Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides

The U.S. National Toxicology Program has shown clear evidence of carcinogenecity of nickel subsulfide (Ni3S2) and some evidence of carcinogenecity of NiO (green) in rats. In the present study, DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. In cultured HeLa cells, Ni3S2 induced a significant increase in 8-hydroxydeoxyguanosine (8-OH-dG) formation, whereas NiO (black), NiO (green), and NiSO4 did not. On the other hand, in rats, intratracheal instillation of all these nickel compounds significantly increased 8-OH-dg content in the lungs. The disparities in DNA damage between cultured cells and animals could be accounted for by two different mechanisms for nickel-induced oxidative DNA damage in lungs of rats. One is direct oxidative DNA damage: Ni(II) enters the cells and then reacts with endogenous and/or nickel sulfide-produced hydrogen peroxide (H2O2) to give reactive oxygen species that cause DNA damage. This mechanism is supported by oxidative damage to isolated DNA treated with Ni(II) and H2O2. The other mechanism is indirect oxidative DNA damage due to inflammation. This double mechanism for DNA damage may explain the relatively high carcinogenic risk associated with Ni3S2.