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Influence of chronic cadmium exposure on the tissue distribution of copper and zinc and oxidative stress parameters in rats
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The aim of this study was to investigate the effect of oral cadmium (Cd) intoxication on the antioxidant response and its relationship with essential bioelements like copper (Cu) and zinc (Zn). The experimental group was chronically exposed to Cd daily for 8 weeks via consumption of water containing 15 ppm cadmium chloride. Cu, Zn, and Cd concentrations and oxidative stress parameters were analyzed in liver, kidney, and heart tissues. Exposure to Cd led to a significant decrease in the activities of superoxide dismutase in all considered samples while a significant increase in the activity of glutathione peroxidase except for the kidney. We found a significant increase in malondialdehyde concentration in the tissues except for heart. Also oral administration of Cd caused a significant reduction of Zn and Cu in the tissues. Our results allow us to hypothesize that higher Cd concentration in the tissues causes oxidative stress by increasing malondialdehyde as a means of altering antioxidant defense system and deterioration of bioelements in rat liver, kidney, and heart. In addition, further studies are needed to explain the effect of long-term, low-dose exposure to Cd on distribution of bioelements and its relationship with oxidative stress.
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... It is known that essential elements such as zinc (Zn), copper (Cu), calcium (Ca), and magnesium (Mg) are closely related to oxidation processes and can directly or indirectly protect cells from oxidative damage [20]. Many studies indicate the presence of interactions between Cd and key essential elements (Cu, Zn, Ca, and Mg) [21][22][23][24][25][26][27], although it is unknown whether the resulting changes are long-lasting. ...
... There are also numerous reports that environmental exposure to Cd can also lead to hepatotoxicity [14,15]. Findings in both animals and humans indicate that chronic exposure to Cd induces multimodal toxicity in various organs, with one route involving interactions with essential elements (Cu, Zn, Ca, Mg, and Fe), particularly Zn and Cu [21,26,27]. However, it has not been verified whether such disruption of essential element homeostasis may persist for a long period after the end of subchronic exposure to Cd. ...
... Cd redistribution can disrupt the homeostasis of essential elements in both the liver and kidneys and the body as a whole. Although the interaction of Cd with trace elements is well documented [21][22][23][24][25][26]40], the direction of these changes is not clear. This study showed that Cd accumulation after environmental exposure can disrupt the homeostasis of essential elements and can increase Zn and Cu levels in the liver. ...
Cadmium (Cd) is one of the most dangerous environmental pollutants. Its mechanism of action is multidirectional; among other things, it disrupts the balance of key essential elements. The aim of this study was to assess how cumulative exposure to Cd influences its interaction with selected essential elements (Cu, Zn, Ca, and Mg) in the kidney and liver during long-term observation (90 and 180 days) after subchronic exposure of rats (90 days) to Cd at common environmental (0.09 and 0.9 mg Cd/kg b.w.) and higher (1.8 and 4.5 mg Cd/kg b.w.) doses. Cd and essential elements were analyzed using the F-AAS and GF-AAS techniques. It was shown that the highest bioaccumulation of Cd in the kidney occurred six months after the end of exposure, and importantly, the highest accumulation was found after the lowest Cd dose (i.e., environmental exposure). Organ bioaccumulation of Cd (>21 μgCd/g w.w. in the kidney and >6 μgCd/g w.w. in the liver) was accompanied by changes in the other studied essential elements, particularly Cu in both the kidney and liver and Zn in the liver; these persisted for as long as six months after the end of the exposure. The results suggest that the critical concentration in human kidneys (40 μgCd/g w.w.), currently considered safe, may be too high and should be reviewed, as the observed long-term imbalance of Cu/Zn in the kidneys may lead to renal dysfunction.
... With regards to the cardiovascular system, there is an increasing amount of epidemiological evidence showing that cadmium has an impact on cardiovascular health (Lee et al., 2011;Fagerberg et al., 2015;Deering et al., 2018;Gao et al., 2018;Noor et al., 2018). Studies have also reported the deposition and accumulation of cadmium in the heart and arterial tissue in both humans (Egger et al., 2019) as well as animal models (Erdem et al., 2016;Young et al., 2019). Histopathological studies of cardiovascular tissues after cadmium exposure have reported alteration of tissue structure and integrity, fibrosis and depletion of collagen fiber (Veličkov et al., 2013;Sangartit et al., 2014;Saleh and Awadin, 2017;Bhattacharjee et al., 2019). ...
