Discriminative uptake of metals by the liver and its relation to induction of metallothionein by cadmium, copper and zinc

1. Disappearance from plasma and uptake by the liver of cadmium (Cd), copper (Cu) and zinc (Zn) were examined with a view to studying the biological discrimination between essential and non-essential heavy metals. 2. Cd injected intravenously at a single dose of 0.8 mg/kg body wt disappeared from rat plasma rapidly within about 10 min, while Cu and Zn injected at the same dose disappeared slowly in plasma and decreased to the control level after about 3 hr. 3. Uptake of Cd by the liver corresponded well with the rapid disappearance from plasma, while Cu and Zn accumulated slowly in the liver and their concentrations started to increase after their plasma concentrations had decreased. 4. Metallothionein was induced in the liver at a similar time course for the three metals, suggesting the presence of discriminative uptake processes by the liver with similar or the same detoxification mechanisms through induction of metallothionein.     

Effect of supplemental magnesium on the kidney levels of cadmium, zinc, and copper of mice exposed to toxic levels of cadmium

In this report, we present the results of our investigations on the effect of Mg pretreatment on Cd and bioelements (Cu and Zn) contents in kidney of mice exposed to acute and subacute Cd intoxication. Acute intoxication was performed on male Swiss mice given a single oral dose of 20 mg Cd/kg body weight and mice given the same dose of Cd but pretreated with 40 mg Mg/kg body weight. For subacute intoxication one group of mice was given 10 mg Cd/kg body weight every day, for 2 wk, and the other one received the same dose of Cd after oral Mg intake of 20 mg/kg body weight. Cd, Cu, and Zn content was determined in kidney by atomic absorption spectrophotometry. In acute Cd intoxication, Mg pretreatment resulted in significant decrease of Cd in kidney after 4 and 6 h, compared with animals given only Cd. Under the condition of subacute Cd intoxication, Mg supplementation reduced Cd kidney content after 2 wk for about 30%, compared with animals treated with Cd only. The effect of Mg on Cu and Zn kidney content was also beneficial.     

Metabolism of zinc and copper in the neonate: Effect of cadmium administration during late gestation in the rat on the zinc and copper metabolism of the newborn

Rats that have been treated with Cd (1.0 mg/kg body wt., i.v.) on the 18th day of gestation give birth to young, the livers of which are low in Zn, but not in Cu. With increasing age after birth the hepatic concentrations of total and thionein-bound Zn in these animals increase rapidly to maxima at about 7 days, approx. 6 days later than in the newborn of normal dams, whereas the liver Cu concentration reaches a higher maximum at an earlier age than in the control neonate. This rapid uptake of Cu into the liver of the newborn of the Cd-treated dam is not accompanied by a concomitant increase in the concentration of soluble thionein-bound Cu.Cadmium-treatment of the dam retards the weight gain of the liver and, at least during the first 6–8 days postpartum, the increase in body wt. of the newborn. When the hepatic concentrations of thionein-bound Zn is expressed relative to liver wt. instead of age, there is no significant difference between the newborn from normal and Cd-treated dams.The Zn concentrations in blood, brain, stomach, duodenum, pancreas, spleen, kidney and muscle of newborn rats either remain constant, or increase only slightly with age after birth and are not affected significantly by the administration of Cd to the dam in late gestation. This treatment, which probably increases the demand for Zn in the newborn, delays the deposition of Zn in bone and causes a reduction in the Zn concentration of the skin. The Cu concentrations in skin and bone, as well as in other organs of the newborn during the first 24 days postpartum, seem to be unaffected by Cd-treatment of the dam.It is suggested that hepatic Zn-thionein has an essential function in the Zn metabolism of the liver, but is unlikely to control the supply of Zn to other organs in the newborn rat.     

