Sequential events in the induction of transformation in cell culture by specific nickel compounds

Crystalline metal sulfides (i.e., Ni3S2, NiS, CoS, CuS) are potent inducers of transformation in Syrian Hamster Embryo cells while the respective amorphous compounds exhibit low transforming activity. Both crystalline and amorphous compounds are relatively water insoluble and when these particulate compounds (2-4 µm) are added to various types of cultured fibroblasts, they exhibit striking differences in their phagocytosis. These differences in uptake were directly related to their surface charge, since crystalline NiS had a negative surface charge (-27 mV, zeta potential) while amorphous NiS had a positively charged surface (+9 mV, zeta potential). Chemical reduction of amorphous NiS with LiA1H4 resulting in acquisition of a negative surface charge, enhanced phagocytosis and caused an incidence of transformation equalling that of crystalline NiS. Following phagocytosis of crystalline NiS, video time lapse microscopy and studies using(63)NiS show that the particles undergo cytoplasmic dissolution that appears to be mediated by lysosomal interaction. Later, the phagocytized NiS particles aggregate in the perinuclear region, their movement by saltation decreases and in some instances vacuoles form around the particles. Particle dissolution products then enter the nucleus and induce strand breaks in the DNA as determined by alkaline sucrose gradient and alkaline elution techniques. Cesium chloride gradient analysis also indicates that phagocytized NiS particles induce repair of DNA. Damage to DNA appears to be a very selective and sensitive action of all metal compounds with potential carcinogenic activity.