Effect of zinc deficiency on the accumulation of metallothionein and cadmium in the rat liver and kidney

The effects of zinc (Zn) deficiency and repeated exposure to cadmium (Cd) on the accumulation and distribution of metallothionein (MT), Cd and Zn in the liver and kidney were studied. Male Sprague-Dawley rats were fed either a Zn-deficient (1 ppm) or a Zn-adequate (40 ppm) diet during the experiment, and the rats were injected subcutaneously with a cadmium chloride solution (1.0 mg Cd/kg of body weight, 5 days a week) for 4 weeks. Cadmium, Zn, and Cd-induced MT concentrations in the liver and kidney were lower in the Zn-deficient rats (–Zn + Cd) than in the Zn-adequate rats (+ Zn + Cd), while the content of Cd bound to high molecular weight proteins (HMWP) was greater in the Zn-deficient rats (–Zn + Cd). The Zn bound to Cd-induced MT was reduced to 30% in the liver and to 60% in the kidney of the Zn-deficient rats (–Zn + Cd) as compared with that of the Zn-adequate rats (+ Zn + Cd). In the kidney of Zn-deficient rats, exposure to Cd caused a decrease in essential Zn associated with HMWP as compared with that of Zn-adequate rats (+ Zn + Cd). Thus, Zn-deficiency affected the distribution of Cd in tissues, MT and HMWP and accelerated substantially Cd-induced Zn-deficiency in the kidney. Although the renal Cd concentration was lower in the Zn-deficient rats (–Zn + Cd) than in the Zn-adequate rats (+ Zn + Cd), exposure to Cd for four weeks resulted in glucosuria and an increase in liver and kidney weights in the Zn-deficient rats (–Zn + Cd), but not in the Zn-adequate rats (+ Zn + Cd). These results suggest that development of Cd toxicity is related to the Zn status of the body, to the accumulation of Cd in HMWP and to the amount of essential Zn associated with HMWP.     

An iron-rich diet protects the liver and kidneys against cadmium-induced injury in the bank vole (Clethrionomys glareolus)

The objective of this study was to determine whether supplemental dietary iron (Fe) would protect against cadmium (Cd)-induced injury in the liver and kidneys of bank voles. The rodents were provided, for 6 weeks, Fe-adequate (60-80 microg/g) and Fe-enriched (250-270 microg/g) diets containing 0.05 (control), 40, and 80 microg Cd/g. Histological examinations and analyses of Cd, Cd bound and not bound to metallothionein (MT), Fe, and lipid peroxidation in liver and kidneys were carried out. The Fe-enriched diet prevented Cd-induced histopathological changes as well as deprivation of tissue Fe and lipid peroxidation. Also, supplemental Fe significantly decreased hepatic and renal Cd burden. However, in the Cd-80 bank voles fed the Fe-enriched diet, the non-MT-bound Cd, considered a toxic species, reached 4.7 microg/g liver and 13.7 microg/g kidney, these values being similar to those at which histopathological changes occurred in the voles fed Cd diets not supplemented with Fe. The data indicate that the protective effect of supplemental Fe in the bank vole may be due to the prevention of Cd-induced deprivation of tissue Fe and Fe-dependent oxidative processes rather than to reduction of cadmium accumulation.     

Protective role of diallyl tetrasulfide on cadmium-induced testicular damage in adult rats: a biochemical and histological study