Accumulation of cadmium, zinc, and copper by Helianthus annuus L.: impact on plant growth and uptake of nutritional elements

We investigated the effects on physiological response, trace elements and nutrients accumulation of sunflower plants grown in soil contaminated with: 5 mg kg(-1) of Cd; 5 and 300 mg kg(-1) of Cd and Zn, respectively; 5, 300, and 400 mg kg(-1) of Cd, Zn, and Cu, respectively. Contaminants applied did not produce large effects on growth, except in Cd-Zn-Cu treatment in which leaf area and total dry matter were reduced, by 15%. The contamination with Cd alone did not affect neither growth nor physiological parameters, despite considerable amounts of Cd accumulated in roots and older leaves, with a high bioconcentration factor from soil to plant. By adding Zn and then Cu to Cd in soil, significant were the toxic effects on chlorophyll content and water relations due to greater accumulation of trace elements in tissues, with imbalances in nutrients uptake. Highly significant was the interaction between shoot elements concentration (Cd, Zn, Cu, Fe, Mg, K, Ca) and treatments. Heavy metals concentrations in roots always exceeded those in stem and leaves, with a lower translocation from roots to shoots, suggesting a strategy of sunflower to compartmentalise the potentially toxic elements in physiologically less active parts in order to preserve younger tissues.     

Influence of cadmium on the distribution of the essential trace elements zinc and copper in the liver and kidneys of rats

Cd induced changes of Zn and Cd distribution in the liver and kidneys were studied in relation to Cd metallothionein (MT) synthesis. Wistar male rats were given CdCl₂ by sc injection of .8, 1.5, and 3.0 mg Cd/kg three times a week for three weeks. Cd levels of liver and kidneys increased with the increment of Cd dosage and 80–90% of Cd was found in the cytosol. The MT fractions contained 80–89% cytosolic Cd in the liver and 55–75% Cd in the kidneys. Zn concentrations in the liver increased following Cd administration, But Zn in the kidneys showed only slight increase. There was a distinct decrease of Cu concentration in the liver of the 3.0 mg group. In contrast, Cu concentrations in the kidneys increased about three times in the .8 and 1.5 mg Cd groups, but Cu in the 3.0 mg group showed only 1.5 times increase. The changes of these metal concentrations were observed mainly in the cytosol. Non-MT-Cd in the kidneys was maximum in the 1.5 mg group, but the 3.0 mg group showed significant decrease. In parallel with this decrease of Cd, Cu and Zn in the kidneys showed similar decrease. When the kidneys are injured, Zn and Cu appear to leak from this organ.     

Uptake of copper from the bloodstream and its relation to induction of metallothionein synthesis in the rat

1. Female rats of the Wistar strain (12 weeks old; body wt, 200 g) were injected intravenously with a single dose of cupric chloride (0.8 mg Cu/kg body wt) and the uptake of copper (Cu) by the liver and kidneys was determined in relation to the disappearance of Cu from the bloodstream and the excretion to bile and urine. 2. Serum Cu level decreased rapidly within 30 min and then returned slowly to the control level by 3 hr post-injection, while the hepatic uptake of Cu continued linearly after the injection up to 4 hr post-injection. 3. The time lag between the disappearance of Cu from the blood serum and the uptake of Cu by the liver was not explained by the temporal distribution to red blood cells or by the enterohepatic circulation. 4. Cu taken up by the liver and distributed to its soluble fraction was bound to metallothionein, suggesting that the uptake of Cu by the liver depends on the induction of metallothionein synthesis. 5. Rapid uptake of Cu by the kidneys was observed at the beginning, which may indicate the role of the existing metallothionein in the control rat.     

In vivo effects of cadmium on calmodulin and calmodulin regulated enzymes in rat brain.

