Recent advances in metal carcinogenicity*

The carcinogenicity of nickel, chromium, arsenic, cobalt, and cadmium compounds has long been recognized. Nevertheless, the mechanisms involved in tumor formation are not well understood. The carcinogenic potential depends on metal species; major determinants are oxidation state and solubility. Two modes of action seem to be predominant: the induction of oxidative DNA damage and the interaction with DNA repair processes, leading to an enhancement of genotoxicity in combination with a variety of DNA-damaging agents. Nucleotide excision repair (NER) is inhibited at low, non-cytotoxic concentrations of nickel(II), cadmium(II), cobalt(II), and arsenic(III); the repair of oxidative DNA base modifications is disturbed by nickel(II) and cadmium(II). One reason for repair inhibition appears to be the displacement of zinc(II) and magnesium(II). Potentially sensitive targets are so-called zinc finger structures present in several DNA repair enzymes such as the mammalian XPA protein and the bacterial formamidopyrimidine-DNA glycosylase (Fpg protein); detailed studies revealed that each zinc finger protein exerts unique sensitivities toward toxic metal ions. Taken together, toxic metal ions may lower the genetic stability by inducing oxidative DNA damage and by decreasing the repair capacity towards DNA lesions induced by endogenous and exogenous mutagens, which may in turn increase the risk of tumor formation. CARCINOGENIC METAL COMPOUNDS: OCCURRENCE, CHEMICAL SPECIATION, AND INTERFERENCE WITH CELLULAR FUNCTION RELATED TO CARCINOGENICITY Metal compounds are part of the earth crust and thus ubiquitously distributed in the environment. Yet, combustion and industrial use contribute significantly to human exposure at workplaces and in the general environment. Some metals, including chromium, nickel, arsenic, cadmium, and cobalt, have long been recognized as human and/or animal carcinogens [1–4]. Their carcinogenic potentials depend largely on factors like oxidation state and solubility. Thus, exposure to chromium(VI) is strongly associated to human lung cancer, while chromium(III) is largely inactive. This discrepancy is related to differences in bioavailability; while chromium(III) is unable to cross the cell membrane, chromium(VI) is readily taken up by anion transporter followed by intracellular reduction to chromium(III) (reviewed in ref. 5). The impact of solubility is most evident for nickel compounds. While particulate nickel compounds with intermediate water solubility (like nickel subsulfide) are strong carcinogens, soluble nickel(II) salts exert considerably weaker effects. This difference could be attributed to differences in bioavailability. While water-soluble nickel salts are taken up only slowly by cells, particulate nickel compounds are phagocytosed and gradually dissolved in lysosomes because of the low pH, yielding high concentrations of nickel ions in the nucleus [6]. Nevertheless, the underlying molecular mechanisms of metal carcinogenicity are not well understood, especially since they are not mutagenic in bacterial test systems and only weakly mutagenic in cultured mammalian cells. Recent studies have identified levels of interaction which may be relevant for the carcinogenic process. They include the induction of oxidative DNA damage [7], the interference with diverse DNA repair systems [8], as well as changes in the expression of certain oncogenes or tumor suppressor genes by interference with signal transduction