Project Summary (1995-2000)

The overall objective of this project is to understand the mechanism by which toxic metals effect cellular oxidative stress. Oxidative stress has been implicated in a number of human diseases including cancer, aging, atherosclerosis, and fibrosis. The ability of the toxic and/or carcinogenic metals-chromium, nickel, cadmium, lead, iron and arsenic- individually and in combinations found at contaminated Superfund sites, to induce oxidative stress are being determined in chick embryo in vivo and cultured endothelial cells. The focus is on genotoxic and non-genotoxic effects of low levels of chromium and arsenic. The project examines possible induction of oxidative DNA damage by toxic metals, and the propensity of these metals to cause aberrant gene induction through alteration of cell signaling. The proposed studies should provide evidence of oxidative pathways for toxic metal action on expression of specific genes, and provide insight into the mechanism by which metals cause their toxic effects. This, in turn, could provide fundamental insights into strategies designed to prevent metal induction of oxidative stress and related proliferative diseases such as cancer, atherosclerosis and angiogenesis.