Effect of chronic cadmium (Cd) exposure and the influence of diethyldithiocarbamate (DDC) on Cd absorption was studied on the brain of young male Wistar rats. A significant amount of Cd accumulated in cerebral cortices of rats after 4 weeks of Cd (6 mg/kg body wt) exposure (through gastric intubation). The biological activity of calmodulin (CaM) decreased significantly (p less than 0.001) in the cerebral cortices of these animals in comparison to the control group. 3'-5' Phosphodiesterase and synaptic membrane Ca(2+)-Mg(2+) ATPase were also significantly affected (p less than 0.01 and p less than 0.001 respectively). However, Cd treatment did not alter synaptic membrane adenylate cyclase activity and DDC (9.2 mg/kg body wt, intraperitoneal) treatment along with Cd (6 mg/kg body wt) enhanced Cd accumulation in cerebral cortices of treated animals resulting in an increased inhibition of CaM and CaM dependent enzymes. These data suggest that Cd may be acting via binding to CaM and uncoupling it from its normal cellular control of calcium.     

Associations of cadmium with zinc and copper in cancer cases and controls

This study was performed in order to search for possible associations between cadmium (Cd) and other metals~ Cd, zinc (Zn), and copper (Cu) levels of renal cortex and liver samples obtained from 196 cancer cases and 198 noncancer controls were analyzed in eight regional institutes in Japan. Cd, Zn, and Cu concentrations in liver and renal cortex of the selected cancer cases were compared to the controls whose localities, age, and sex were matched with the cancer cases. The cancer cases clearly showed higher accumulations of Zn in liver and renal cortex than the noncancer group. Cd showed a similar tendency, but there was no statistical significance between case and control subjects. There was no marked difference in Cu accumulation between the pairs. The best fit regression curve of Zn to Cd on a molar basis in renal cortex was obtained. Curvilinear regression equations of Zn to Cd for both cancer and noncancer groups were drawn. From these two equations, the Zn level of the cancer cases was found to reach a maximum when the Cd level showed 1.4 mmol/kg (157 pxg/g), whereas Zn in the noncancer group peaked at 1.6 mmol/kg (180 Ixg/g) of Cd in renal cortex. This may suggest that excessive Cd accumulation deprives binding sites of Zn in renal cortex when both metals are saturated.     

Effect of zinc supplementation on metallothionein,copper, and zinc concentration in various tissues of copper-loaded rats

The present study was designed to investigate the effects of Zn administration on metallothionein concentrations in the liver, kidney, and intestine of copper-loaded rats. Male CD rats were fed a diet containing 12 mg Cu and 67 mg Zn/kg body wt. They were divided into either acute or chronic experimental protocols. Rats undergoing acute experiments received daily ip injections of either Cu (3 mg/kg body wt) or Zn (10 mg/kg body wt) for 3 d. Chronic experiments were carried out on rats receiving Cu ip injections on d 1, 2, 3, 10, 17, and 24, Cu injections plus a Zn-supplemented diet containing 5 g Zn/kg solid diet, or a Zn-supplemented diet alone. Rats injected Zn or Cu had increased MT concentrations in liver and kidney. Zn produced the most important effects and the liver was the most responsive organ. Rats fed a Zn-supplemented diet had significantly higher MT concentrations in liver and intestine with respect to controls. Increased MT synthesis in the liver may contribute to copper detoxification; the hypothesis of copper entrapment in enterocytes cannot be confirmed.     

Accumulation of cadmium by channel catfish (Ictalurus punctatus): influx from environmental solutions.

1. The accumulation of cadmium (Cd) from external environmental solutions was measured in channel catfish (Ictalurus punctatus) with the aid of 109Cd and by direct analysis of tissues. 2. Acute uptake (with 109Cd) was concentration dependent and was increased by changing the external pH from 7.3 to 5.0 and decreased by raising the Ca concentration from 0.1 mM to 3.0 mM. 3. The presence of external Zn did not change the uptake of the Cd. 4. In chronic 7-day experiments, fasted catfish were found to accumulate the toxic metal in their liver and kidneys from external media with Cd concentrations as low as 10(-9) M (about 0.1 microgram/l). 5. Concentrations were greater in the kidneys than the liver. 6. Detectable amounts of Cd (less than 0.03 microgram/g net wt) were not found in muscle in this time at external concentrations of Cd less than 10(-5) M (less than 1.0 mg/l).     

