Cadmium Toxicity In Rats Research Articles

Dietary modulation of the symptoms of cadmium toxicity in rats: Effects of vitamins A, C, D, D hormone, and fluoride

The effects of vitamins A, C, D, and D hormone (1,25-dihydroxyvitamin D 3), and fluoride and combinations of these micronutrients on the toxic symptoms of young rats exposed to 80 ppm cadmium (Cd 2+) in the drinking water and fed a modified AIN-76 diet were studied for 14 weeks. Cd 2+ treated rats displayed smaller body weight gains and larger relative kidney and testis weights than controls. Treatment of Cd 2+ exposed rats with vitamins A or D ameliorated these symptoms. When combined, these two vitamins were synergistic in this protection as was the combination of vitamin A and 1,25-dihydroxyvitamin D 3. Animals exposed to Cd 2+ and treated with vitamin A or a combination of A and D had lower femur dry weights than rats exposed to Cd 2+ alone but this effect was not seen with the combination of vitamin A and 1,25-dihydroxyvitamin D. Vitamin C had no protective action on the kidneys or testes but caused an increase in the dry weight of the femurs of the exposed rats. Fluoride partially reduced the weight depression of the Cd 2+ exposed rats at certain time periods and lowered the relative weights of the testes in these animals. Fluoride, in combination with 1,25-dihydroxyvitamin D 3, significantly increased the dry and mineral (ash) weights of the femurs of the Cd 2+ exposed rats above that of the controls, a finding which may be relevant to the treatment of osteoporosis. Exposure of rats to Cd 2+ significantly depressed the hematocrits and erythrocyte counts and altered the ratio of granuloid to mononuclear peripheral leukocytes. Treatment of Cd 2+ exposed rats with either vitamin A and 1,25-dihydroxyvitamin D 3 or vitamins A and 1,25-dihydroxyvitamin D 3 and fluoride appeared to lessen the hematotoxicity associated with Cd 2+ exposure.

Protective effects of selenium on cadmium toxicity in rats: Role of altered toxicokinetics and metallothionein

Selenium prevents the toxicity of the carcinogenic metal cadmium through undefined mechanisms. In this study, we determined the effects of selenium on cadmium toxicokinetics and on the ability of cadmium to induce metallothionein, a metal-binding protein that is thought to confer tolerance to cadmium toxicity. To assess the acute protective effects of selenium, male Wistar (WF/NCr) rats were given selenium (as SeO2; 10 mumol/kg, sc) at -24, 0, and +24 h relative to cadmium (as CdCl2; 45 mumol/kg, sc). Over a 14-d period this dose of cadmium killed 6 out of 10 rats, while 100% of the cadmium-treated rats given concurrent selenium treatments survived. The acute increases in testicular weight that were seen with cadmium, indicative of edematous damage, were also prevented by concurrent selenium treatments. Further studies assessed the distribution and excretion of cadmium and its ability to induce metallothionein in rats given 40 mumol Cd/kg, sc, at time 0 and selenium (10 mumol/kg, sc) at -24 and 0 h. Selenium treatments enhanced cadmium accumulation at 24 h in the liver (23%), testes (145%), and epididymis (35%) but reduced renal accumulation by more than half. Urine samples, collected at 0-3, 3-6, and 6-24 h following cadmium administration, indicated a markedly reduced excretion of cadmium in selenium treated rats during all time periods. The synthesis of metallothionein was stimulated to a much lesser extent by cadmium in selenium-treated rat kidney (41% decrease) but was unaffected in liver. The levels of cadmium-binding proteins within the testes were markedly reduced by cadmium treatment, an effect unmodified by selenium treatments. These results suggest selenium prevents acute cadmium toxicity through a mechanism that does not involve induction of metallothionein and in spite of a markedly enhanced retention of cadmium.

Acute toxicity of cadmium in rats with or without cadmium pretreatment.

