Cadmium-Induced Oxidative Stress

Many authors reported an increase in oxidative stress under conditimis of heavy metal toxicity, early reports about this are reviewed by Prasad and Hagemeyer [74], Clijsters et al. [75], and Pinto et al. [76]. 

NADPH dehydrogenases, ascorbate peroxidase (APX), glutathione reductase (GR), the ascorbate-glutathione cycle, and several small molecules can scavenge or neutralize oxygen radicals. Under normal conditions, the formation and neutralization of ROS is balanced. Under stress, however, an imbalance leads to accumulation of ROS, to oxidative stress. 

The direct effect of Cd on either expression or activity of antioxidant enzymes was shown in several studies. Sandalio et al. [89] found an increased lipid peroxidation coupled with a reduction in Zn/Cu-superoxide dismutase activity in the shoots, starting at 10 pM Cd . In this case, the decrease in SOD activity was most likely the primary effect, which then led to oxidative stress. The decrease of the Zn-dependent SOD was most likely caused by Cd-induced Zn-deficiency, since Cd significantly reduced Zn translocation from roots to shoots [89]. The expression of Cu/Zn-SOD in Cd-treated pea plants (50 pM) decreased but could be reversed by Ca - supply, suggesting a competition for uptake [90]. This imbalance of other metals or micronutrients due to Cd application has been verified in various studies (e.g., [91-93]). While Mn-SOD expression was also down-regulated, plastidic Fe-SOD expression went up as measured by semiquantitative reverse transcription 

Cd tolerance most likely involves the antioxidant system. The Cd hyperaccumulator Solanum nigrum possessed a significantly higher amotmt of antioxidant enzymes compared to related non-hyperaccumulator [110]. Upregulation of small antioxidant molecules like GSH and Cd-binding phytochelatins was observed also for non-accumulators [111,112]. They also were fotmd to be higher in Cd-tolerant plants than sensitive ones, e.g., for rice [113] and Arabidopsis [99]. 

The specific detection of ROS revealed insights in the sub-cellular location of their production during Cd stress. Pea plants treated with 50 pM Cd showed reduced NO and enhanced ROS production detected with DAB staining and 

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F5. Figueiredo-Pereira, M. E., Yakushin, S., and Cohen, G., Disruption of the intracellular sulfhydryl homeostasis by cadmium-induced oxidative stress leads to protein thiolation and ubiquitination in neuronal cells. J. Biol. Chem. 273, 12703-12709 (1998). 

Bagchi, D. et al.. Chromium- and cadmium-induced oxidative stress and apoptosis in cultured J774A.1 macrophage cell, 7n Vitro Mol Toxicol, 11, 171, 1998. 

Antibodies to hydroxymethyl uracil, an oxdized DNA base, were determined in workers exposed to nickel and cadmium, and in welders (Frenkel et al. 1994). Compared to controls, a significant increase in these antibodies was noted in the most highly exposed workers. Personal monitoring of 12 workers exposed to nickel and cadmium showed correlation coefficients between exposure concentrations and the antibodies of 0.4699 for cadmium and 0.7225 for nickel. Antibodies to hydroxymethyl uracil were not increased among welders. The levels of antibodies in the control populations for the nickel cadmium workers and for the welders were different indicating the importance of determining the distribution of a new biomarker in controls for each population that is studied. This preliminary study suggests that antibodies to oxidized DNA products may be useful biomarkers for nickel and other metals that induce oxidative stress. 

Thevenod, F. and J.M. Friedmann. Cadmium-mediated oxidative stress in kidney proximal tubule cells induces degradation of Na+/K+-ATPase through proteasomal and endo-/lysosomal proteolytic pathways. FASEBJ. 13 1751-1761, 1999. 

These proteins are important for binding potentially toxic metals such as cadmium, mercury, and lead, which all bind to sulfydryl groups. Consequently, the binding and removal of these metals are protective functions. Metallothioneins are markedly induced by cadmium exposure and the small protein, rich in SH groups, can then sequester the metal. They also may have a protective role in oxidative stress and protect redox-sensitive processes. The protein also has a role in cadmium nephrotoxicity (see chap. 7). 

Figueiredo-Pereira, M.E. and G. Cohen. The ubiquitin/proteasome pathway friend or foe in zinc-, cadmium-, and H4 K-induced neuronal oxidative stress. Mol. Biol. Rep. 26 65—69, 1999. 

Although both metals and glucocorticoids can directly induce MT synthesis, divalent metals like cadmium and zinc are the best-known inducers of MT synthesis. Metal-responsive elements (MREs) and glucocorticoid-responsive elements (GREs) have been identified in MT genes (Palmiter 1987). In addition to these inducers, several other compounds (which do not even bind with MT), oxidative stress, and inflammatory conditions have been shown to induce MT synthesis in various systems. Several mechanisms are proposed for such induction of MT synthesis and they may involve lipid peroxidation with free radical formation, release of cytokines during inflammation, and changes in tissue distribution of zinc. 