Soil-applied zinc and copper suppress cadmium uptake and improve the performance of cereals and legumes

The present study aimed to evaluate the effect of soil-applied Zn and Cu on absorption and accumulation of Cd applied through irrigation water in legume (chickpea and mung bean) and cereal (wheat and maize) crops. The results revealed that Cd in irrigation water at higher levels (2 and 5 mg L^?1) significantly (p < 0.05) reduced the plant biomass while the soil application of Zn and Cu, singly or combined, favored the biomass production. Plant tissue Cd concentration increased linearly with the increasing application of Cd via irrigation water. While Cd application caused a redistribution of metals in grains, straw, and roots with the highest concentration of Cd, Zn, and Cu occurred in roots followed by straw and grains. Zinc addition to soil alleviated Cd toxicity by decreasing Cd concentration in plant tissues due to a possible antagonistic effect. The addition of Cu to the soil had no consistent effects on Zn and Cd contents across all crops. Inhibitory effects of Cd on the uptake and accumulation of Zn and Cu have also been observed at higher Cd load. Thus, soil-applied Zn and Cu antagonized Cd helping the plant to cope with its toxicity and suppressed the toxic effects of Cd in plant tissues, thus favoring plant growth.     

Mercury,cadmium, zinc and copper concentrations and stable isotope ratios of carbon and nitrogen in tiger sharks (Galeocerdo cuvier) culled off Ishigaki Island,Japan

We analyzed Hg, Cd, Zn and Cu in the liver as well as Hg and stable isotope ratios of carbon and nitrogen (δ¹³C and δ¹⁵N) in muscle from tiger sharks (Galeocerdo cuvier) in Japan. The Hg concentration in the muscle increased slightly and proportionally with increases in body length, but the Hg concentration in the liver increased markedly after maturation (exceeding 2.7 m precaudal length). The Hg concentration in the liver of mature shark was higher than that in the muscle. The Cd concentration in the liver increased with increases in body length. On the other hand, the Zn and Cu concentrations in the liver decreased during the growth stage, but thereafter increased with increased Cd burden due to growth. The marked increase in hepatic Hg in mature sharks may be explained by the continuous intake of Hg via food, slower growth and Hg–Se complex formation. High concentrations of Zn and Cu in the liver of immature sharks and concomitant increases in Zn and Cu with the Cd burden in the liver of mature sharks may be explained by the physiological requirements of Zn and Cu during the growth stage, the induction of metallothionein synthesis due to the Cd burden and the subsequent binding of these metals to metallothionein. The δ¹⁵N and δ¹³C values decreased with increases in body length, suggesting a shift from coastal feeding to pelagic feeding with shark growth. The Hg and Cd concentrations tended to be negatively correlated with the δ¹⁵N and δ¹³C values as a result of the increase in Hg and Cd accumulation due to the growth and the decreases in δ¹⁵N and δ¹³C values due to the sift of feeding area.     

Heavy Metals in Antarctic Notothenioid Fish from South Bay, Livingston Island, South Shetlands (Antarctica)

The Pb, Cd, Cu, Zn, and Mn contents of the liver, spleen, muscle, bones, scales, gills, and the whole body of 3- to 7-year-old notothenioid Antarctic cod (Notothenia coriiceps, Richardson, 1844) were measured. The highest heavy metal concentrations obtained are as follows: Cd in liver, the mean value was 1.36 ± 0.19 mg/kg dry weight (wt); Pb and Zn in spleen, the mean values were 3.33 ± 0.86 and 143.97 ± 16.17 mg/kg dry wt, respectively; Cu in gills, 3.76 ± 1.16 mg/kg dry wt; and Mn in scales, 14.80 ± 4.77 mg/kg dry wt. The comparison with the data reported up to now shows that the metal concentrations varied within relative wide ranges. These first data obtained could be used as a baseline to investigate further relationships among metal contents in fish, their diet, and habitat.     

