respiratory exposure to asbestos has been linked with mesothelioma in humans. However, its carcinogenic mechanism is still unclear. Here we studied the ability of chrysotile, crocidolite and amosite fibers to induce oxidative DNA damage and the modifying factors using four distinct approaches. Electron spin resonance analyses revealed that crocidolite and amosite containing high amounts of iron, but not chrysotile, catalyzed hydroxyl radical generation in the presence of H(2)O(2), which was enhanced by an iron chelator, nitrilotriacetic acid, and suppressed by desferal. Natural iron chelators, such as citrate, adenosine 5'-triphosphate and guanosine 5'-triphosphate, did not inhibit this reaction. Second, we used time-lapse video microscopy to evaluate how cells cope with asbestos fibers. RAW264.7 cells, MeT-5 A and HeLa cells engulfed asbestos fibers, which reached not only cytoplasm but also the nucleus. Third, we utilized supercoiled plasmid DNA to evaluate the ability of each asbestos to induce DNA double strand breaks (DSB). Crocidolite and amosite, but not chrysotile, induced DNA DSB in the presence of iron chelators. We cloned the fragments to identify break sites. DSB occurred preferentially within repeat sequences and between two G:C sequences. Finally, i.p. administration of each asbestos to rats induced not only formation of nuclear 8-hydroxy-2'-deoxyguanosine in the mesothelia, spleen, liver and kidney but also significant iron deposits in the spleen. Together with the established carcinogenicity of i.p. chrysotile, our data suggest that asbestos-associated catalytic iron, whether constitutional or induced by other mechanisms, plays an important role in asbestos-induced carcinogenesis and that chemoprevention may be possible through targeting the catalytic iron.
authors.affiliation: Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nagai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohara
authors.forename: Shigeo
authors.initials: S
authors.lastname: Hara
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Tachibana
authors.forename: Seishiro
authors.initials: S
authors.lastname: Hirano
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shinohara
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kohyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Akatsuka
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
mesh_terms: D000818:Animals; D001194:Asbestos / Q000008:administration & dosage / Q000633:toxicity*; D017638:Asbestos, Crocidolite / Q000008:administration & dosage / Q000633:toxicity; D001483:Base Sequence; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004578:Electron Spin Resonance Spectroscopy; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D018715:Microscopy, Video; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000473:pathology
chemical_list: D017638:Asbestos, Crocidolite; D001194:Asbestos; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; D007501:Iron
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