Role of DNA Repair Inhibition in Lead- and Cadmium-Induced Genotoxicity: A Review

Abstract

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(lIl) is weakly mutagenic after long incubation times and generates DNA strand breaks only after treatment with high, toxic doses. Cadmium(ll) induces DNA strand breaks and chromosomal aberrations, but its mutagenic potential is rather weak. However, both metals exert pronounced indirect genotoxic effects. Lead(ll) is comutagenic towards UV and N-methyl-N-nitro-Nnitrosoguanidine (MNNG) and enhances the number of UV-induced sister chromatid exchanges in V79 Chinese hamster cells. With regard to DNA repair, lead(ll) 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(ll) 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).

Genotoxicity of 11 heavy metals detected as food contaminants in two human cell lines

“…In our assay, PbCl 2 was found to be genotoxic only in LS-174T cells, with a high and significant increase in H2AX phosphorylation. This genotoxic potential has also been reported in other studies, in which it was mainly explained by interference of lead with the DNA repair system [Hartwig, 1994;Restrepo et al, 2000]. None of the concentrations of lead we tested were found to be cytotoxic in either of the two cell lines tested.…”

Protective Effect of Volatile Oil, Alcoholic and Aqueous Extracts ofOriganum majoranaon Lead Acetate Toxicity in Mice

“…Furthermore, several authors have demonstrated a protective role of several antioxidants of natural sources against clastogeny induced by several agents in bone marrow cells of mice (Jagetia et al 2003;Liopiz et al 2004). Hartwig (1994) suggested that lead genotoxicity may occur by indirect DNA repair, and Albert & Robert (1991), suggested that specific DNA damage does not determine production (and frequency) of chromosomal aberrations, but rather that the substrate available during repair is the determining factor. So we suggest that the three extracts of O. majorana provide variable protection to genetic material indicated by reduction of the number of micronucleus, total aberrant cells or different types of chromosomal aberrations.…”

Assessment of abnormal DNA repair responses and genotoxic effects in lead exposed workers

“…Pb can interact with zinc binding sites of human protamine and inhibits protamine binding to consensus sequences in DNA. One consequence of this interaction between Pb and protamine may cause decrease in protection of DNA to mutagens [Silbergeld et al, 2000, Hartwig, 1994].…”