The acute toxicity of cadmium (Cd) in male rats was examined with or without Cd pretreatment. Firstly, the metallothionein (MT) contents in the liver and kidney after Cd exposure (2.0 mg/kg, i.v.) were determined. The MT contents in the liver increased immediately to a peak (36.0 +/- 5.5 n mol/g wet tissue) 2 days after Cd exposure and were 55-fold higher than that at 0 day (0.64 +/- 0.25 n mol/g wet tissue). On the other hand, the MT contents in the kidney increased slightly but steadily for 14 days after Cd exposure. In the study for comparison of Cd-induced toxicity, the LD50 value of the Cd-pretreatment group (Group II) was approximately 2-fold higher than that of the non-pretreatment group (Group I). In microscopic findings, differences between rats in Group I and Group II were recognized in the kidney. Cytoplasmic vacuolation of the proximal tubular epithelium in the kidney was observed in Group I, while degeneration or coagulative necrosis in the proximal tubular epithelium was observed in some rats in Group II in addition to the cytoplasmic vacuolation. Because the toxic changes other than in the kidney in Group II were almost equal to or less than that in Group I, in spite of the doubled dosage of Cd, the toxic effects of Cd, except on the kidneys, were considered to be reduced by the pretreatment with Cd.

Protective mechanism of sodium molybdate against the acute toxicity of cadmium in rats. II. Prevention of cytoplasmic acidification

In order to clarify the protective mechanism of sodium molybdate against the acute toxicity of cadmium chloride in rat, the effect of in vivo sodium molybdate pretreatment on the cytotoxic action of cadmium in isolated hepatocytes was studied. The cytosolic pH of hepatocytes isolated from untreated rats immediately decreased with incubation in either neutral Hank's balanced salt solution (HBS), pH 7.4, containing 5 microM cadmium chloride minimum or acidic HBS (pH 7.1, 6.8, 6.5, and 6.2). The presence of 5 microM cadmium in HBS adjusted to pH 7.1 aggravated cytosolic acidification induced by the acidic medium alone. Cell viability of hepatocytes incubated in HBS at pH 6.2 was significantly reduced as compared to that of control cells in HBS at pH 7.4, but the presence of cadmium in the acidic HBS had no aggravating action against such a toxic action of the acidic medium although cellular uptake of the metal in the medium increased, as compared to that in HBS at pH 7.4. Molybdenum pretreatment alleviated cytoplasmic acidification induced by the treatment with HBS at pH 7.4 or 7.1 containing cadmium or by extracellular acid load without cadmium. This pretreatment also prevented the loss of cell viability induced by the treatment with HBS at pH 6.2 but could not attenuate that when cadmium was present in the medium. These facts suggest that molybdenum pretreatment alleviated the acute toxicity of cadmium in rat by preventing cytoplasmic acidification caused by the harmful metal.

Behavioral toxicity of cadmium in rats in relation to the level of protein nutrition

The behavioral toxicity of cadmium (Cd, 100 ppm, through drinking water for 60 days) was assessed in growing male rats maintained on diets containing 21, 8 and 5% protein. Cd exposure in the 21% protein diet fed rats resulted in decreased body weight and growth, spontaneous locomotor activity and learning ability. The response latency in the learning situation was enhanced significantly. The decreases in the locomotor activity and learning ability were more marked in the 5% protein diet fed animals. The increase in the response latency was, however, more marked in the 8% protein diet fed group. Data indicate the enhanced vulnerability of protein malnourished animals to the behavioral deficits induced by Cd.

Interaction of dietary Ca, P, Mg, Mn, Cu, Fe, Zn and Se with the accumulation and oral toxicity of cadmium in rats

The toxicity of Cd was examined in rats fed diets containing 30 mg Cd/kg as CdCl 2 for 8 wk. The Cd-containing diets were supplemented with various combinations of the minerals Ca, P, Mg, Mn, Cu, Fe, Zn and Se in order to investigate the protective effect of these mineral combinations on Cd accumulation and toxicity. The mineral combinations were chosen such that the effect of the individual components could be analysed. At the end of the 8-wk feeding period, the Cd concentrations in the liver and renal cortex were 13.9 and 19.5 mg/kg body weight, respectively. The feeding of 30 mg Cd/kg diet alone resulted in well known Cd effects, such as growth retardation, slight anaemia, increased plasma transaminase activities and alteration of Fe accumulation. Only supplements that contained extra Fe resulted in a significant protection against Cd accumulation and toxicity. The most pronounced effect was obtained using a supplement of Ca/P, Fe and Zn, which resulted in a 70–80% reduction in Cd accumulation in the liver and kidneys, as well as a reduction in Cd toxicity. The protective effect of the mineral combinations was mainly due to the presence of Fe 2+, but in combinations with Ca/P and Zn the effect of Fe was most pronounced. Compared with Fe 2+ the protective effect of Fe 3+ was significantly lower. Addition of ascorbic acid to Fe in both forms improved the Fe uptake, but consequently did not decrease Cd accumulation. Thus, the mineral status of the diet may have a considerable impact on the accumulation and toxicity of Cd, fed as CdCl 2 in laboratory animals. For the risk assessment of Cd intake, special consideration should be given to an adequate intake of Fe.

