Ferroptosis as a mechanism of non-ferrous metal toxicity.

Ferroptosis is a recently discovered form of regulated cell death, implicated in multiple pathologies. Given that the toxicity elicited by some metals is linked to alterations in iron metabolism and induction of oxidative stress and lipid peroxidation, ferroptosis might be involved in such toxicity. Although direct evidence is insufficient, certain pioneering studies have demonstrated a crosstalk between metal toxicity and ferroptosis. Specifically, the mechanisms underlying metal-induced ferroptosis include induction of ferritinophagy, increased DMT-1 and TfR cellular iron uptake, mitochondrial dysfunction and mitochondrial reactive oxygen species (mitoROS) generation, inhibition of Xc-system and glutathione peroxidase 4 (GPX4) activity, altogether resulting in oxidative stress and lipid peroxidation. In addition, there is direct evidence of the role of ferroptosis in the toxicity of arsenic, cadmium, zinc, manganese, copper, and aluminum exposure. In contrast, findings on the impact of cobalt and nickel on ferroptosis are scant and nearly lacking altogether for mercury and especially lead. Other gaps in the field include limited studies on the role of metal speciation in ferroptosis and the critical cellular targets. Although further detailed studies are required, it seems reasonable to propose even at this early stage that ferroptosis may play a significant role in metal toxicity, and its modulation may be considered as a potential therapeutic tool for the amelioration of metal toxicity.

Cobalt in athletes: hypoxia and doping - new crossroads.

Cobalt is an essential trace element that is known to mimic hypoxia and hypoxic training. Inorganic Co compounds are capable of Hypoxia-inducible factor-1 (HIF-1) activation, resulting in up-regulation of gene expression including erythropoietin (Epo). Experimental studies have demonstrated that Co treatment may increase hypoxic tolerance of different tissues, improve muscle metabolism and exercise performance. Other mechanisms may also involve modulation of steroid hormone and iron metabolism. Based on these experimental studies, in 2017 inorganic cobalt compounds were added into the World Anti-Doping Agency (WADA) prohibited list as doping agents. However, the existing data on beneficial effects of cobalt on exercise performance in athletes are scarce. Similarly, only experimental studies demonstrated exercise-induced decrease in tissue Co levels, whereas human data are inconsistent. In addition, multiple studies have demonstrated that excessive Co intake may be toxic due to prooxidant, proinflammatory, and proapoptotic activity. Therefore, monitoring of Co deficiency and overload is required to prevent potential health hazards in athletes. At the same time, modulation of Co status should be performed through supplementation avoiding excessive doses of inorganic cobalt that are used for doping and are accompanied by adverse health effects of metal toxicity.

Effect of CoCl2 on the content of different metals and a relative activity of DNA-hydrolyzing abzymes in the blood plasma of mice.

Cobalt is a transition metal and an essential trace element that is required for vitamin B12 biosynthesis, enzyme activation, and so on but is toxic in high concentrations. It was shown that the content of different elements in the plasma of 2-month-old BALB/c mice (control group) decreased in the following order: Ca > Mg > Si > Fe > Zn > Cu ≥ Al ≥ B. The treatment of mice with CoCl2 did not appreciably change the relative content of Ca, Cu, and Zn, but a significant increase in the content of B (2.3-fold), Mg (1.5-fold), Al and Fe (2.1-fold), and Si (3.4-fold) was found. The treatment of mice led to a 2.2-fold decrease in the concentration of the total blood protein and a 1.7 ± 0.2-fold decrease of total immunoglobulin Gs (IgGs). Deoxyribonuclease IgGs corresponding to mice treated (t-IgGs) and non-treated (nt-IgGs) with CoCl2 contained intrinsically bound metal ions; these IgGs hydrolyzed DNA with very low activity but were not active in the presence of ethylenediaminetetraacetic acid or after Ab dialysis against ethylenediaminetetraacetic acid. The average RAs of deoxyribonuclease nt-IgGs increased after addition of external metal ions in the following order: Zn²âº< Ca²âº < Cu²âº < Fe²âº < Mn²âº < Mg²âº < Co²âº < Ni²âº. Interestingly, t-IgGs demonstrated lower activities than those for nt-IgGs either in the absence of external metal ions (2.7-fold) or in the presence of Cu²âº (9.5-fold) > Co²âº (5.6-fold) > Zn²âº (5.1-fold) > Mg²âº (4.1-fold) > Ca²âº (3.0-fold) > Fe²âº (1.3-fold). However, the RAs of t-IgGs were remarkably more active than nt-IgGs in the presence of best activators of t-IgGs Ni²âº (1.4-fold) and especially Mn²âº (2.2-fold). The data may be useful for an understanding of Co toxicity, its effect on the concentration of other metal ions, and a change of metal-dependent specificity of Abzs.

The role of cadmium in obesity and diabetes.

Multiple studies have shown an association between environmental exposure to hazardous chemicals including toxic metals and obesity, diabetes, and metabolic syndrome. At the same time, the existing data on the impact of cadmium exposure on obesity and diabetes are contradictory. Therefore, the aim of the present work was to review the impact of cadmium exposure and status on the risk and potential etiologic mechanisms of obesity and diabetes. In addition, since an effect of cadmium exposure on incidence of diabetes mellitus and insulin resistance was suggested by several epidemiologic studies, we carried out a meta-analysis of all studies assessing risk of prevalence and incidence of diabetes. By comparing the highest versus the lowest cadmium exposure category, we found a high risk of diabetes incidence (odds ratio=1.38, 95% confidence interval 1.12-1.71), which was higher for studies using urine as exposure assessment. On the converse, results of epidemiologic studies linking cadmium exposure and overweight or obesity are far less consistent and even conflicting, also depending on differences in exposure levels and the specific marker of exposure (blood, urine, hair, nails). In turn, laboratory studies demonstrated that cadmium adversely affects adipose tissue physiopathology through several mechanisms, thus contributing to increased insulin resistance and enhancing diabetes. However, intimate biological mechanisms linking Cd exposure with obesity and diabetes are still to be adequately investigated.

The tetraethylammonium salt of monensic acid-An antidote for subacute cadmium intoxication: a study using an ICR mouse model.

In this study, the ability of the chelating agent monensic acid (administered as the tetraethylammonium salt) to reduce the cadmium (Cd) concentration in the kidneys, liver, heart, lungs, spleen and testes of Cd-intoxicated mice was investigated. Chelation therapy with the tetraethylammonium salt of monensic acid led to a significant decrease of the Cd concentration in all of the organs of the Cd-treated mice. This effect varied from 50% in the kidneys to 90% in the hearts of the sacrificed animals (compared to the Cd-treated controls). No redistribution of the toxic metal ions to the brain of the animals as a result of the detoxification with the chelating agent was observed. The detoxification of the animals with the antibiotic salt did not perturb the endogenous levels of copper (Cu) or zinc (Zn). The tetraethylammonium salt of monensic acid significantly ameliorated the Cd-induced total iron (Fe) depletion in the liver and spleen of Cd-treated mice. It also restored to control levels the values of transferrin-bound Fe and the total iron binding capacity (TIBC) of the plasma. These results imply that the tetraethylammonium salt of monensic acid could be an efficient antidote in cases of Cd-intoxication.