Influence of dietary cadmium on the distribution of the essential metals copper,zinc and iron in tissues of the rat

The effect of long-term dietary cadmium treatment upon the distribution of the metals copper, iron and zinc has been compared in various organs of male and female rats. The renal accumulation of cadmium was similar in both sexes without a plateau being reached. In contrast, the hepatic accumulation of cadmium was higher in the female than in the male rat and a plateau was observed after 30–35 weeks of dietary cadmium treatment. Most of the cadmium which accumulated in these organs was recovered in the metallothionein fraction and the concentration of hepatic cadmiumthionein in the female rat was correspondingly higher than in the male rat. Accumulation of cadmium was associated with an increased zinc concentration in the liver and an increased copper concentration in the kidney; these increases were correlated with increases in liver and kidney metallothioneins induced by cadmium. Uptake of cadmium into organs other than liver and kidney occurred to a small extent but was not associated with changes in the concentration of copper and zinc. Cadmium also accumulated in the intestinal mucosa where it could be recovered in a fraction corresponding to metallothionein. A loss of iron from the liver and kidney was also observed following dietary cadmium treatment and involved mainly a loss of iron from ferritin.     

Low iron diet and parenteral cadmium exposure in pregnant rats: the effects on trace elements and fetal viability

The effects of latent iron deficiency combined with parenteral subchronic or acute cadmium exposure during pregnancy on maternal and fetal tissue distribution of cadmium, iron and zinc, and on fetal viability were evaluated. Timed-pregnant Sprague-Dawley rats were fed on semisynthetic test diets with either high iron (240 mg kg) or low iron (10 mg kg), and concomitantly exposed to 0, 3 or 5 mg cadmium (as anhydrous CdCl₂) per kilogram body weight. Animals were exposed to cadmium from gestation day 1 through 19 by subcutaneously implanted mini pumps (Subchronic exposure) or on gestation day 15 by a single subcutaneous injection (Acute exposure). All rats were killed on gestation day 19. Blood samples, selected organs and fetuses were removed and prepared for element analyses by atomic absorption spectrometry. Low iron diet caused decreases in maternal body weight, maternal and fetal liver weights, placental weights and tissue iron concentrations. By cadmium exposure, both subchronic and acute, tissue cadmium concentrations were increased and the increase was dose-related, maternal liver and kidney zinc concentrations were increased, and fetal zinc concentration was decreased. Cadmium concentration in maternal liver was additionally increased by low iron diet. Acute cadmium exposure caused lower maternal body and organ weights, high fetal mortality, and decreased fetal weights of survivors. In conclusion, parenteral cadmium exposure during pregnancy causes perturbations in essential elements in maternal and fetal compartments. Acute cadmium exposure in the last trimester of gestation poses a risk for fetal viability especially when combined with low iron in maternal diet.     

Urinary cadmium levels during pregnancy and postpartum

It is well established that pregnancy induces physiological, metabolical and hormonal changes. As a consequence, trace metal metabolism can be affected. The aim of the present study was to assess the urinary cadmium levels in women during gestation and postpartum. The survey was conducted in a group of nonoccupationally cadmium-exposed women from Southern Catalonia (NE, Spain). Urine samples were obtained before pregnancy, during the 6th, 10th, 26th, and 30th wk of gestation, as well as during the 5th and 24th wk after delivery. Urinary cadmium levels were determined by graphite furnace atomic absorption spectrophotometry. The concentrations of zinc and copper in plasma were also measured. Moreover, to assess the effect of the diet during pregnancy, dietary ingestions of zinc, iron, and calcium were also determined. A significant decrease of plasma zinc levels could be observed during the last two trimesters of pregnancy, while plasma copper concentrations significantly increased during the same period. Urinary cadmium concentrations ranged from 0.05 to 3.79 μg/g creatinine (geometric mean 0.49±2.26 μg/g creatinine). No significant changes in urinary cadmium concentrations during pregnancy and postpartum could be observed.     