... Histopathological studies of cardiovascular tissues after cadmium exposure have reported alteration of tissue structure and integrity, fibrosis and depletion of collagen fiber (Veličkov et al., 2013;Sangartit et al., 2014;Saleh and Awadin, 2017;Bhattacharjee et al., 2019). It was reported that the heart tissue accumulated the lowest amount of cadmium after the liver and kidney (Erdem et al., 2016). However, from the previously cited studies, it can be inferred that even at low concentrations of cadmium, there are biochemical and molecular alterations in the heart. ...
... The present study did not include the role of chronic cadmium exposure on the kidneys and its relation to the described cardiac dysfunction has not been examined. On the other hand, several prior studies have reported that cadmium at the same dose has resulted in renal and cardiac injuries (Kacar Kocak et al., 2009;Yazihan et al., 2011b;Erdem et al., 2016). The authors reported hypertension associated with renal injury which may be mediated by oxidative stress, deteriorating bioelements like zinc, inducing apoptosis and inflammation. ...
The aim of this study was to evaluate the role of chronic cadmium exposure in modulating cardiac matrix metalloproteinases (MMPs) in the heart of rats. Adult male Sprague-Dawley rats were exposed to 15 ppm CdCl2 in drinking water for 10 weeks followed by withdrawal of cadmium treatment for 4 weeks. Following the completion of the treatment, gene expression of inflammatory mediators (IL-1β, IL-6, IL-10, TNF-α and NF-κB), protein expression of MMP-2, MMP-9 and their respective inhibitors- TIMP-1 and TIMP-2, and gelatinolytic activity of MMP-2 and MMP-9 were determined. At the protein level, cadmium incites a differential effect on the expression and activity of gelatinases and their endogenous inhibitors in an exposure-dependent manner. Results also show that the administered cadmium dose elicits an inflammatory response until week 10 that slightly diminishes after 4 weeks. This study provides evidence of cadmium-induced imbalance in the MMP-TIMP system in the cardiac tissue. This imbalance may be mediated by cadmium-induced inflammation that could contribute to various cardiovascular pathologies.
... Cadmium is a toxic metal which promotes oxidative stress and contributes to the development of serious degenerative changes in several tissues. Various reports have shown that Cd inducses oxidative stress by altering the antioxidative status (Erdem, Yazihan, Kocak, Sayal, & Akcil, 2015;Safhi et al., 2016). Lipid peroxidation (LPO) is one of the main manifestations of oxidative damage and has been found to play an important role in the toxicity of Cd. ...
... The renal cortex showed clear evidence of tubulo-interstitial nephritis ( Figure 1B and Table 2). This result is in accord with numerous studies (Erdem et al., 2015;Jemai, Lachkar, Messaoudi, & Kerkeni, 2010). Cd-induced nephrotoxicity is thought to be mediated through the Cd-MT complex, which is synthesized in the liver, released into circulation, and taken up by renal proximal tubule cells (Vesey, 2010). ...
... This was confirmed by the analysis of interactions between metals, showing a negative correlation between the content of Cd and Zn, Cu, Fe, and Mn in the liver. Similar results were obtained by other authors investigating various animal species [44,45]. An association between Cd and Ni has been faintly described and its exact mechanisms are not well understood. ...
... In our research, no statistically significant differences were found in the content of the examined metals in the meat of male and female loin. Sikora et al. [44] found no significant differences between the content of copper and manganese in the muscles of males and females; however, they noted differences in the content of iron (11.93 mg/kg and 17.21 mg/kg, respectively). Similarly, studies by Hermoso de Mendoza García et al. [20] and Bortey-Sam et al. [51] indicated that sex could represent an important source of variation in the bioaccumulation of metals in animals. ...
