Nickel mutagenesis: Alteration of the MuSVts 110 thermosensitive splicing phenotype by a nickel‐induced duplication of the 3′ splice site

Abstract

We investigated DNA damage caused by carcinogenic metals in a murine sarcoma virus (MuSV)-based mutagenicity assay in which mutations targeted to v-mos expression can be selected. Nickel chloride treatment of NRK cells (termed 6m2 cells) infected with MuSVts110, a retrovirus conditionally defective in viral RNA splicing and cell transformation, caused the outgrowth of transformed "revertants" with changes in the MuSVts110 RNA splicing phenotype. Cadmium and chromium treatment of 6m2 cells resulted in the selection of a second class of revertants with what appeared to be frameshift mutations allowing the translation of a readthrough gag-mos protein. In both classes of metal-induced revertants, viral gene expression was distinct from that observed in revertants arising in untreated 6m2 cultures, arguing that metal treatment did not simply enhance the rate of spontaneous reversion. In one representative nickel revertant line the operative nickel-induced mutation affecting MuSVts110 RNA splicing was a duplication of 70 bases surrounding the 3' splice site. The effect of this mutation was to direct splicing to the most downstream of the duplicated 3' sites and concomitantly relax its characteristic thermosensitivity. These data establish the mutagenic potential of nickel and provide the first example of a defined nickel-induced mutation in a mammalian gene.

Scientific Opinion on the risks to public health related to the presence of nickel in food and drinking water

“…In rat kidney epithelial cells (NRK) infected with MuSVts110 retrovirus, Ni(II) induced insertion mutation at a 70 bp-long stretch of DNA (Chiocca et al, 1991).…”

Exploring the molecular mechanisms of nickel-induced genotoxicity and carcinogenicity: a literature review

“…Prokaryotic systems and mammalian cell mutagenicity assays provide evidence of mutagenic nickel compounds. Cohort studies by Maehle et al /81/ and Chiocca et al /82/ provided evidence that nickel induces a duplication of the region containing MuSVts 110 3′ splice site, suggesting nickel’s ability to act as a mutagen in mammalian cells. A more detailed determination of genetic changes during the stepwise progression of neoplastic transformation after nickel treatment is presently being investigated.…”

“…A more detailed determination of genetic changes during the stepwise progression of neoplastic transformation after nickel treatment is presently being investigated. Future studies will determine the p53 mutation spectra in nickel (II)- associated renal and lung human cancer in comparisons with a spectra with those found in renal and lung cancers occurring in the general population /81/.…”

Nickel Toxicity and Carcinogenesis

“…In cultured human lymphocytes, nickel sulfate induced a nearly twofold increase in SCEs [308], while Ni 3 S 2 increased the frequency of micronuclei formation [309]. Other symptoms of nickel genotoxicity included microsatellite mutations in human lung cancer cells [310], insertion mutations in rat kidney epithelial (NRK) cells infected with MuSVts110 retrovirus [311], and deletion mutations in CHO cells [312]. The G → T transversion, typical for oxidative DNA damage, was found in the K-ras gene (codon 12) in renal tumors induced by Ni 3 S 2 alone or combined with iron powder [313].…”