The effects of cadmium and copper on the renal uptake and metallothionein binding of gold in the rat and hamster

Rats and hamsters, (pre)-treated with copper and cadmium, were used to investigate whether species-differences in renal metallothionein synthesis in response to gold were determined by changes in the kidney concentrations of other metals. The effects of both dietary copper limitation and excess on the renal metabolism of gold also were studied in the rat. In this species, all of the pre-treatments affected the renal concentrations of total and metallothionein-bound copper, but none of them altered either the kidney uptake or thionein-binding of gold. Incorporation of zinc into the metallothionein, which accompanied the binding of gold in this fraction of the kidney, however, was influenced slightly by the pretreatments. In hamsters, pretreatment with cadmium, which increased the concentrations of total and thionein-bound zinc in the kidneys, also did not affect the renal uptake of gold, although it increased significantly the binding of gold to the metallothionein fraction of the renal cytosol. This increased binding of gold also was accompanied by further increases in the zinc and copper contents of the metallothionein; the contents of total and thionein-bound cadmium, however, remained essentially unchanged. Concentrations of copper and zinc in the hamster kidney were not affected significantly by subcutaneous administration of copper alone (five daily doses, each of 3.2 mg Cu/kg body wt.), but were increased when gold was given during the copper-treatment. The concentrations of gold, copper and zinc in the renal metallothionein fraction also were increased under these conditions. From these results it seems that kidney metallothionein synthesis in response to gold may be related to the changes in either the concentration or distribution of zinc, rather than copper.     

The effects of age and sex on seven elements of Sprague-Dawley rat organs

This study reports age-related changes in 7 element (iron, copper, zinc, manganese, mercury, cadmium and lead) concentrations in the liver, kidney and brain of male and female Sprague-Dawley rats from 1 to 364 days of age. Atomic absorption spectrometry was used for the measurements. Copper, mercury and cadmium in the male and female kidneys increased from weaning until 127 days of age, as did iron concentrations in the female liver and kidney. After 127 days, especially, the copper concentration in the female kidney and cadmium concentration in the male and female kidney increased further. Consistent and statistically significant (P less than 0.05) sex differences in element concentrations were found for three elements (iron, copper and zinc). Except for the zinc concentration in the liver from 50 to 72 days, iron (in liver and kidney), zinc (in kidney) and copper (in liver, kidney and brain) concentrations in female rats during the adult stage, were all higher than those of male rats. Isolated differences for other elements (manganese, mercury and cadmium) were also found. The data will be helpful when setting up long-term animal investigations of the biological effect of elements.     

EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc

The efficacy of a chelating agent in binding a given metal in a biological system depends on the binding constants of the chelator for the particular metals in the system, the concentration of the metals, and the presence and concentrations of other ligands competing for the metals in question. In this study, we make a comparison of the in vitro binding constants for the chelator, ethylenediaminetetraacetic acid, with the quantitative urinary excretion of the metals measured before and after EDTA infusion in 16 patients. There were significant increases in lead, zinc, cadmium, and calcium, and these increases roughly corresponded to the expected relative increases predicted by the EDTA-metal-binding constants as measured in vitro. There were no significant increases in urinary cobalt, chromium, or copper as a result of EDTA infusion. The actual increase in cobalt could be entirely attributed to the cobalt content of the cyanocobalamin that was added to the infusion. Although copper did increase in the post-EDTA specimens, the increase was not statistically significant. In the case of magnesium, there was a net retention of approximately 85% following chelation. These data demonstrate that EDTA chelation therapy results in significantly increased urinary losses of lead, zinc, cadmium, and calcium following EDTA chelation therapy. There were no significant changes in cobalt, chromium, or copper and a retention of magnesium. These effects are likely to have significant effects on nutrient concentrations and interactions and partially explain the clinical improvements seen in patients undergoing EDTA chelation therapy.     

Effects of zinc, copper, and selenium on placental cadmium transport

The objective of the present study was to evaluate the potential effects of zinc, copper, and selenium on placental cadmium transport. From November 2002 through January 2003, a total of 47 healthy pregnant women from Da-Ye City, Hubei Province in Central China participated in the study. Their age, parity, gestational age, pregnancy history, and lifestyle data were obtained by questionnaire interview. The placental, whole-blood, and cord blood levels of cadmium were determined by inductively coupled plasma mass spectrometer (ICP-MS), whole-blood zinc was measured by flame atomic absorption spectrometry (F-AAS), whole-blood copper by ICP-MS, and selenium was by atomic fluorescence spectrophotometry (AFS). The cord blood cadmium concentration (0.020-1.48 microg/L) was significantly lower than in maternal blood (0.80-25.20 microg/L, p<0.01). The placental cadmium concentration was from 0.082 to 3.97 microg/g dry weight. Multiple linear regression analysis indicated that lower levels of maternal blood copper were significantly associated with higher cadmium concentrations in cord blood. Placental cadmium in women with lower levels of maternal blood zinc was significantly higher than in those with normal zinc levels. The placental cadmium level in women with lower whole-blood selenium was significantly lower than in subjects with normal selenium levels. It was concluded that the essential elements copper, selenium, and zinc might significantly affect placental cadmium transport.     

