Effects of carcinogenic metals on gene expression.

Six metals and/or their compounds have been recognized as carcinogens: arsenic, beryllium, cadmium, chromium, cobalt and nickel. With the exception of arsenic, the main rote of exposure is inhalation and the main target organ is the lung. Arsenic is exceptional because it also produces tumors of skin and lung after oral uptake. With the exception of hexavalent chromium, carcinogenic metals are weak mutagens, if at all, and their mechanisms of carcinogenicity are still far from clear. A general feature of arsenic, cadmium, cobalt and nickel is their property to enhance the mutagenicity and carcinogenicity of directly acting genotoxic agents. These properties can be interpreted in terms of the ability of these metals to inhibit the repair of damaged DNA. However, because carcinogenic metals cause tumor development in experimental animals even under exclusion of further carcinogens, other mechanisms have to be envisaged, too. Evidence will be discussed that carcinogenic metal compounds alter patterns of gene expression leading to stimulated cell proliferation, either by activation of early genes (proto-oncogenes) or by interference with genes downregulating cell growth. Special reference will be devoted to the effects of cadmium and arsenic on gene expression, which have been studied extensively. Possible implications for occupational safety and health will be discussed.