Mutagenesis and comutagenesis by lead compounds.
We have previously reported that lead(II) is weakly mutagenic to Chinese hamster V79 cells. A transgenic cell line G12 containing a single copy of the E. coli gpt gene was developed in this laboratory from Chinese hamster V79 cells. The gpt locus in the G12 cells is more mutable by radiation and oxidative agents compared with the endogenous hprt locus of wild-type V79 cells. We have investigated the mutagenicity of two lead compounds at the gpt locus in G12 cells. Only at a toxic dose is lead acetate significantly mutagenic to G12 cells. Lead nitrate is not significantly mutagenic at any dose. Although both compounds are water-soluble, lead acetate, but not lead nitrate, forms a fine white insoluble precipitate upon addition to growth medium. A nick translation assay on cells treated with lead compounds and then permeabilized indicated that lead nitrate and, to a greater extent, lead acetate causes the appearance of nicks in chromosomal DNA. Lead ions in the presence of hydrogen peroxide, but not alone, introduced nicks into supercoiled plasmid DNA in vitro, suggesting that lead ions can partake in a Fenton reaction and thereby damage DNA. At lower nonmutagenic concentrations, lead acetate enhances the mutagenicity of MNNG and ultraviolet light. DNA damage by ultraviolet light is not enhanced by lead ions in vitro. Our data support the concept that non-toxic concentrations of lead(II) can inhibit DNA repair. Thus, at biologically relevant doses, lead(II) could act as a comutagen and possibly a cocarcinogen, but is not likely to act as an initiating genotoxic carcinogen.
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004278:DNA, Superhelical / Q000187:drug effects; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins; D005798:Genes, Bacterial / Q000187:drug effects*; D007854:Lead / Q000633:toxicity*; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009566:Nitrates / Q000633:toxicity*; D009942:Organometallic Compounds / Q000633:toxicity*; D010430:Pentosyltransferases; D011506:Proteins; D014162:Transfection; D014466:Ultraviolet Rays
D001426:Bacterial Proteins; D004278:DNA, Superhelical; D029968:Escherichia coli Proteins; D009153:Mutagens; D009566:Nitrates; D009942:Organometallic Compounds; D011506:Proteins; D008769:Methylnitronitrosoguanidine; D007854:Lead; C017461:lead nitrate; D010430:Pentosyltransferases; C071962:Gpt protein, E coli; C008261:lead acetate