Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds

DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. DNA strand breaks in cultured cells exposed to nickel compounds were measured by using a pulsed field gel electrophoresis technique. Among nickel compounds (Ni3S2, NiO (black), NiO (green), and NiSO4), only Ni3S2, which is highly carcinogenic, induced lesions of both double- and single-stranded DNA in cultured human cells (Raji and HeLa cells). Treatment of cultured HeLa cells with Ni3S2 (10 μg/ml) induced a 1.5-fold increase in 8-hydroxy-2′-deoxyguanosine (8-OH-dG) compared with control, whereas NiO (black), NiO (green), and NiSO4 did not enhance the generation of 8-OH-dG. Intratracheal instillation of Ni3S2, NiO(black), and NiO(green) to Wistar rats increased 8-OH-dG in the lungs significantly. NiSO4 induced a smaller but significant increase in 8-OH-dG. Histological studies showed that all the nickel compounds used induced inflammation in lungs of the rats. Nitric oxide (NO) generation in phagocytic cells induced by Ni3S2, NiO(black), and NiO(green) was examined using macrophage cell line RAW 264.7 cells. NO generation in RAW 264.7 cells stimulated with lipopolysaccharide was enhanced by all nickel particles. Two mechanisms for nickel-induced oxidative DNA damage have been proposed as follows: all the nickel compounds used induced indirect damage through inflammation, and Ni3S2 also showed direct oxidative DNA damage through H2O2 formation. This double action may explain relatively high carcinogenic risk of Ni3S2.