The literature on herbal additives for rabbit feed offers little information on the use of nettle and fenugreek. Both of these herbs are valuable sources of vitamins and minerals. These herbs affect the growth, health, and meat quality of rabbits. They regulate the digestive system, stimulate the appetite, have a positive effect on the functioning of the immune system, and exhibit antibacterial activity. The purpose of the present study was to determine the effect of nettle (Urtica dioica L.) leaves or fenugreek (Trigonella foenum-graecum L.) seeds in the feed on the content of selected heavy metals in the liver and meat of the rabbit. The rabbits were divided into three groups: group C (n = 20; 10 ♂ and 10 ♀) was fed ad libitum with a complete feed, N group (n = 20; 10 ♂ and 10 ♀) was fed a complete mixture with 1% added nettle, and group F (n = 20; 10 ♂ and 10 ♀) was fed with a complete mixture with 1% added fenugreek. The experiment lasted 7 weeks (from the 35th to the 84th day of the rabbits’ lives). All the rabbits were slaughtered on the 84th day of age, with a body weight of about 2.6 kg. The concentration of heavy metals (Zn, Cu, Ni, Mn, Fe, Pb, Cd) was determined by the atomic absorption spectrometry (AAS). The additives to the feed significantly affected the content of elements in both the liver and the meat of rabbits (p < 0.05). The highest level of the heavy metals, regardless of the used diet, was recorded in the liver (p < 0.05). The meat (m. longissimus lumborum) and the liver of rabbits fed with herbal fodder contained less tested metals than in animals fed with fodder without additives (p < 0.05). Moreover, more essential metals were found in the liver of rabbits fed with fenugreek than rabbits fed with nettle. In the meat and liver of rabbits, the permissible content of cadmium and lead was not exceeded. Additionally, male livers had a significantly higher content of copper and manganese compared to female livers (p < 0.05). It is important to study the content of heavy metals in the used animal herbal feed additives and their interaction with each other, as they affect the distribution of elements in tissues and organs.
... The results indicated that a high Cd concentration in vivo could affect the concentration of biological elements, such as Zn (18,19), and the toxicity of Cd is inhibited by an appropriate dose of Zn. Researchers (20) similarly have pointed out that when Cd and Zn were joined, the content of the Cd was raised, while the Zn concentration reduced, indicating antagonistic actions within the two elements. ...
Heavy metals have a wide application in the industrial world, affecting the health and longevity of living organisms. The current study assessed the possible effects of Cadmium (Cd) and Zinc (Zn) on the liver and kidney. Therefore, 150 male and female white mice C57BL were treated in three different groups with 0.685 mg/L CdCl2. 2.5H2O (group 1), and 0.567 mg/L ZnSO4.7H2O (group 2) in drinking water, while the control group only received water for 90 days to investigate how these elements accumulated in the liver/kidney and evaluate the possible histological changes in the liver and kidney. During 90 days, the histopathological consequences of Cd and Zn on the liver and kidneys were recorded. The results pointed out that exposure to heavy metals, such as Cd and Zn, led to organ accumulation of these elements. The histological evaluations demonstrated significant detrimental effects on the liver and kidney. Under the influence of Cd, light microscopic examination revealed significant histological alterations in both organs. In the animals exposed to Cd and Zn, histopathological alterations were observed in the liver, including extensive degeneration, necrosis, depletion, and necrosis of hepatocytes with significant nuclear hypertrophy. When animals are exposed to Cd and Zn, histological alterations in the kidneys include severe vascular degeneration and renal tubule necrosis. In conclusion, heavy metal intoxication has been shown to cause histopathological changes in the liver and kidneys of experimental animal models.
... Zn is one of the most important dietary nutrients in influencing heavy metal metabolism and toxicity, including Cd [12]. Cd displaces Zn once it enters the body by interfering with ionic and covalent bonds to sulphur, oxygen, and hydrogen [13], resulting in a considerable drop in systemic Zn and malfunction of many zincessential enzymes [14]. ...
Cadmium is a heavy metal that enters the body in various ways, is involved in metabolic processes, accumulates in tissues and organs and can cause pathological changes and diseases. Thus, cadmium significantly affects the condition of the liver and kidneys, nervous, cardiovascular and reproductive systems. Copper and zinc show the ability to compete with cadmium for certain receptors or metabolic pathways, which allows them to reduce its negative effects. This may open prospects for the use of copper and zinc as potential bioantagonists. This competitive process can lead to a decrease in the absorption of cadmium by cells, which, in turn, reduces its toxic effect. The interaction of cadmium with copper or zinc is a complex process, and indicators of the level of accumulation of these metals in the embryos and hearts of female rats, as well as indicators of the heart mass index, can somewhat clarify the toxicological and antagonistic nature of these interactions. Understanding these processes is important for the development of strategies to protect against cadmium toxicity and the further development of preventive measures in maintaining heart health. The study was conducted on pregnant female Wistar rats during the entire gestation period, which were divided into 4 groups. Indicators of quantitative accumulation of cadmium, copper and zinc in the embryos and hearts of females in all four groups were analyzed, which made it possible to reveal certain regularities of interactions between copper and zinc in relation to cadmium.