Cadmium (Cd)-induced oxidative damage is the most serious problem that leads to reproductive system failure in both human and animals. Our previous studies indicate that diallyl tetrasulfide (DTS) from garlic has the cytoprotective and antioxidant activity against Cd-induced toxicity in vivo and in vitro. The present investigation was carried out to find the influence of DTS on peroxidative damage induced by Cd in rat testes. The Cd-exposed rat testis showed a significant (p < 0.05) decrease in testes to body weight ratio, along with a significant (p < 0.05) increase in Cd accumulation, lipid peroxidation and protein carbonyl levels. In Cd-exposed rats, we also observed a significant (p < 0.05) decrease in the activities of antioxidant (superoxide dismutase, catalase and glutathione peroxidase) and glutathione metabolizing (glutathione-S-transferase, glutathione reductase and glucose-6-phosphate dehydrogenase) enzymes as well as reduced levels of non-enzymic (reduced glutathione, ascorbate and total sulphydryl groups) antioxidants. In contrast, treatment with DTS (40 mg/kg body weight orally) significantly (p < 0.05) reduced the accumulation of Cd and lipid peroxidation markers and also significantly improved the activities of antioxidant defense system in testes. Testicular protection by DTS is further substantiated by remarkable reduction of Cd-induced pathological changes. Our study has revealed that DTS renders protection against Cd-induced testicular injury by reducing Cd-mediated oxidative damage.     

Anti-apoptotic effects of curcumin on cadmium-induced apoptosis in rat testes

Cadmium (Cd) is one of the environmental pollutants affecting various tissues and organs including testis. The aim of this study was to investigate the anti-apoptotic effects of curcumin (Cur) on Cd-induced apoptosis in rat testes. The rats were randomly allotted into one of three experimental groups: control, Cd treated and Cd treated with Cur; each group contained 10 animals. The control group received 2 ml/day of dimethyl sulfoxide (DMSO). To induce toxicity, Cd (1 mg/kg body weight) was dissolved in normal saline and subcutaneously injected into rats for 4 weeks. The rats in Cur-treated group was given a daily dose of 100 mg/kg of Cur for 4 weeks. To date, no examinations of the anti-apoptotic properties of Cur on Cd-induced apoptosis in rat testes have been reported. The mean seminiferous tubule diameter, mean testicular biopsy score values and serum testosterone levels were significantly decreased in Cd-treated groups were compared to the control group. Furthermore, the Cur-treated animals showed an improved histological appearance and serum testosterone levels in Cd-treated group. Our data indicate a significant reduction in the activity of in situ identification of apoptosis using terminal dUTP nick end-labeling in testis tissues of the Cd-treated group with Cur therapy. The present study showed that Cur treatment protected testes against toxic effects of Cd. We believe that further preclinical research into the utility of Cur may indicate its usefulness as a potential treatment on the spermatogenesis after testicular injury caused by Cd-treated rats.     

Anemia induced by cadmium intoxication

Anemia is commonly induced by chronic cadmium (Cd) intoxication. Three main factors are involved in the development of Cd-induced anemia: hemolytic, iron-deficiency, and renal. Intravascular hemolysis can occur at the early stage of Cd exposure owing to the direct damaging effect on erythrocytes. In addition, Cd that accumulates in erythrocytes affects membrane cytoskeletons and decreases cell deformability, and these cells are then trapped and destroyed in the spleen. Iron deficiency can be detected in animals after an oral exposure to Cd, which competes with iron for absorption in the intestines, leading to anemia. However, an increase in body iron content along with anemia is often observed in cases of parenteral exposure or itai-itai disease. Therefore, it is estimated that Cd disrupts the efficient usage of iron in hemoglobin synthesis in the body. Renal anemia is observed during the very last phase of chronic, severe Cd intoxication, such as itai-itai disease, showing a decrease in the production of erythropoietin from renal tubular cells. Because the renal anemia is based on the same pathophysiology as Cd-induced osteomalacia, which is derived from the disturbance of mineral metabolism due to renal tubular dysfunction, it is reasonable to include renal anemia in the criteria for the diagnosis of itai-itai disease. Hemodilution could also contribute to the development of Cd-induced anemia. Bone marrow hypoplasia or the inhibition of heme synthesis might only be involved in Cd-induced anemia in severe cases of Cd intoxication.     

