Molecular Mechanisms of Nickel Carcinogenesis

Abstract

Abstract Humans are exposed to carcinogenic nickel (Ni) compounds both occupationally and environmentally. In thispaper, molecular mechanisms of nickel carcinogenesis are considered from the point-of-view of the uptake of nickelsulfide particles in cells, their dissolution and their effects on heterochromatin. Molecular mechanisms by which nickelinduces gene silencing, DNA hypermethylation and inhibition of histone acetylation, will be discussed. © 2002Elsevier Science Ireland Ltd. All rights reserved. Keywords :Chromosome damage; Heterochromatin; Gene silencing; Nickelwww.elsevier.com/locate/toxlet 1. Introduction Industrial usage of Ni compounds includesnickel refining, electroplating, the production ofstainless steel and nickel–cadmium batteries.Moreover, the combustion of fossil fuels and in-cineration of nickel-containing solid waste causespreading of nickel-containing aerosols in the sur-rounding environments as well as in theworkplace.Epidemiological studies have confirmed thatwater-insoluble nickel compounds such as crys-talline NiS and NiO represent the suspected agentin the induction of human lung and nasal cancers(IARC, 1990; Doll et al., 1970, 1977). In experi-mental animals, water-insoluble nickel com-pounds are also very potent carcinogens. They areable to induce a very high incidence of cancers atthe site of administration. For example, in arecent inhalation study conducted by the NationalToxicology Program, ‘‘NTP Bioassay of Carcino-genic Activity of Nickel Subsulfide’’, the sub-sulfide was found to induce lung cancer in rats,whereas the water-soluble nickel sulfate did notcause a statistically higher incidence of lung can-cer in this species (Dunnick et al., 1995).Despite their potency as human and rodentcarcinogens, nickel compounds are weakly muta-genic. DNA methylation and histone acetylationare important in organizing the genome into tran-scriptionally active and inactive regions. Here, we