Exposure to cadmium may produce oxidative stress, which may result directly in toxicity or may occur secondary to cadmium toxicity. Results from studies using cultured cells have demonstrated cadmium-induced formation of superoxide anion radicals (Amoruso et al. 1982) and implicated superoxide anions in Cd-induced DNA single-strand scissions (Ochi et al. 1983). Cadmium inhibited superoxide dismutase in vivo, resulting in elevated superoxide levels (Shukla et al. 1987). Cadmium has been shown to increase peroxidation of lipids in isolated rat hepatocytes (Stacey et al. 1980) and in other target tissues in vivo and in vitro (Gabor et al. 1978 Wahba and Waalkes 1990) thus, increased levels of lipid peroxides following exposure to cadmium could constitute a source of active oxygen species. 

Some authors explain the phytotoxicity of heavy metals at their ability to induce cells reactive oxygen species, leading to oxidative stress [21], From this viewpoint, due to the ability of a plant organism under the influence of the metal to keep activity of antioxidant enzymes (catalase, peroxidase), the resistant plants are at a certain level [18], We have shown earlier that white mustard plants, the seeds of which were pne-treated by the bacteria when exposed to high concentrations of cadmium, had higher growth and activity of catalase and peroxidase at the same time there was a simultaneous decrease in the intensity of lipid peroxidation [22], We assume that the anti-stress effect of bacilli in the rye plants when exposed to cadmium ions is also related to the preservation of the activity of antioxidant enzymes. 

Heavy metals ate potentially dangerous toxicants which are the destabilizing factor in the ecological system of established biocoenosis. lead, cadmium, meicuiy, cobalt, and other heavy metals may be inducers of the oxidative stress, which is based on formation of excessive quantity of free radicals [1, 2], Their reactivity is extremely high and initiates chain oxidation reaction. Free radicals become the reason for serious functional disorders, because various cell components are damaged [3]. Initiation of hpid peroxidation in biological membranes is an example and promotes disturbance of their structure and penetrability increase. Specialized enzymatic and nonenzymatic antioxidant systerrrs are protection against free radicals [4]. 

Paramecium caudatum (the wild strain) cell culture was cultivated in the Lozina-Lozinsky medium with addition of nutritive medium yeasts containing Saccharomy-ces cerevisiae yeasts. The oxidative stress was induced by cadmium chloride, lead acetate, and hydrogen peroxide (H O ). Infusorians sensitivity to toxic agents was determined by time of their death established by protozoa motion cessation, often accompanied by cell deformation and cytolysis. The exposure time was 2hours. The control in all tests was the number of cells in 10 ml of the medium containing the intact culture of infusorian (without oxidative stress induction). 

Fowler, B. A., M. H. Whittaker, M. Lipsky, et al. 2004. Oxidative Stress Induced by Lead, Cadmium, and Arsenic Mixtures 30-Day, 90-Day, and 180-Day Drinking Water Studies in Rats An Overview. Biometals 17 567-568. 

Abstract Cadmium is an important poiiutant in the environment, toxic to most organisms and a potential threat to human heaith Crops and other plants take up Cd from the soil or water and may enrich it in their roots and shoots. In this review, we suimnarize natural and anthropogenic reasons for the occurrence of Cd toxicity, and evaluate the observed phytotoxic effects of plants growing in Cd-supplemented sou or nutrient solution. Cd-induced effects include oxidative stress, genotoxicity, inhibition of the photosynthetic apparatus, and inhibition of root metabolism. We explain proposed and possible interactimis between these modes of toxicity. WhUe discussing recent and older studies, we further emphasize the environmental relevance of the experiments and the physiological response of the plant. 

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. 

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... 

Cadmium (Cd) is a highly toxic heavy metal element, that in plants may cause oxidation damage or even death.1 Research indicated salicylic acid (SA) and lanthanum, may adjust plant physiology pathways or change ion channels to reduce Cd absorption and repair damage caused by Cd stress. SA has been reported to induce a number of defense responses to abiotic stress,2 and La3+ can decrease the accumulation of Cd in crops,3however, whether the mixture of SA and La3+ could alleviate Cd stress is still unclear, and this is the focus of these studies. 

The proximal mechanism for induction of stress protein synthesis leading to the activation of HSF and gene activation is not completely understood, but evidence for several possibilities exists. Activation of HSF by prooxidants does not result in the accumulation of specific stress proteins (Bruce et al. 1993). These results suggest that induction of stress proteins by specific metals, whose toxicity is mediated via oxidative damage to membranes or DNA, may be fundamentally different from that of the heat-induced activation of the stress response (Keyse and Tyrrell 1987 Bruce et al. 1993). Thus, metals such as cadmium, mercury, nickel, arsenite, copper, lead, and iron, which induce oxygen free radicals or promote formation of lipid peroxides (Stacey and Klaassen 1981 Halliwell and Gutteridge 1984 Christie and Costa 1984 Kasprzak 1991 Donati et al. 1991), may... 

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