Nickel carcinogenesis, mutation, epigenetics, or selection.

ofcells to carcinogenic nickel compounds induces many genes that are commonly expressed in cancer cells but not in normal cells. Nickel compounds have been well established as human carcinogens. Investigations into the molecular mechanisms of nickel car-cinogenesis have revealed that not all nickel compounds are equally carcinogenic: certain water-insoluble nickel compounds exhibit potent carcinogenic activity, whereas highly water-soluble nickel compounds exhibit less potency (1). The reason for the high carcinogenic activity of certain water-insoluble nickel compounds relates to their bioavailability and the ability of the nickel ions to enter cells and reach chromatin. The water-insoluble nickel compounds enter cells quite efficiently via phagocytic processes, and subsequent intracellular dissolution yields very high cellular levels of Ni2+. Mathematical estimations indicated that if a 1.45-pm nickel sulfide particle totally dissolved in a cell, the potential nickel concentration would be 250 mM, and if a 4.0-pm nickel sulfide particle totally dissolved in a cell, the potential nickel concentration would be 4.75 M. Thus, the process of phagocytosis represents a very efficient manner for the accumulation of nickel inside the cell. Nickel is classified as a borderline metal ion because it has both soft and hard metal properties and it can bind to sulfur, nitrogen, and oxygen groups. Nickel ions are very similar in structure and coordination properties to magnesium. Like magnesium, nickel binds to the oxygen of the DNA phosphate backbone; but like copper and cobalt, nickel enjoys a high affinity for the imidazole nitrogen of histidine in proteins. Investigations of the mutagenic activity of highly carcinogenic nickel compounds have failed to reveal much activity in most of the mutational systems examined thus far (2). However, carcinogenic nickel compounds induce chromosomal aberrations, including those that are specific to heterochromatic chromosome regions (3). Carcinogenic nickel compounds have also been shown to increase the extent of DNA methylation. In one experimental system in which transgenes were located either near or distant from a hete-rochromatic chromosome region in hamster cells, carcinogenic nickel compounds were shown to hypermethylate the transgene located near heterochromatin, but not the transgene more distant from hete-rochromatin (4). Although the mechanisms by which nickel induces DNA hypermethylation are presently unknown, a possible model might include the ability of nickel to substitute for magnesium and increase DNA and chromatin condensation more efficiently than magnesium, thereby triggering a de novo DNA methylation of the genome region that was condensed by the presence of nickel (5). Other …