Direct and Indirect Genotoxicity

Cadmium salts do not cause DNA damage in cell extracts or with isolated DNA [14] but rather interact with proteins therefore, the genotoxicity of cadmium is likely due to indirect mechanisms. Predominantly the induction of oxidative stress and interactions with the DNA damage response systems may be relevant in cadmium-induced genotoxicity. 

Cadmium compounds are not mutagenic in classical short term test systems, but rather exert clastogenic activity in mammalian cells. Thus, in most bacterial assays water soluble cadmium compounds were not mutagenic, and in standard mammalian mutagenicity tests effects of cadmium salts with respect to point mutations were usually weak and/or restricted to comparatively high concentrations. In contrast. 

Especially transition metal icMis play an important role in the induction of oxidative DNA damage. While neither superoxide anions nor hydrogen peroxide are able to react with DNA directly, in the presence of transition metals like iron, copper, cobalt, or nickel they are converted into highly reactive hydroxyl radicals by Fenton-type reactions. In contrast, cadmium ions are not able to participate in redox reactions under physiological conditions, yet, oxidative stress and the interference with cellular redox regulation may be of high relevance in cadmium-induced carcinogenicity. Increased levels of ROS due to cadmium exposure have been observed both in vitro and in vivo [31]. Different cadmium compounds have been shown to induce DNA strand breaks and oxidative DNA base modifications in 

The induction of DNA strand breaks and chromosomal aberrations by cadmium in mammalian cells was suppressed by antioxidants and antioxidant enzymes, indicating the involvement of ROS [34—36], Since the extent of ROS and damage to cellular macromolecules depends on the equilibrium between their generation and detoxification or repair, respectively, the occurrence of oxidative DNA damage is assumed to be due to an inhibition of the antioxidant defense by cadmium, such as the antioxidant enzymes catalase, superoxide dismutase, glutathione reductase, and glutathione peroxidase. One other mechanism proposed consists in the displacements of redox active metal ions, e.g., Fe , for example in metallothionein, giving rise to Fenton reactions [35-37]. 

Finally, enhanced frequencies of oxidative DNA lesions in cells and in vivo may also be due to impaired removal of the respective lesions (see below). Thus, ROS may be involved in cadmium-induced genotoxicity, but - perhaps more important - also in later steps of cadmium-induced carcinogenicity, by interaction with redox-controlled signaling pathways. With respect to the latter, moderately elevated levels of ROS have been implicated in later steps of tumor formation, such as cell proliferation due to mitotic stimuli and the activation of redox-sensitive transcription factors [36,38] (see below). 

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Eder E, Schiffmann D, Dornbusch K, et al. 1986. Direct and indirect genotoxicity of alkylating allylic compounds competing bioactivation mechanisms. In 4th International Congress Toxicology,... 

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