Cardiac toxicity is a public health issue that can be caused by both environmental and occupational exposures. The current study aimed to investigate the effectiveness of carvedilol (CV), Acetovanillone (ACET), and their combination for ameliorating cadmium (Cd)-induced oxidative stress, inflammation, and necroptosis. Rats were assigned to; the normal group, Cd group (2 mg/kg; i.p., single dose), and the other three groups received orally CV (10 mg/kg), ACET (25 mg/kg), and CV plus ACET, respectively and a single dose of Cd. Oral administration of CV, ACET, and their combination significantly dampens cardiac oxidative injury by increasing antioxidants GSH and SOD levels, while it decreases MDA and NADPH oxidase levels mediated by decreasing cardiac abundance of Nrf2, HO-1, and SIRT1 and downregulating KEAP-1 and FOXO-3 levels. Also, they significantly attenuated inflammatory response as indicated by reducing MPO and NOx as well as proinflammatory cytokines TNF-α and IL-6 mediated by downregulating TLR4, iNOS, and NF-κB proteins expression as well as IκB upregulation. Moreover, they potently counteracted cardiac necroptosis by downregulating RIPK1, RIPK3, MLKL, and caspase-8 proteins expression. Of note, the combination of CV and ACET have marked protection that exceeded each drug alone. Conclusively, CV ad ACET potently mitigated Cd-induced cardiac intoxication by regulating NADPH oxidase, KEAP-1/Nrf2/HO-1, SIRT1/FOXO-3, TLR4/NF-κB/iNOS, and RIPK1/RIPK3/MLKL signals.
The effects of selenium (Se) on antioxidant defense system in liver and kidneys of rats with cadmium (Cd)-induced toxicity were examined. Cd exposure (15 mg Cd/kg b.m./day as CdCl(2) for 4 weeks) resulted in increased lipid peroxidation (LP) in both organs (p<0.005 and p<0.01). Vitamin C (Vit C) was decreased in the liver (p<0.005), whereas vitamin E (Vit E) was increased in the liver and kidneys (p<0.005 and p<0.05) of Cd-exposed animals. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were decreased in both tissues (p<0.05 and p<0.005), whereas catalase (CAT) activity was decreased only in liver (p<0.005). Glutathione S-transferase (GST) increased in both tissues (p<0.005 and p<0.01). Treatment with Se (0.5 mg Se/kg b.m./day as Na(2)SeO(3) for 4 weeks) significantly increased liver and kidneys SOD and GSH-Px activities (p<0.05 to p<0.005), as well as CAT and GST activities only in the liver (p<0.01). In animals exposed to Se, both the concentrations of Vit C (p<0.01) and Vit E (p<0.005) were increased in both tissues. Co-treatment with Se resulted in reversal of oxidative stress with significant decline in analyzed tissues Cd burden. Our results show that Se may ameliorate Cd-induced oxidative stress by decreasing LP and altering antioxidant defense system in rat liver and kidneys and that Se demonstrates the protective effect from cadmium-induced oxidative damage.
Lead acetate (300 mg/L) and/or cadmium chloride (50 mg/L) were administered as drinking water to Sprague-Dawley rats for 9 weeks to investigate the effects of concurrent exposure to lead and cadmium on the distribution patterns of five essential trace elements. Inductively coupled plasma mass spectrometry was used to determine the concentrations of zinc, copper, manganese, selenium and iron in the urine at different exposure times, as well as their levels in the renal cortex and serum at the end of treatment. Compared with the control group, exposure to lead and/or cadmium resulted in a significant increase in the urinary excretion of these five elements during the experiment, whereas significant decreased levels of these elements were found in kidney and serum. In conclusion, increased urinary loss of antioxidant trace elements due to lead and/or cadmium exposure induced the deficiency of antioxidants in the body, which could result in further oxidative damage. Moreover, there was an obvious synergistic effect of lead combined with cadmium on the distribution patterns of these essential trace elements, which may be related to the severity of co-exposure to these two metals.
The presence of toxic substances in the workplace environment requires systematic evaluation of exposure and health status in exposed subjects. Cadmium is a highly toxic element found in water. Although free mediated cellular damage and reactive oxygen species (ROS), had been theorized as contributing to the cadmium mechanism of toxicity, and recent investigations have established that free radicals may be important contributors to cardiac dysfunction, there is little information on the effect of cadmium exposure on markers of oxidative stress in cardiac tissue. Cadmium exposure (Cd2+ - 100 mg/1-from CdCl2) in drinking water, during 15 days, significantly increased lipoperoxide and decreased the activities of superoxide dismutase and glutathione peroxidase. No alterations were observed in catalase activity in heart of rats with cadmium exposure. We also observed decreased glycogen and glucose concentration and increased total lipid content in cardiac tissue of rats with cadmium exposure. The decreased activities of alanine transaminase and aspartate transaminase reflected decreased metabolic protein degradation, and increased lactate dehydrogenase activity was related with increases in capacity of glycolysis. Since the metabolic pathways were altered by cadmium exposure, we can conclude that Cd2+ exposure induced ROS and initiate some series of events that occur in the heart and resulted in metabolic pathways alterations.