Effect of spirulina and Liv-52 on cadmium induced toxicity in albino rats

Oral administration of cadmium (6mg/kg body weight/day) as cadmium chloride (CdCl2) for 30 days resulted in a significant increase in thiobarbituric acid reactive substances (TBARS) level and a decrease in the levels of copper, zinc, iron, selenium, glutathione, superoxide dismutase, catalase, glutathione peroxidase when compared to normal control. Administration of either Liv-52 alone or in combination with spirulina produced a well pronounced protective effect in respect to these parameters in cadmium intoxicated rats. The protective effect of spirulina and Liv-52 in respect to biochemical changes were also confirmed by histopathological study in the liver and kidney sections.     

Chronological changes in tissue copper, zinc and iron in the toxic milk mouse and effects of copper loading

The toxic milk (tx) mouse is a rodent model for Wilson disease, an inherited disorder of copper overload. Here we assessed the effect of copper accumulation in the tx mouse on zinc and iron metabolism. Copper, zinc and iron concentrations were determined in the liver, kidney, spleen and brain of control and copper-loaded animals by atomic absorption spectroscopy. Copper concentration increased dramatically in the liver, and was also significantly higher in the spleen, kidney and brain of control tx mice in the first few months of life compared with normal DL mice. Hepatic zinc was increased with age in the tx mouse, but zinc concentrations in the other organs were normal. Liver and kidney iron concentrations were significantly lower at birth in tx mice, but increased quickly to be comparable with control mice by 2 months of age. Iron concentration in the spleen was significantly higher in tx mice, but was lower in 5 day old tx pups. Copper-loading studies showed that normal DL mice ingesting 300 mg/l copper in their diet for 3 months maintained normal liver, kidney and brain copper, zinc and iron levels. Copper-loading of tx mice did not increase the already high liver copper concentrations, but spleen and brain copper concentrations were increased. Despite a significant elevation of copper in the brain of the copper-loaded tx mice no behavioural changes were observed. The livers of copper-loaded tx mice had a lower zinc concentration than control tx mice, whilst the kidney had double the concentration of iron suggesting that there was increased erythrocyte hemolysis in the copper-loaded mutants.     

Uptake of six heavy metals by oat as influenced by soil type and additions of cadmium,lead, zinc and copper

Summary The influence of heavy metal additions on availability and uptake of cadmium, lead, zinc, copper, manganese and iron by oat was studied. The experiments were carried out as pot experiments using sandy loam, sandy soil and organic soil. Selective extractants were used to remove metals held in different soil fractions.Lead and copper were preferently bound by organics and oxides, zinc by oxides and inorganics, and cadmium by inorganics and organics.Addition of cadmium to the soils resulted in higher cadmium concentrations in all plant parts but lower concentrations of lead, zinc, copper, manganese and iron, and the accumulation indexes of these metals were also lower when cadmium was added to the soil.Addition of cadmium plus lead, zinc and copper resulted in higher cadmium concentrations in leaves and straw of plants grown in sandy loam and sandy soil, but lower concentrations when plants were grown in organic soil as compared with the results when cadmium was added separately. The transfer of cadmium, lead, zinc and copper from soil to plant was greatest from sandy soil, and zinc and cadmium were more mobile in the plant than were lead and copper.Cadmium concentrations in leaves correlated significantly with CaCl₂ and CH₃COOH extractions in sandy loam and sandy soil and with CH₃COOH extractions in organic soil.Generally, the total metal uptake was lowest from organic soil.     

Comparative distributions of zinc, cadmium and mercury in the tissues of experimental mice

Different groups of mice were injected with cadmium, zinc and mercury. Zinc injections had no effect on zinc tissue levels while both mercury and cadmium accumulated in various tissues. Cadmium persisted in the tissues much longer than mercury, and while the mercury concentrations began to decline as soon as dosing ceased, cadmium concentrations in kidney and intestine increased even after dosing ceased. There appeared to be an interrelationship between cadmium concentrations in spleen and intestine which warrants some further investigations. There was a linear, but discontinuous, effect of cadmium on zinc concentrations in liver, kidney and pancreas which may depend on metallothionein biochemistry. Mercury injections had no effect on zinc metabolism. It is proposed that differences in the rate of excretion of cadmium and mercury from the kidney could explain the differential accumulation of cadmium and mercury in animals.     