Modifying effects of supplemental selenium and sulfur on cadmium toxicity in rats.

Interactions among dietary supplements of selenium (Se), cadmium (Cd), and sulfur (S), and their effects on Cd toxicity in the cardiovascular system were explored in rats. Weanling male Sprague-Dawley rats were fed a Torula yeast-based diet in a 23 factorial design, which provided two levels each of supplemental Se (0 and 0.5 ppm-mg/kg diet—as Na2SeO3), and S (0 and 2% as K2SO2). Supplemental Cd (0 and 25 ppm-mg/L as Cd (C2H3O2)2 · 2H2O) was added to drinking water. Supplemental Cd induced cardiac hypertrophy only in rats not supplemented with Se. Selenium supplementation enhanced growth more markedly in Cd-fed rats than in rats not receiving Cd. Renal Cd content was increased by Cd feeding, but there was no significant effect of Cd feeding on hemoglobin or blood pressure. Supplemental Cd did not influence Se-GSH-Px activity in heart or kidney cytosol. Interactions between Se and Cd were not altered by S supplementation. These results suggest 1) that hypertension is not associated with increased kidney accumulation of Cd,per se; 2) a supplement of 0.5 ppm Se as selenite is sufficient to protect against Cd-induced reductions in Se-GSH-Px activity in heart and kidney cytosol; and 3) increased S intake does not compromise Se's protective effect against certain manifestations of Cd toxicity.

Studies on the influence of calcium on cadmium absorbed by rat liver and the resistivity against the toxicity of cadmium in rat.

There have been reports on the effect of Ca on the uptake of Cd. A low dietary uptake of Ca can result in an increasing accumulation of Cd in the kidney and can increase the susceptibility to the deleterious effects of environmental Cd. However, up to now, there have been no reports on what role Ca plays in the uptake of Cd after supplementary Ca is added to the diet. One of the purposes of this work was to compare the amount of Cd in the livers of rats which were fed by rations containing various amounts of supplementary Ca (Ca-Cd test in brief). In addition, we determined the intestinal absorption of Ca, using drinking water containing 100 ppm Cd to feed the rats for seventeen days (Cd treatment in brief) and then in vitro determined the absorption capability of Cd in the duodenum.

Influence of protein deficiency on cadmium toxicity in rats.

The effects of a low protein diet on the body uptake and retention of cadmium, levels of essential trace elements, and cadmium-induced biochemical alterations in liver and kidneys of the rat were investigated. Low dietary protein disturbs cadmium induced alterations in carbohydrate metabolism, essential trace elements metabolism and offsets the hepatic and renal process of cadmium detoxification. Protein malnutrition enhances the susceptibility to cadmium intoxication.

The antagonism between selenium and cadmium in a freshwater mollusc.

The protective effect of selenium against cadmium toxicity in rats is well documented. Data concerning such protection are lacking in invertebrates. The object of this study was to check whether such an antagonism between Se and Cd can be found in the freshwater mollusc Lymnaea stagnalis L. In the presence of sublethal amounts of selenium, sensitivity with respect to cadmium is nearly halved. Sublethal amounts of cadmium give additional protection against the toxic effects of selenium, since this concentration completely prevented mortality due to high doses of selenite (3 mg/L Se) and selenate (15 mg/L Se).

