Is the capacity of lead acetate and cadmium chloride to induce genotoxic damage due to direct DNA-metal interaction?

Even though the toxic effects of lead and cadmium compounds have been studied over many years, inconsistent results have been obtained about their mutagenic, clastogenic and carcinogenic properties. However, these metals are considered to be potential human carcinogens. The mechanism of metal-induced carcinogenesis is still unknown, but one possible pathway may involve the interaction of metals with DNA, either directly or indirectly. In this work we explore the capacity of lead, cadmium or a mixture of both metals to interact with acellular DNA, by employing a variant of the comet assay. Our results, using low non-cytotoxic metal concentrations (0.01, 0.1 and 1.0 microM) with the standard protocol for the acellular assay, showed an induction of DNA damage in cells of all organs studied; however, basal DNA damage was different in each organ. To confirm that we were working with pure DNA, proteinase K was added to the lysis solution. With this enriched-lysis solution we found a negative response in the induction of DNA damage in cells derived from the liver, kidney and lung of CD-1 male mice. To support the results obtained by the enriched-acellular assay, we studied the capacity of lead and cadmium (0.1 microM) to induce breaks in pooled genomic DNA in cells of the same organs, with negative results. Consistent with these findings, these metals do not induce DNA breaks in the plasmid pUSE amp+. On the whole, we did not detect direct induction of DNA strand breaks by lead acetate, cadmium chloride or a mixture of both metals, all at low non-cytotoxic concentrations. However, we found an induction of lipid peroxidation and an increase in free radical levels in the different organs of CD-1 male mice after inhalation of lead acetate (0.0068 microg/cc) or cadmium chloride (0.08 microg/cc) for 1 h, suggesting the induction of genotoxicity and carcinogenicity by indirect interactions, such as oxidative stress.