Studies of Zn, Mg, Cu, Ca and Fe in cadmium poisoned toads before and after treatment with EDTA

Zn, Mg, Cu, Ca and Fe were determined spectrophotometrically in liver, kidneys, muscle, spleen and blood of Bufo regularis after a single i.m. injection of 6.2 mg Cd/kg (which represents the 96 hr LD50) alone or in combination with 40 mg EDTA/kg (the minimal EDTA concentration causing 100% survival over that period). Cadmium administration caused recognizable effects on the essential metals levels in different tissues and organs. In the majority of the tissues and organs studied, zinc and copper concentrations returned to their normal ranges in animals that received both cadmium and EDTA. In contrast, magnesium, calcium and iron contents not only returned back to their control values but also exceeded them.     

Dithiocarbamates and prevention of cadmium teratogenesis in the hamster

Certain dithiocarbamates (DTC) have been reported to protect against cadmium (Cd)-induced lethality and to decrease Cd body burden. The present study evaluated the influence of sodium N-benzyl-D-glucamine dithiocarbamate, sodium N-di(hydroxyethyl)amine dithiocarbamate, sodium 4-carboxyamidopiperidine-N-dithiocarbamate, and sodium N-methyl-D-glucamine dithiocarbamate on Cd-induced teratogenesis in the hamster. When given as a single ip injection at 2.2 mmol/kg 15 min prior to iv CdCl2 (2 mg/kg), all of the DTC afforded significant protection against Cd-induced developmental toxicity and reduced kidney [Cd] in the dam. Maternal liver [Cd] was reduced with the glucamine and dihydroxyethyl amine analogs, but treatment with the piperidine failed to influence hepatic [Cd]. Pretreatment of the dams with DTC 24 hr prior to Cd challenge failed to protect against Cd-induced embryotoxicity, and provided minimal, if any, reduction in renal or hepatic [Cd]. Pretreatment with the N-methyl-D-glucamine congener 24 hr prior to Cd exposure increased embryolethality. The dose-time relationships found here suggest that pharmacologically effective levels of these DTC decline within 24 hr of treatment and that induction of metallothionein does not play a major role in DTC antagonism of Cd poisoning.     

Metallothionein in the liver of the small lizard Podarcis muralis

A cysteine-rich protein presenting optical and biochemical features typical of metallothionein and a similar amino acid composition was found in the liver of the small lizard Podarcis muralis. Animals were given either CdCl2 (0.8 mg Cd2+/kg body wt) or saline (NaCl 0.9%) by i.p. injection for 3 days. A second group of animals were injected with a single dose of [35S]cysteine plus CdCl2 or saline. Lizard MT contained Zn and Cu when injected with saline and also Cd when injected with CdCl2. Metallothionein induction by cadmium was demonstrated by radioactive labelling.     

Inducibility and amounts of metallothionein as influenced by cadmium and zinc in the developing rat

Information on the accumulation and/or depletion of Zn in metallothionein (MT) of rat fetus, rat pup, and maternal rat liver at various ages was obtained with pregnant rats fed a basal casein diet or this diet plus either 100 ppm Zn or 50 ppm Cd. Rats fed each of the respective diets were sacrificed on 12, 16, and 20 d of gestation and 0, 7, 14, and 28 d post-partum. No Cd was detected in the placenta or fetal tissue and the Cd did not affect the accumulation of Zn in the fetal MT, but it did increase the Zn content in liver MT of the dams. Very little Zn in MT was found on day 12 of gestation, but Zn rapidly increased in MT to a maximum at time of birth. The accumulation of Zn in MT was independent of the diet for the fetuses, but the Zn accumulation in the dam and pup tissues was diet dependent. In order to study age-dependent difference in the inducibility of MT, newborn, 5-week-old, or 24-week-old rats were injected with zinc at the levels of 0, 3, 6, or 9 mg/kg and 5 h later injected with³⁵S-cystine. In rats sacrificed 1 h later, the amount of radioactivity in liver MT demonstrated that this protein in older animals was more readily induced by Zn than in younger animals.     

