• Open Access

Characteristics and modifying factors of asbestos-induced oxidative DNA damage

Authors

  • Li Jiang,

    1. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501;
    2. Department of Pathology and Biological Responses, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550;
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  • Hirotaka Nagai,

    1. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501;
    2. Department of Pathology and Biological Responses, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550;
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  • Hiroki Ohara,

    1. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501;
    2. Department of Pathology and Biological Responses, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550;
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  • Shigeo Hara,

    1. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501;
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  • Mitsuhiro Tachibana,

    1. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501;
    2. Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8501;
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  • Seishiro Hirano,

    1. Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506;
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  • Yasushi Shinohara,

    1. National Institute of Occupational Health and Safety, 6-21-1 Nagao, Tama-ku, Kawasaki 214-8585;
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  • Norihiko Kohyama,

    1. National Science Laboratory, Faculty of Economics, Toyo University, 5-28-20, Hakusan, Bunkyo-ku, Tokyo 112-8606, Japan
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  • Shinya Akatsuka,

    1. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501;
    2. Department of Pathology and Biological Responses, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550;
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  • Shinya Toyokuni

    Corresponding author
    1. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501;
    2. Department of Pathology and Biological Responses, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550;
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To whom correspondence should be addressed. E-mail: toyokuni@med.nagoya-u.ac.jp

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 H2O2, 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. (Cancer Sci 2008; 99: 2142–2151)

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