镉致贫血及铁、锌、铜的预防作用

本文探讨了饲镉小鸡发生贫血的性质、原因及补充铁、锌、铜的预防作用。将1日龄雄性京白鸡依体重随机分为6组:对照组、饲镉组、补铁组、补锌组、补铜组及同时补充铁,锌,铜组。实验3周后,测定血红蛋白、红细胞压积、红细胞计数、红细胞脆性、红细胞形态、红细胞游离原卟啉、血浆铜蓝蛋白及肝脏中各元素的浓度。结果表明:1.饲镉小鸡发生了正细胞低色素性贫血,其原因与镉致红细胞变形、渗透脆性增大及机体缺铁、缺铜有关;2.补充铁或铜预防了镉致贫血,补充锌无预防作用;3.饲镉小鸡产生了生长阻滞,补充铁、锌或铜有预防作用。     

Longitudinal studies on the health effects of exposure to environmental cadmium

Renal damage induced by cadmium (Cd) results in a proximal renal tubular dysfunction, characterized by low-molecular weight (LMW) proteinuria, renal glucosuria, generalized aminoaciduria and decreased renal tubular reabsorption of uric acid and phosphate. Since LMW proteinuria is thought to be one of the earliest adverse health effects caused by Cd, the prevention of the progress of LMW proteinuria is important to avoid further deteriorations in the health condition. Follow-up studies on residents in Cd-polluted areas and Cd-exposed workers have indicated that Cd-induced LMW proteinuria is generally irreversible and progressive even after the cessation or reduction of exposure. The intensity of exposure and the body burden of Cd before the reduction of exposure may influence the prognosis of Cd-induced LMW proteinuria. Several studies have reported a gradual decline in the glomerular filtration rate even after the reduction of Cd exposure. Cohort studies performed in Cd-polluted areas of Japan showed that renal tubular dysfunction and a decreased glomerular filtration rate were strongly associated with increased risk of mortality. However, the results also suggested that overall mortality rates in Cd-polluted areas were not necessarily increased, because of the low mortality among those with urinary beta 2-microglobulin concentrations < 1,000 micrograms/g creatinine. At present, incidence data are too limited to draw a conclusion regarding the cancer risk among residents in Cd-polluted areas.     

Protective effects of selenium (Se) and zinc (Zn) on cadmium (Cd) toxicity in the liver of the rat: Effects on the oxidative stress

Cadmium (Cd) is a very harmful environmental pollutant that transfers between various levels of the food chain. To study the protective effect of Se and Zn on Cd-induced oxidative stress in livers, male rats received either, tap water, Cd, Cd+Zn, Cd+Se or Cd+Zn+Se in their drinking water, for 35 days. The activities of total superoxide dismutase (SOD), copper, zinc-superoxide dismutase (CuZn SOD), glutathione peroxidase (GPx) and catalase (CAT), malondialdehyde (MDA) level and the ratio of CuZn SOD to GPx activity, were determined in the liver. Exposure to Cd lowered total SOD, CuZn SOD, GPx and CAT activities, while it increased MDA level and the ratio of CuZn SOD to GPx activity, in the organ studied. With Se or Zn administration during exposure to Cd, only partial corrective effects on Cd-induced oxidative stress in the liver have been observed, while Se and Zn together assured a more efficient protection of the organ against the observed oxidative stress.     

Metallothionein and occupational exposure to cadmium

The relationship between metallothionein (MT), chronic exposure to cadmium (Cd), and renal function was investigated in 53 men who were occupationally exposed to Cd. The aim was to determine if MT is a potential biological monitor for chronic exposure to Cd which would be useful for preventing Cd nephropathy. In this study MT excretion, serum MT, and serum creatinine concentrations were significantly higher in subjects with abnormal renal function who had been exposed to Cd. MT excretion was also linearly related on an individual basis to protein excretion, beta 2-microglobulin (beta 2-M) excretion, and cumulative time weighted exposure (dose). MT excretion was also a better predictor of dose than either beta 2-M excretion or Cd excretion. The findings suggest that MT is a potential biological monitor for chronic Cd exposure that would be useful for preventing Cd-induced nephropathy. Further studies of non-specific nephropathies and MT are needed to determine if MT is a specific indicator of proximal tubule function secondary to chronic exposure to Cd.     

