Project Summary (1995-2000)

The purpose of this project is to understand the mechanisms by which chromium causes mutations in mammalian cells and to provide a link between the mutagenic and carcinogenic activities of chromium. Premutagenic DNA damage induced by chromium compounds are being identified and the mutagenic specificity of this damage determined. The effect of chromium-induced template damage on the cellular DNA replication apparatus is being studied. The relationship between DNA replication fidelity and the direct effects of chromium on DNA replication factors are being investigated. In addition, a link between chromium mutagenesis and carcinogenesis is being sought by examination of the mutagenic effects of inhaled calcium chromate dust in the lungs of mice. It is proposed that glutathione reduction of chromium is a major pathway for the generation of reactive intermediates that are responsible for chromium mutagenesis in cells and carcinogenesis in animals. An understanding of the mechanistic basis for chromium mutagenesis will aid in risk assessment and may suggest methods for intervention and prevention of adverse health effects of chromium exposure.