| Role of DNA Repair Inhibition in Lead- and Cadmium-induced Genotoxicity: A Review Environ Health Perspect Key words: lead, cadmium, genotoxicity, comutagenicity, DNA repair
This paper was presented at the Second International Meeting on Molecular Mechanisms of Metal Toxicity and Carcinogenicity held 10-17 January 1993 in Madonna di Campiglio, Italy.
This work was supported by Grant no. Be 561/6-1 of the Deutsche Forschungsgemeinschaft and by the University of Bremen.
Address correspondence to Dr. Andrea Hartwig, University of Bremen, Department of Biology and Chemistry, 2800 Bremen 33, Germany. Telephone 49 421 218 3259. Fax 49 421 218 4042.
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Compounds of lead and cadmium have been shown to be carcinogenic to humans and experimental animals. However, the underlying mechanisms are still not understood. In mammalian cells in culture, lead(II) is weakly mutagenic after long incubation times and generates DNA strand breaks only after treatment with high, toxic doses. Cadmium(II) induces DNA strand breaks and chromosomal aberrations, but its mutagenic potential is rather weak. However, both metals exert pronounced indirect genotoxic effects. Lead(II) is comutagenic towards UV and N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and enhances the number of UV-induced sister chromatid exchanges in V79 Chinese hamster cells. With regard to DNA repair, lead(II) causes an accumulation of DNA strand breaks after UV-irradiation in HeLa cells, indicating an interference with the polymerization or ligation step in excision repair. Cadmium(II) enhances the mutagenicity of UV light in V79 Chinese hamster cells and an increased sensitivity toward UV light is observed in various rodent and human cell lines. Furthermore, an inhibition of unscheduled DNA synthesis after UV-irradiation and a partial inhibition of the removal of UV-induced DNA lesions has been shown. For both metals, the indirect genotoxic effects are observed at low, nontoxic concentrations, suggesting that an interference with DNA repair processes may be predominant at biologically relevant concentrations. This might also explain the conflicting results of epidemiological studies obtained for both metals. Possible mechanisms of repair inhibiton are discussed. -- Environ Health Perspect 102(Suppl 3) :45-50 (1994) . Key words: lead, cadmium, genotoxicity, comutagenicity, DNA repair
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