石油污灌渠底泥生态毒性诊断研究

底泥样品采自沈阳东部石油污水灌渠的上、中、下游.进行了重金属Cu、Zn、Pb、Cd、矿物油含量分析和生态毒性试验.结果表明,所有底泥均有污染物积累.矿物油含量为408～118 300 mg·kg^-1,Cu为17.83～78.53 mg·kg^-1,Zn为35.76～155.16 mg·kg^-1,Pb为8.50～31.03 mg·kg^-1,Cd为0.1 mg·kg^-1～1.0mg·kg^-1.底泥对高等植物有不同程度的生长抑制或刺激效应,对蚯蚓有急性致死及慢性亚致死效应.种子发芽根伸长抑制率为-29.81%～93.8%,蚯蚓14d死亡率最大值为100%.蚯蚓14d和28d体重增长抑制率分别为-36.6%～6.08%和-40.4%～6.1%.研究表明,长期石油污水灌溉导致河道底泥中污染物的积累和较强生态毒性.     

Cadmium regulation by Lasius niger: A contribution to understanding high metal levels in ants

Ants (Formicinae, Hymenoptera) are considered efficient accumulators of Zn and Cd. In this study the relationship between Cd concentrations in soil and in Lasius niger workers was assessed for 20 colonies located along a gradient of Cd pollution. As soil Cd concentration increased from 1 to 8 mg/kg, ant body Cd concentration increased rapidly to about 40 mg/kg, and remained stable at this level, through a progressive increase of soil Cd concentration from 8 to 21 mg/kg. The phase of rapid increase confirms the high ability of L. niger for Cd accumulation, while the stabilization of Cd body concentration indicates either increasing elimination rate or decreasing rate of uptake. Therefore it can be concluded that Lasius niger has a high ability to accumulate Cd, but simultaneously an ability for Cd regulation was detected.     

Effects of thiol agents on the accumulation of cadmium by rat liver parenchymal and Kupffer cells

The rate of Cd accumulation by adult rat liver parenchymal cells in serum free primary culture in the presence of 100 μM CdCl₂ was 10 times greater than that by non-parenchymal Kupffer cells. Addition of the monothiol chelating agents, cysteine and penicillamine, decreased Cd uptake in both cell types, the effect becoming more pronounced as the monothiol concentration was increased from 0.1 to 1.0 mM. These monothiols thus appear to reduce the availability of Cd for transport across the cell membrane. In contrast 1–10 molar excesses of the dithiol agents 2,3-dimercaptopropanol (BAL) or dithiothreitol (DTT) stimulated to variable extents the rate of Cd accumulation 2–10-fold in parenchymal cells and by over 100-fold in Kupffer cells. Supplementation of the media with 3% serum had little effect on the Cd accumulation in the presence of monothiols but substantially depressed Cd uptake in the presence of dithiols. Intravenous injection of Cd (0.05 mg/kg CdCl₂) with up to a 10-fold molar excess of cysteine or penicillamine had little effect on the hepatocellular Cd distribution. However Cd uptake by non-parenchymal cells was increased markedly by the simultaneous administration of BAL or DTT in 2 or 10 molar excess. Evidence is provided that these results may be partially explained by the endocytosis, particularly in Kupffer cells, of colloidal complexes of Cd which are formed with the dithiols but not the monothiols. These observations demonstrate that the physicochemical form of Cd determines its hepatocellular distribution which may be an important factor in the manifestation of Cd toxicity after thiol treatment.