Preventive Effects of Pretreatment with Zinc on Cadmium Toxicity in Rats (Regular Presentations) (Proceedings of the 8th Symposium on Environmental Pollutants and Toxicology)

Preventive Effects of Pretreatment with Zinc on Cadmium Toxicity in Rats (Regular Presentations) (Proceedings of the 8th Symposium on Environmental Pollutants and Toxicology)

Effect of Dietary Supplementation of Iron and Ascorbic Acid on Lead Toxicity in Rats

In our laboratory, the protective and therapeutic effects of surplus dietary iron and ascorbic acid on cadmium toxicity in rats have been studied and in this experiment, an effect of surplus iron and ascorbic acid on lead toxicity was examined. In young rats ingesting a diet containing 500 ppm of lead, growth retardation and anemia were observed. Suplementation of 400 ppm of iron and 1% of ascorbic acid to the lead containing diet prevented the growth depression and anemia and caused reductions of concentrations of lead in the kidney and tibia. Whereas, addition of 50 ppm of cadmium to the lead containing diet aggravated the growth retardation and anemia, but reduced the concentrations of lead in the kidney and tibia. Dietary supplementation of iron to the lead containing diet prevented the growth depression and anemia and reduced the accumulation of lead in the kidney, however the supplementation of ascorbic acid alone did not show any ameliolative effects. Rats were fed the lead containing diet and then transferred to the basal diet with or without iron and ascorbic acid. Recoveries from the growth retardation and anemia were not observed in rats within a week after the transfer to the non-lead diet with or without iron and ascorbic acid. These results suggest that iron prevents the growth depression and anemia in rats ingesting lead by an inhibition of lead asborption.

Effects of dietary level of iron and ascorbic acid on cadmium toxicity in rats.

Effects of dietary level of iron and ascorbic acid on cadmium toxicity in rats.

Long-term effectiveness of dietary iron and ascorbic acid in the prevention and cure of cadmium toxicity in rats

The protective and curative effects of dietary iron and ascorbic acid on chronic (180 days) cadmium toxicity in rats were examined. Growth retardation and anemia were observed in rats fed a diet containing 50 ppm of cadmium for 180 days; during this period the contents of iron in the liver, kidney, spleen, testis, intestine, and tibia decreased and the zinc contents of the liver and kidney increased, but the calcium content of bone did not change. Addition of 400 ppm of iron and 1% of ascorbic acid to the cadmium-containing diet overcame the growth retardation and anemia due to cadmium toxicity and reduced the tissue levels of cadmium; however, it did not restore the zinc contents in the liver, kidney, and bone to normal. Similar effects were observed when these compounds were added to cadmium containing diet for 90 days after feeding the cadmium diet alone for 90 days. The glutamic-pyruvic transaminase and glutamic-oxaloacetic transaminase activities in the plasma of rats fed the cadmium diet increased significantly and these increases were prevented by supplementing the diet with iron and ascorbic acid. Glucose, urea, and alkaline phosphatase in the plasma and glycogen in the liver were not changed by feeding the cadmium diet for 180 days. These results indicate the long-term effectiveness of supplementing the diet with iron and ascorbic acid for preventing and curing dietary cadmium toxicity in rats.

Role of Dietary Calcium and Calcium Binding Protein in Cadmium Toxicity in Rats

Growing male rats were fed a purified diet containing 0.6% Ca (two groups) or 0.1% Ca (two groups) for 8 weeks. One 0.6% Ca group and one 0.1% Ca group received 25 ppm Cd (as CdC12) in the drinking water. Diets were fed on an equalized basis with the 0.1% Ca + Cd group determining the amount of diet fed to the other groups. Water was provided ad libitum. Terminal body weights were not different among the four groups. Packed cell volumes were depressed in the Cd-exposed groups, especially the 0.1% Ca + Cd group. The highest concentrations of Cd were found in the lungs, liver, and kidneys of the 0.1% Ca + Cd group. More Cd was bound to low molecular weight proteins of the intestinal mucosa from the 0.1% Ca + Cd group than the 0.6% Ca + Cd group. Rats fed the 0.1% Ca diet appeared to have a greater capacity to absorb either Ca or Cd than rats fed the 0.6% Ca diet, as shown by an enhanced binding of 45Ca and 115mCd to intestinal calcium-binding protein (CaBP) in the rats fed the low calcium diet. A portion of the mucosal Cd was accounted for as Cd bound to metallothionein. It was concluded, based upon these experiments, that cadmium retention and signs of toxicity are enhanced by feeding low Ca diet and that the increased CaBP activity due to Ca restrictions is responsible for the increased Cd uptake observed.