Occupational and environmental exposures to metals are closely associated with an increased risk of various cancers. Although carcinogenesis caused by metals has been intensively investigated, the exact mechanisms of action are still unclear. Accumulating evidence indicates that reactive oxygen species (ROS) generated by metals play important roles in the etiology of degenerative and chronic diseases. This review covers recent advances in (1) metal-induced generation of ROS and the related mechanisms; (2) the relationship between metal-mediated ROS generation and carcinogenesis; and (3) the signaling proteins involved in metal-induced carcinogenesis, especially intracellular reduction-oxidation-sensitive molecules.
Cadmium (Cd), an industrial and environmental pollutant, is toxic to several tissues, most notably causing hepatotoxicity on acute administration and nephrotoxicity following chronic exposure. The therapeutic efficacy of Picroliv – a standardized fraction of Picrorhiza kurroa, was investigated in male rats treated with Cd as CdCl2 (0.5 mg/kg, sc) 5 days/week for 24 weeks and Picroliv at two doses (6 and 12 mg/kg, p.o.) was given during the last 4 weeks.The Cd induced levels of malondialdehyde and membrane fluidity and decreased levels of non protein sulphydryls and Na+K+ATPase activity of hepatic tissue, along with liver function serum enzymes were restored to near normalcy on treatment with the higher dose of Picroliv. Enhanced excretion of urinary proteins, Cd, Ca and enzymes (lactate dehydrogenase and N-acetyl-β-d-glucosaminidase) evident at 24 weeks of Cd exposure, indicated severe renal damage. Picroliv appeared less effective in causing restoration of these urinary parameters as well as oxidative stress indices in the renal tissue. Picroliv not only reduced the accumulated levels of Cd, Zn and Ca and Cd-metallothionein in liver, but also enhanced the bile flow and biliary Cd. The morphological alterations in liver caused by Cd appeared less marked on Picroliv treatment. However, the renal morphology remained uninfluenced. Our earlier data on 18 weeks of Cd and 4 weeks of Picroliv co-treatment showed significant amelioration of both hepatic and renal manifestations of Cd. The hepatic protection by Picrilov is clearly demonstrated in this study, while marginal lowering of urinary proteins and enzymes is a positive signal of renal protective efficacy of Picroliv, which could be augmented by adopting higher doses and extended regimen.
Cadmium (Cd) is a toxic metal and can induce and/or promote diseases in humans (cancer, aging diseases, kidney and bone diseases, etc.). Its toxicity involves many mechanisms including the alteration of copper (Cu) and zinc (Zn) homeostasis leading to reactive oxygen species (ROS) production, either directly or through the inhibition of antioxidant activities. Importantly, ROS can induce oxidative damages in cells. Cadmium, Cu and Zn are also able to induce glutathione (GSH) and metallothioneins (MT) synthesis in a cell-type-dependent manner. As a consequence, the effects induced by these three metals result simultaneously from the inhibition of antioxidant activities and the induction of other factors such as GSH and MT synthesis. MT levels are regulated not only by the p53 protein in a cell-type-dependent manner, or by transcription factors such as metal-responsive transcription factor 1 (MTF-1) and cellular Zn levels but also by cellular GSH level. As described in the literature, DNA damage, GSH and MT levels are sensitive biomarkers used to identify Cd-induced toxicity alone or together with Cu and Zn homeostasis alteration.
We investigated the effect of oral cadmium intoxication on the antioxidant/prooxidant status in serum and heart. Wistar rats, separated into four groups, that received: (1) tap water for 60 days (control); (2), (3) and (4) Cd(2+) (15 ppm)-containing water, during 15, 30 and 60 days, respectively. Lipoperoxidation increased in serum and heart of group 4. Circulating paraoxonase-1 activity was higher in groups 2 and 3. Protein carbonyl-groups increased while total and reduced glutathione levels decreased in the heart after 15 days of cadmium intoxication. Cardiac catalase activity was higher in groups 3 and 4 but glutathione peroxidase activity diminished in the heart of all poisoned groups. Superoxide dismutase transcript levels as well as Nrf2 expression also increased in the heart of groups 2 and 3, while gp91phox and p47phox mRNA levels rose only in group 3. We suggest cadmium intoxication modifies antioxidant/prooxidant ratio in serum and heart in a time-of-exposure-dependent way.