Metallothionein and occupational exposure to cadmium.

The relationship between metallothionein (MT), chronic exposure to cadmium (Cd), and renal function was investigated in 53 men who were occupationally exposed to Cd. The aim was to determine if MT is a potential biological monitor for chronic exposure to Cd which would be useful for preventing Cd nephropathy. In this study MT excretion, serum MT, and serum creatinine concentrations were significantly higher in subjects with abnormal renal function who had been exposed to Cd. MT excretion was also linearly related on an individual basis to protein excretion, beta 2-microglobulin (beta 2-M) excretion, and cumulative time weighted exposure (dose). MT excretion was also a better predictor of dose than either beta 2-M excretion or Cd excretion. The findings suggest that MT is a potential biological monitor for chronic Cd exposure that would be useful for preventing Cd-induced nephropathy. Further studies of non-specific nephropathies and MT are needed to determine if MT is a specific indicator of proximal tubule function secondary to chronic exposure to Cd.     

Cadmium Accumulation in Tomato Cultivars and Its Effect on Expression of Metal Transport-Related Genes

Cadmium (Cd) content was quantified in the shoot of six tomato cultivars and the Cd effect on the expression of LeNRAMP3, LeFER, LeIRT1 and LeNRAMP1 was evaluated. The six tomato cultivars accumulated high Cd concentrations and were able to transport Cd to the fruits. Among the evaluated genes, the Cd-induced level of LeFER expression appeared to provide an evidence regarding the capacity of foliar Cd accumulation in tomato. The results indicate that tomato represents a possible pathway for Cd entry into the food chain and an attractive model organism for the elucidation of the mechanisms involved in Cd accumulation.     

Roles of reactive oxygen species and mitochondria in cadmium-induced injury of liver cells

The roles of reactive oxygen species (ROS) and mitochondrial damage in the cadmium (Cd)-induced injury of liver cells were studied by using N-acetyl-L-cysteine (NAC) and acetyl-L-carnitine hydrochloride (ALCAR). After exposure of experimental rats to cadmium (Cd) for 16 h, mitochondrial membrane potential (MMP), ROS production, glutathione peroxidase (GSH-Px) activity, glutathione (GSH) content, malondialdehyde (MDA) content and DNA single-strand break (DNA-SSB) were analyzed. Loss of MMP, increase of ROS production, inhibition of GSH-Px activity, elevation of GSH content, rise of MDA content and DNA-SSB level suggest the participation of ROS and mitochondrion in Cd-induced injury of liver cell. NAC pretreatment attenuated oxidative stress, reversed the decline in GSH-Px activity and reduced GSH and MDA levels significantly. However, Cd-induced loss in MMP was significantly exacerbated by NAC. For another, ALCAR did not perform as well as NAC in terms of reducing ROS production, restoring GSH-Px activity and reducing GSH content. Nevertheless, it significantly improved the recovery of MMP and reduction of MDA content. In addition, conspicuous DNA damage was observed in the samples treated with NAC or ALCAR, indicating Cd could attack DNA through other pathways. These results suggest that oxidative stress or mitochondrial impairment plays a main role in different injuries respectively.     

Comparative analysis of antioxidants against cadmium induced reproductive toxicity in adult male rats

