Role of oxidative stress and intracellular calcium in nickel carbonate hydroxide-induced sister-chromatid exchange, and alterations in replication index and mitotic index in cultured human peripheral blood lymphocytes.

Human peripheral lymphocytes from whole blood cultures were exposed to either soluble form of nickel carbonate hydroxide (NiCH) (0-60 microM), or of nickel subsulfide (Ni(3)S(2)) (0-120 microM), or of nickel oxide (NiO) (0-120 microM), or nickel sulfate (NiSO(4)) (0-120 microM) for a short duration of 2 h. The treatments occurred 46 h after the beginning of the cultures. The cultures were harvested after a total incubation of 72 h, and sister-chromatid exchange (SCE), replication index (RI), and mitotic index (MI) were measured for each nickel compound. The soluble form of NiCH at 30 microM but those of Ni(3)S(2) and NiO at 120 microM produced significant increase in the SCE per cell compared to the control value, whereas NiSO(4) failed to produce any such significant increase. Except NiSO(4), the soluble forms of NiCH, Ni(3)S(2), and NiO produced significant cell-cycle delay (as measured by the inhibition of RI) as well as significant inhibition of the MI at respective similar concentrations as mentioned above. Pretreatment of human blood lymphocytes with catalase (H(2)O(2) scavenger), or superoxide dismutase (superoxide anion scavenger), or dimethylthiourea (hydroxyl radical scavenger), or deferoxamine (iron chelator), or N-acetylcysteine (general antioxidant) inhibited NiCH-induced SCE, and changes in RI and MI. This suggests the participation of oxidative stress involving H(2)O(2), the superoxide anion radical, the hydroxyl radical, and iron in the NiCH-induced genotoxic responses. Cotreatment of NiCH with either verapamil (inhibitor of intracellular calcium ion ([Ca(2+)](i)) movement through plasma membranes), or dantrolene (inhibitor of [Ca(2+)](i) release from sarcoplasmic reticulum), or BAPTA (Ca(2+) chelator) also inhibited the NiCH-induced responses. These results suggest that [Ca(2+)](i) is also implicated in the genotoxicity of NiCH. Overall these data indicate that various types of oxidative stress including iron-mediated oxidative stress involving the Fenton-Haber/Weiss reaction, and alterations in calcium homeostasis are involved in the genetic damage produced by the soluble form of NiCH.