(Taken from application) The long-range goal of this research is to understand the mechanisms of action of the carcinogenic metals/metalloids chromium and arsenic, and to determine the impact of these metals on the mutagenic activity of polycyclic aromatic hydrocarbons (PAH). Both metals are important contaminants at Superfund sites, and in many cases they exist in complex mixtures with PAHs. Exposure by inhalation to chromate compounds has been associated with the development of lung cancer, particularly in cigarette smokers. Exposure to arsenite in drinking water has been associated with the development of skin cancer, as well as internal cancers of the lung, liver, and bladder. Chromate has been shown to be mutagenic in a variety of test systems; in contrast, arsenite and arsenate have generally tested negative for mutagenesis. However, there is evidence that arsenic is clastogenic and it appears to enhance the mutagenic activity of other agents in co-exposures. During the previous grant period, we demonstrated that chromate induces oxidative damage to DNA in a process that involves intracellular glutathione(GSH)-mediated reduction of chromate (CrVI). Furthermore, the mutagenic specificity of chromate is consistent with oxidative DNA damage in yeast, mammalian cells and the lungs of transgenic mice. In this renewal application, we propose to characterize further the mutagenic potential and mutagenic specificity of chromate, particularly with respect to the induction of deletion mutations. In addition, we propose to expand our investigation of mechanisms of metal-induced mutagenesis to include the analysis of the mutagenic potential of arsenic. We are particularly interested in determining the activity of these metals as co-mutagens in combination with PAHs, because environmental exposures often involve complex mixtures of the two classes of carcinogenic compounds. We propose to test the following two hypotheses: 1) Arsenic and chromium function as mutagens by mechanisms involving interaction with intracellular GSH and generation of reactive oxygen species. 2) Arsenic and chromium act as co-mutagens by potentiating the mutagenic activity of PAHs We propose to address these hypotheses by investigating the mutagenic, and co-mutagenic potential with PAHs, of arsenic and chromium in yeast, mammalian cells, and transgenic mice.
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