Abstract

The present study was conducted to compare and evaluate the potential benefits of three different antioxidants in reversing cadmium (Cd)-induced reproductive toxicity in adult male rats. Rats (n?=?5) weighing 180?±?20?gm were divided into five groups (control, Cd, Cd?+?sulforaphane, Cd?+?vitamin E, and Cd?+?plant extract). Treated groups received CdCl₂ (0.2?mg/kg), sulforaphane (25?µg/rat), vitamin E (75?mg/kg), and plant extract (100?mg/kg) for 15 days. Blood samples and testicular tissues were obtained for estimation of testosterone, Zn, and Cd concentration and daily sperm production/efficiency of sperm production. Cadmium exposure caused a significant decrease in final body weight (p?<?0.0001). The plasma concentrations of Cd were significantly increased and Zn concentration decreased (p?<?0.0001) in the Cd group as compared to the control group. The testicular concentrations of Cd were significantly increased and Zn concentration decreased (p?<?0.0001) in the Cd group as compared to the control group. Cadmium exposure caused a significant decrease (p?<?0.0001) in plasma testosterone concentrations and daily sperm production as compared to the control group. More significant effects were observed with Cd+sulforaphane, Cd?+?vitamin E, and Cd?+?plant extract treated groups in slashing Cd-induced toxicity. Present findings suggest that Ficus religiosa and sulforaphane are more powerful antioxidants as compared to vitamin E in reversing the oxidative stress and can have a protective role against Cd induced reproductive toxicity in adult male rats. Part of the mechanism involved in this protective role seems to be associated with the antioxidant properties of these agents in reducing reproductive damage.     

Differential Susceptibility to Cadmium-Induced Liver and Kidney Injury in Wild and Laboratory-Bred Bank Voles Myodes glareolus

The objective of the study was to compare the sensitivity of wild and laboratory-bred bank voles to cadmium (Cd)-induced histopathological changes in the liver and kidneys. For 4 weeks, the male bank voles—both wild and laboratory-bred—were provided with diet containing Cd in quantities <0.1 (control), 30, and 60 μg/g dry weight. At the end of exposure period, histopathology and analyses of Cd, metallothionein (MT), glutathione (GSH), zinc (Zn), copper (Cu), iron (Fe), and lipid peroxidation—all considered to be critical factors during the development of Cd toxicity in the liver and kidneys—were carried out. Histopathological changes (focal hepatocyte swelling, vacuolation and inflammation [leukocyte infiltration] in the liver, and focal proximal tubule degeneration [including epithelial cell swelling] in the kidneys) occurred only in the wild bank voles fed a diet containing 60 μg Cd/g. There were no differences in concentrations of Cd, MT, GSH, Zn, and Cu in liver and kidney between the respective groups of wild and laboratory-bred animals. However, a decrease of hepatic Fe and lipid peroxidation was observed in the wild voles exhibiting histopathological changes. These data indicate the following: (1) wild bank voles are more susceptible to Cd-induced liver and kidney injury than those bred and raised in the laboratory; (2) the difference in sensitivity may be associated with a distinct decrease of hepatic Fe in response to Cd exposure between the two groups of bank voles; and (3) dietary Cd may produce histopathological changes indirectly through decreasing the hepatic Fe and Fe-dependent oxidative processes. These results also suggest that histopathology in the liver and kidney of wild bank voles living in a contaminated environment may occur at relatively low levels of tissue Cd.     

Cow’s Milk Protein Allergy as a Model of Food Allergies

Cow’s milk allergy (CMA) is one of the most common food allergies in infants, and its prevalence has increased over recent years. In the present paper, we focus on CMA as a model of food allergies in children. Understanding the diagnostic features of CMA is essential in order to manage patients with this disorder, guide the use of an elimination diet, and find the best moment to start an oral food challenge (OFC) and liberalize the diet. To date, no shared tolerance markers for the diagnosis of food allergy have been identified, and OFC remains the gold standard. Recently, oral immunotherapy (OIT) has emerged as a new therapeutic strategy and has changed the natural history of CMA. Before this, patients had to strictly avoid the food allergen, resulting in a decline in quality of life and subsequent nutritional, social, and psychological impairments. Thanks to the introduction of OIT, the passive approach involving rigid exclusion has changed to a proactive one. Both the heterogeneity in the diagnostic process among the studies and the variability of OIT data limit the comprehension of the real epidemiology of CMA, and, consequentially, its natural history. Therefore, well-planned randomized controlled trials are needed to standardize CMA diagnosis, prevention, and treatment strategies.     

