Nickel subsulfide is genotoxic in vitro but shows no mutagenic potential in respiratory tract tissues of BigBlue rats and Muta 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 standard mutation assays, in contrast, they were found to be either inactive or weakly active. In our in vitro mutation studies in a lacI transgenic embryonic fibroblast cell line, nickel subsulfide (Ni3S2) increased mutation frequency up to 4. 5-fold. We subsequently applied the comet assay and transgenic rodent mutation assays to investigate the DNA damaging effect and mutagenic 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 following inhalative treatment of mice and rats, leading only in the mouse nasal mucosa to high DNA damage. When the same inhalative treatment was applied to lacZ and lacI transgenic mice and rats, the spontaneous mutation frequency of these target genes in the respiratory tissues was not increased. These results support a recently proposed non-genotoxic model of nickel carcinogenesis, which acts through gene silencing via DNA methylation and chromatin condensation. This model may also explain our in vitro mutation data in the lacI transgenic cell line, in which nickel subsulfide increased mutation frequency, but in about one-third of the mutants, molecular analysis did not reveal any DNA sequence change in the coding region of the lacI gene despite of the phenotypic loss of its function.
Mayer
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Division of Toxicology and Cancer Risk Factors, German Cancer Research Centre, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Klein
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RG
Wesch
H
H
Schmezer
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P
D000280:Administration, Inhalation; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry; D053938:DNA Fragmentation; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004587:Electrophoresis, Agar Gel; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016296:Mutagenesis / Q000187:drug effects*; D009297:Nasal Mucosa / Q000187:drug effects* / Q000473:pathology; D009532:Nickel / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D017422:Sequence Analysis, DNA; D013054:Spectrophotometry, Atomic
D002273:Carcinogens; D017931:DNA Primers; D009532:Nickel; D004247:DNA; C017557:nickel subsulfide