Postinductive actinomycin D effects on the concentrations of cadmium thionein, zinc thionein, and copper chelatin in rat liver

The time courses of induction in rat liver of copper chelatin by copper, cadmium thionein by cadmium, and zinc thionein by copper, cadmium, and zinc were monitorg metal were used in order to avoid toxic effects, being 5 mg zinc, 0.5 mg copper, and 0.25 mg cadmium per kg body weight. Peak times of induction and half times of decay observed were: copper chelatin (9 h, 8.6 h), cadmium thionein (18 h, 6.80 days), and zinc thionein (zinc rats, 18 h, 10.1 h; copper rats, 9 h, 18.2 h; cadmium rats, 24 h, 4.53 days). Administration of actinomycin D (1 mg per kg body weight) at the peak times of induction of the various proteins had no effect on the concentrations of chelatin or cadmium thionein observed up to 24 hours later, but in the case of zinc thionein, induced by zinc, copper, or cadmium, elevated concentrations were observed up to 23 h after administration of the drug. Such behavior is reminiscent of superinduction previously seen with other proteins and enzymes. We postulate that the intracellular concentration of free zinc in liver is of fundamental importance in the induction of zinc thionein, and this can be distributed by exogenous copper or cadmium resulting in the induction of synthesis of zinc thionein.     

Hepatic metallothionein production and resistance to heavy metals by rainbow trout (Salmo gairdneri)--I. Exposed to an artificial mixture of zinc, copper and cadmium

Rainbow trout developed elevated hepatic metallothionein concentrations after 4 weeks in a solution containing zinc, copper and cadmium in a fixed ratio of 400:20:1. Resistance to a combination of these metals increased in proportion to the concentration to which they were exposed for 4 weeks. The concentration of copper but not zinc or cadmium in the low molecular weight proteins separated by gel filtration was related to the concentrations of metallothionein present. The combined toxicity of the metals in the mixture was additive.     

Cadmium,zinc and iron interactions in the tissues of bank vole <Emphasis Type="BoldItalic">Clethrionomys glareolus</Emphasis> after exposure to low and high doses of cadmium chloride

In present study, bank voles Clethrionomys glareolus were peritioneally injected with different doses of cadmium, 0, 1.5, 3.0 mg Cd/kg body mass. Animals were sacrificed on the 21st day after cadmium exposure and the liver and kidney were obtained for cadmium, zinc and iron analysis using atomic absorption spectrometry. Results showed that cadmium had accumulated in the tissues according to dosage and sex. Cadmium affected the survival and body masses of dosed females. Cadmium decreased the iron concentrations in the liver of voles, whereas zinc concentrations increased in both the kidney and liver.     

Effects of Selenium on Liver and Muscle Contents and Urinary Excretion of Zinc,Copper, Iron and Manganese

Selenium is a main component of glutathione peroxidase (GPX), a key antioxidant enzyme. Other elements, such as zinc, copper, manganese and iron, are also involved in the pathogenesis of oxidative damage as well as in other important metabolic pathways. The effects of selenium supplementation on the metabolism of these elements have yield controversial results .The aim of this study is to analyse the effects of selenium supplementation on liver, muscle and urinary excretion of zinc, copper, iron and manganese in a situation of oxidative stress, such as protein deficiency. The experimental design included four groups of adult male Sprague–Dawley rats, which received the Lieber–DeCarli control diet, an isocaloric 2 % protein-containing diet and another similar two groups to which selenomethionine (6 mg/l liquid diet) was added. After sacrifice (5 weeks later), muscle, liver and serum selenium were determined, as well as muscle, liver and urinary zinc, copper, manganese and iron and liver GPX activity and liver malondialdehyde. Selenium addition led to decreased liver copper, increased muscle copper, increased copper excretion and increased liver iron, whereas zinc and manganese parameters were essentially unaltered. Muscle, liver and serum selenium were all significantly correlated with liver GPX activity.     

The acute and subacute effects of cadmium on calcium homeostasis and bone trace metals in the rat

The effect of acute and subacute administration of cadmium chloride on calcium homeostasis and the trace metal content of the bone was investigated in the male rat. A single subcutaneous injection of cadmium chloride (1.5 mg Cd⁺⁺/kg) produced a decreased plasma concentration of calcium and a decrease in the femur concentration of both calcium and zinc. Repeated administration of cadmium chloride (1.5 mg Cd⁺⁺/kg daily, for 28 days) caused a marked hypocalciuria that persisted throughout the period of cadmium treatment. There was an accompanying increased excretion of alkaline phosphatase into the urine, and plasma inorganic phosphate was also elevated in these animals. Both of these effects are considered to be evidence of kidney damage.A possible mechanism for this cadmium-induced effect may involve a disturbance of the renal biotransformation of vitamin D, and decreased bioavailability of the essential trace metals due to metallothionein synthesis and excessive loss into the urine.     

