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Characteristics and modifying factors of asbestos-induced oxidative DNA damage.
Cancer Sci. 2008 Nov; 99(11):2142-51.CS

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+Show Affiliations

Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18775024

Citation

Jiang, Li, et al. "Characteristics and Modifying Factors of Asbestos-induced Oxidative DNA Damage." Cancer Science, vol. 99, no. 11, 2008, pp. 2142-51.
Jiang L, Nagai H, Ohara H, et al. Characteristics and modifying factors of asbestos-induced oxidative DNA damage. Cancer Sci. 2008;99(11):2142-51.
Jiang, L., Nagai, H., Ohara, H., Hara, S., Tachibana, M., Hirano, S., Shinohara, Y., Kohyama, N., Akatsuka, S., & Toyokuni, S. (2008). Characteristics and modifying factors of asbestos-induced oxidative DNA damage. Cancer Science, 99(11), 2142-51. https://doi.org/10.1111/j.1349-7006.2008.00934.x
Jiang L, et al. Characteristics and Modifying Factors of Asbestos-induced Oxidative DNA Damage. Cancer Sci. 2008;99(11):2142-51. PubMed PMID: 18775024.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characteristics and modifying factors of asbestos-induced oxidative DNA damage. AU - Jiang,Li, AU - Nagai,Hirotaka, AU - Ohara,Hiroki, AU - Hara,Shigeo, AU - Tachibana,Mitsuhiro, AU - Hirano,Seishiro, AU - Shinohara,Yasushi, AU - Kohyama,Norihiko, AU - Akatsuka,Shinya, AU - Toyokuni,Shinya, Y1 - 2008/09/04/ PY - 2008/9/9/pubmed PY - 2009/1/24/medline PY - 2008/9/9/entrez SP - 2142 EP - 51 JF - Cancer science JO - Cancer Sci. VL - 99 IS - 11 N2 - 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. SN - 1349-7006 UR - https://www.unboundmedicine.com/medline/citation/18775024/Characteristics_and_modifying_factors_of_asbestos_induced_oxidative_DNA_damage_ L2 - https://doi.org/10.1111/j.1349-7006.2008.00934.x DB - PRIME DP - Unbound Medicine ER -