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Arsenic is a most likely environmental carcinogenic species that poses a significant health risk in humans. Epidemiological evidence strongly implicates exposure to arsenic in the causation of human cancer of the skin, lung, and urinary bladder (IARC, 2004). Chronic exposure to arsenic leads to the development of lesions on the skin, including hyperkeratosis, hyperpigmentation and cancer. Dermatitis following the exposure to arsenic is a hallmark of the early stages of arsenic poisoning. In this study, we performed immunocytochemical method to examine the formation of 8-nitroguanine, a mutagenic DNA lesion formed during inflammation, in long term arsenic-treated spontaneously immortalized, non-tumorigenic human epidermal keratinocytes (HaCaT) cell line. When HaCaT cells were exposed chronically for 18weeks to an environmentally relevant level of arsenic (0.05ppm) in vitro, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. Arsenic induced 8-nitroguanine formation, inducible nitric oxide synthase (iNOS) and nuclear factor-kB (NF-kB) expression in the HaCaT keratinocytes and xenograft tumors. The staining intensity of 8-nitroguanine, iNOS, NF-kB and p53 in arsenic-treated cells was significantly greater than that in non-treated control at every twenty four days. These results suggest that arsenic can induce formation of 8-nitroguanine via iNOS expression, which may contribute to carcinogenesis. Therefore, the formation of nitrative DNA damage could be one of the mechanisms responsible for arsenic-induced carcinoma. 8-Nitroguanine could be a useful indicator of the risk of skin cancer development in response to chronic arsenic toxicosis. [Copyright &y& Elsevier]

Inflammation mediated by infection is an important factor causing carcinogenesis. Opisthorchis viverrini (OV) infection is a risk factor of cholangiocarcinoma (CHCA), probably through chronic inflammation. Formation of 8-nitroguanine and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), and expression of inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) were assessed in the liver of hamsters infected with OV. We newly produced specific anti-8-nitroguanine antibody without cross-reaction. Double immunofluorescence staining revealed that 8-oxodG and 8-nitroguanine were formed mainly in the same inflammatory cells and epithelium of bile ducts from day 7 and showed the strongest immunoreactivity on days 21 and 30, respectively. It is noteworthy that 8-oxodG and 8-nitroguanine still remained in epithelium of bile ducts on day 180, although amount of alanine aminotransferase activity returned to normal level. A time course of 8-nitroguanine was associated with iNOS expression. Furthermore, this study demonstrated that HO-1 expression and subsequent iron accumulation may be involved in enhancement of oxidative DNA damage in epithelium of small bile ducts. In conclusion, nitrative and oxidative DNA damage via iNOS expression in hamsters infected with OV may participate in CHCA carcinogenesis. [Copyright &y& Elsevier]

Background: Asbestos causes lung cancer and malignant mesothelioma. Chronic inflammation is considered to play a role in asbestos-induced carcinogenesis. Reactive oxygen/nitrogen species generated under inflammatory conditions may contribute to carcinogenesis by causing DNA damage. 8-Nitroguanine is a mutagenic DNA lesion formed during inflammation. In this study, we examined 8-nitroguanine formation in human lung tissues and the association with asbestos exposure. Methods: We obtained autopsy and surgical specimens of non-tumor lung tissues of patients with malignant mesothelioma (n =15) and subjects without asbestos-associated diseases (n =21). Fiber contents (chrysotile, amphiboles and non-asbestos fibers) in tissues were analyzed by transmission electron microscopy. We performed immunohistochemistry to examine 8-nitroguanine formation in lung tissues, and analyzed the correlation of the staining intensity with fiber contents. This study was approved by the Ethics Committee of Mie University School of Medicine, Japan. Results: The fiber contents of chrysotile and amphiboles in lung tissues were significantly larger in mesothelioma patients than in subjects without asbestos-associated diseases (p <0.01). 8-Nitroguanine formation was observed in alveolar and bronchial epithelial cells and inflammatory cells. In subjects without asbestos-associated diseases, the staining intensity of 8-nitroguanine was significantly correlated with the content of amphiboles (p <0.05), but not with those of chrysotile and non-asbestos fibers. 8-Nitroguanine formation in mesothelioma patients was not correlated with asbestos and non-asbestos fiber contents. Conclusion: These results suggest that the generation of reactive oxygen/nitrogen species and resulting DNA damage are largely accounted for by amphibole fibers. 8-Nitroguanine can be a potential biomarker to evaluate the asbestos exposure and predict carcinogenic risk. [Copyright &y& Elsevier]