Dietary cadmium effect on iron metabolism in chickens

A control group of 1-day-old chicks, fed on commercial food, were compared with different experimental lots that had all received a supplement of 100 ppm Cd. The hematocrit, hemoglobin and ceruloplasmin concentrations, and metal contents (Fe, Cu, Zn, Cd) in plasma and in the liver were determined after either 4 or 9 weeks of treatment. The intestinal iron absorption and their ferrokinetics were also studied in 10-week-old Cd-fed chicks. The anemia-producing effect of cadmium was already evident after the second week of treatment. The iron supplement (oral or injected) corrected the anemia, but did not correct the depression of growth effect. Plasma iron was not affected, but the liver stores were reduced by 50%. Neither the plasma copper and ceruloplasmin, nor the copper content in liver, were affected. Zinc in the liver increased significantly (P<0.05). No statistical differences in plasma iron turnover were observed between the control and Cd-fed chicks, but the red blood cell utilization was higher (P<0.01) in Cd-fed groups. The intestinal iron absorption was clearly reduced (P<0.001) where cadmium was presented in the perfusion fluid “in vivo” experiments. This suggested that cadmium reduced the iron liver stores through its effect on intestinal iron absorption. However, it also seems that it did not interfere in iron mobilization, since the plasma iron was unaffected and the Cd-fed chicks presented increased plasma iron after estrogen administration. The indirect effect of cadmium on copper metabolism is uncertain.     

Cadmium-induced alterations in essential trace element homoeostasis in the tissues of scallop Mizuhopecten yessoensis

Studies were performed regarding the effect of cadmium accumulation on the levels of essential elements (copper, zinc and iron) in the tissues of a marine bivalve mollusc, Mizuhopecten yessoensis, exposed to cadmium at 250 ppb during 2 weeks. It was found that the concentration of cadmium in the tissues increased in the order gonads < gills < hepatopancreas < kidney during exposure time. However, the highest value of concentration factor was recorded in the gills. Our data demonstrate that cadmium accumulation in all mollusc tissues is followed by the alterations in copper, zinc and iron concentration, but that the pattern of these changes varies with each tissue. Cadmium had the most pronounced effects on essential trace element homoeostasis in the kidney. The present study suggests that levels of the essential metals in a particular tissue can be modified depending on the level of cadmium accumulation. The possible mechanisms of the effects of cadmium on the essential trace elements are discussed.     

Age dependent changes in metallothionein and accumulation of cadmium in horses

1. Analysis of livers and kidneys from 28 horses for cadmium, zinc and metallothionein showed low cadmium content in liver. There was a gradual increase in cadmium content in kidney with age. 2. Metallothionein values varied with zinc content in the liver and with cadmium content in the kidney; copper values did not vary in either tissue. 3. Metallothionein was localized mainly in the cytoplasms in liver and kidney of horses by immunohistochemistry.     

Evidence for a synergistic interaction between cadmium and endotoxin toxicity and for nitric oxide and cadmium displacement of metals in the kidney.

This study was undertaken to examine changes in Zn and Cu homeostasis in the liver and kidney of rats caused by cadmium (Cd) or lipopolysaccharide (LPS) administration. Twenty-five male, 7- to 8-week-old Wistar rats were divided into five groups: saline only treatment, saline treatment and food deprivation, exposure to a single dose of Cd, exposure to LPS alone, and exposure to Cd + LPS. Changes in plasma nitrate concentrations and hepatic and renal Zn and Cu contents were measured together with urinary excretion rates for the metals and nitrate on 3 consecutive days: 24 h before treatment and 24 and 48 h after treatments. Cd exposure alone for 48 h caused a nearly 2-fold increase in plasma nitrate levels with no changes in urinary nitrate excretion whereas LPS treatment caused plasma nitrate levels to increase by 10-fold and urinary nitrate excretion to increase by 4-fold. Administration of LPS 24 h after Cd exposure caused a 10-fold increase in plasma nitrate concentrations and a 100-fold increase in urinary nitrate excretion compared to the rates prior to LPS administration. These results indicate a synergistic interaction between Cd and LPS toxicity. Cd exposure also caused a marked increase in hepatic Zn levels, but LPS did not cause any changes in hepatic Zn or Cu content. In sharp contrast, both Zn and Cu contents were decreased in the kidneys by 16 and 36% in animals exposed to Cd or LPS. A correlation analysis of measured variables reveals that renal Cu contents were inversely associated with plasma nitrate concentrations while urinary Cu excretion on day 3 showed a strong positive correlation with both urinary nitrate and Cd excretions on the same day. A linear regression analysis shows 20% of the variation in urinary Cu excretion was associated with urinary Cd excretion on the same day. It is concluded that reductions in renal Cu contents caused by Cd or LPS administration may be a result of Cd and NO displacement of Cu previously bound to metallothionein.