Project Summary (1995-2000)

The overall goal of this project is to determine the mechanistic basis for the preferential effects of carcinogenic metals on inducible gene expression, and to investigate the interactions of these pathways when exposure to combinations of carcinogenic metals occurs. Specifically, researchers are examining the basis for increased risk of cancer by four heavy metals, i.e., chromium, nickel, arsenic and cadmium. Specific aims include determination of whether specific DNA regulatory regions within an inducible gene are responsible for the preferential effects of the DNA-damaging metals; determination of whether functional alterations in specific transcriptional factors are responsible for the effects of the non-DNA-damaging metals on gene expression; and examination of the effects of combinations of metals on gene expression. Determining the mechanisms by which these carcinogenic metals selectively alter gene expression would have important implications for understanding the molecular basis for the impact of these agents on the cancer process. While each of these agents may have specific effects and act through independent mechanisms, they may have profound, but different effects when present in different combinations in the environment. Understanding these interactions at the molecular level is critical for an accurate assessment of the overall health effects of these substances on the human population.