Superfund Research Program
Molecular Mechanisms of Chromium Mutagenesis
Project Leader: Kathleen Dixon (University of Arizona)
Grant Number: P42ES004908
Funding Period: 1995 - 2001
- Project Summary
Final Progress Reports
Researchers are investigating the mutagenic and co-mutagenic potential of chromium and arsenite. Recently, it has been shown that, unlike chromate [Cr(VI)], arsenite [As(III)] is not mutagenic in a yeast-based mutagenesis assay system (SUP4-o) that detects mainly base substitution mutations. Interestingly, arsenite at high concentrations also suppressed the mutagenic activity of chromate in this system. This result is consistent with the known interaction of the two metals with intracellular glutathione (GSH). GSH mediates the intracellular reduction of chromate generating reactive intermediates that damage DNA. The inhibition of chromate mutagenesis by higher concentrations of arsenite may be due to the known capacity of arsenite to bind GSH, making it unavailable to mediate chromate reduction and generation of reactive intermediates. In a yeast-based system that detects intra- and inter-chromosomal recombination and deletion mutagenesis (the DEL assay), both carcinogenic metals were mutagenic. Chromate caused both intra- and inter-chromosomal recombination, while arsenite caused only intra-chromosomal events and only at high concentrations. In a mammalian mutagenesis assay system (pZ189) that detects both base substitution and deletion mutations, chromate was found to be highly mutagenic whereas arsenite caused little or no increase in mutagenesis. However, arsenite at low concentrations potentiated the mutagenic activity of other known mutagenic agents. The potentiation of mutagenesis by lower concentrations of arsenite may be due to the suspected capacity of arsenite to interfere with DNA repair. These results demonstrate striking differences in the mechanisms of mutation induction by these two important carcinogenic environmental contaminants. Furthermore, the results illustrate the complex interactions of multiple contaminants in mixtures. These results are particularly significant, given the prevalence of mixtures of metals and other mutagenic agents at Superfund sites.