Dietary Strategies for the Treatment of Cadmium and Lead Toxicity

Cadmium (Cd) and lead (Pb) are toxic heavy metals that cause adverse health effects in humans and animals. Chelation therapy, the conventional treatment for heavy metal toxicity, is reported to have a number of safety and efficacy issues. Recent studies have shown that dietary supplements play important roles in protecting against Cd and Pb toxicity. This paper reviews the evidence for protective effects of essential metals, vitamins, edible plants, phytochemicals, probiotics and other dietary supplements against Cd and Pb toxicity and describes the proposed possible mechanisms. Based on these findings, dietary strategies are recommended for people at risk of Cd and Pb exposure. The application of these strategies is advantageous for both the prevention and alleviation of Cd and Pb toxicity, as such supplements can be added easily and affordably to the daily diet and are expected to have very few side effects compared to the chelation therapy.     

Effects of Nutrition on Cognitive Function in Adults with or without Cognitive Impairment: A Systematic Review of Randomized Controlled Clinical Trials

New dietary approaches for the prevention of cognitive impairment are being investigated. However, evidence from dietary interventions is mainly from food and nutrient supplement interventions, with inconsistent results and high heterogeneity between trials. We conducted a comprehensive systematic search of randomized controlled trials (RCTs) published in MEDLINE-PubMed, from January 2018 to July 2021, investigating the impact of dietary counseling, as well as food-based and dietary supplement interventions on cognitive function in adults with or without cognitive impairment. Based on the search strategy, 197 eligible publications were used for data abstraction. Finally, 61 articles were included in the analysis. There was reasonable evidence that dietary patterns, as well as food and dietary supplements improved cognitive domains or measures of brain integrity. The Mediterranean diet showed promising results, whereas the role of the DASH diet was not clear. Healthy food consumption improved cognitive function, although the quality of these studies was relatively low. The role of dietary supplements was mixed, with strong evidence of the benefits of polyphenols and combinations of nutrients, but with low evidence for PUFAs, vitamin D, specific protein, amino acids, and other types of supplements. Further well-designed RCTs are needed to guide the development of dietary approaches for the prevention of cognitive impairment.     

Activation of Akt kinase accompanies increased cardiac resistance to ischemia/reperfusion in rats after short-term feeding with lard-based high-fat diet and increased sucrose intake

High-fat or high-carbohydrate food consumption contributes to changes in myocardial tolerance to ischemia. However, with respect to experimental models, most studies used diets with very high doses of cholesterol, saturated fatty acids, or fructose. In our study, we fed rats a high-fat diet based on lard in combination with administration of a sweet beverage (30% sucrose solution) (high-fat sucrose diet [HFS]). This diet was used to simulate the unhealthy dietary habit typical for developed countries. We hypothesized that the application of HFS diet for 48 days might initiate progression of pathologic changes in the heart associated with myocardial remodeling and activation of adaptive mechanisms. We investigated the influence of HFS diet on cardiac function and vulnerability to ischemia-reperfusion (I/R) injury in Langendorff-perfused rat hearts subjected to 30-minute global ischemia and 120-minute reperfusion as well as on Akt kinase and matrix metalloproteinases. We found lower food consumption in HFS group compared with controls, but a significant increase in visceral fat mass and concentrations of triacylglycerol, low-density lipoprotein, and very low-density lipoprotein cholesterol. Baseline heart functional parameters and their postischemic recovery were not affected by HFS diet. On the other hand, hearts of HFS group were more resistant to lethal I/R injury manifested by significantly smaller infarct size. In addition, there was lower content of collagen I and III in the left ventricle associated with Akt kinase activation and matrix metalloproteinase 9 up-regulation. In conclusion, feeding rats with HFS diet resulted in heart remodeling associated with activation of some adaptive mechanisms, which can contribute to modulation of myocardial resistance to I/R injury.