Nickel subsulfide is genotoxic in vitro but shows no mutagenic potential in respiratory tract tissues of Big Blue (TM) rats and Muta (TM) Mouse mice in vivo after inhalation

Carcinogenic nickel compounds are known to induce promutagenic DNA lesions such as DNA strand breaks and DNA adducts in cultured mammalian cells. In s tandard mutation assays, in contrast, they were found to be either inactive or weakly active. In our in vitro mutation studies in a la transgenic embr yonic fibroblast cell line, nickel subsulfide (Ni3S2) increased mutation fr equency up to 4.5-fold. We subsequently applied the comet assay and transge nic rodent mutation assays to investigate the DNA damaging effect and mutag enic potential of nickel subsulfide in target cells of carcinogenesis. A 2- h in vitro treatment of freshly isolated mouse nasal mucosa and lung cells with nickel subsulfide clearly induced DNA fragmentation in a concentration dependent manner. The strong effect was not seen in the same cell types fo llowing inhalative treatment of mice and rats, leading only in the mouse na sal mucosa to high DNA damage. When the same inhalative treatment was appli ed to lacZ and lacI transgenic mice and rats, the spontaneous mutation freq uency of these target genes in the respiratory tissues was not increased. T hese results support a recently proposed non-genotoxic model of nickel carc inogenesis, which acts through gene silencing via DNA methylation and chrom atin condensation. This model may also explain our in vitro mutation data i n the lacI transgenic cell line, in which nickel subsulfide increased mutat ion frequency, but in about one-third of the mutants, molecular analysis di d not reveal any DNA sequence change in the coding region of the lad gene d espite of the phenotypic loss of its function. (C) 1998 Elsevier Science B. V. All rights reserved.