Induction of chromosomal damage in Chinese hamster ovary cells by soluble and particulate nickel compounds: preferential fragmentation of the heterochromatic long arm of the X-chromosome by carcinogenic crystalline NiS particles.

Treatment of intact Chinese hamster ovary cells with crystalline NiS and NiCl2 resulted in the induction of chromosomal aberrations which included gaps, breaks, and exchanges. The incidence of these aberrations increased in a time- and concentration-dependent fashion. NiCl2 was more potent in inducing chromosomal aberrations in cells that were maintained with a salts/glucose medium during metal treatment than when cells were treated in culture growth medium. Chromosomal aberrations induced by NiCl2 occurred randomly among the autosomal arms; however, the heterochromatic centromeric regions of the chromosomes were preferentially damaged. In addition to inducing the same type of aberrations found with NiCl2, crystalline NiS particles also caused the selective fragmentation of the heterochromatic long arms of the X-chromosomes. This fragmentation was attributed to the difference in the mechanism of delivery of nickel ions from phagocytized crystalline NiS particles which aggregate around the nuclear membrane and release large amounts of nickel ions from a dissolving phagocytized particle. Previous studies have demonstrated that treatment of intact cells with crystalline NiS particles produces a considerably higher level of nickel in the nucleus compared with similar exposure to water-soluble NiCl2. Since heterochromatin is known to form the inside lining of the interface nucleus, nickel ions, as they are solubilized from a phagocytized particle and enter the nucleus, are likely to encounter heterochromatin before they interact with euchromatin. In contrast, nickel ions derived from NiCl2 do not preferentially accumulate in the cell, and those ions that enter the cell are taken up by a nonphagocytic mechanism. It is proposed that when cells are treated with high levels of NiCl2 in an attempt to achieve the cellular levels of nickel produced by NiS phagocytosis, this overloading results in cytotoxic responses rather than the preferential fragmentation of heterochromatin observed with particles. Since liposome-mediated delivery of NiCl2 also results in fragmentation of the long arm of the X-chromosome, the selective breakage of heterochromatin by NiS particles may be due solely to the mechanism of Ni2+ delivery in cells.