Cadmium toxicity in animal cells by interference with essential metals

Cadmium is found in the environment as part of several, mainly zinc-rich, ores. It has been used in many technological applications, but biological systems generally failed to safely deal with this element. In mammalian biology, cadmium exposure jeopardizes health and mechanisms of cadmium toxicity are multifarious. Mainly because bioavailable cadmium mimics other metals that are essential to diverse biological functions, cadmium follows a Trojan horse strategy to get assimilated. Metals susceptible to cadmium deceit include calcium, zinc, and iron. The wealth of data addressing cadmium toxicity in animal cells is briefly reviewed with special emphasis on disturbance of the homeostasis of calcium, zinc, and iron. A limited number of tissues and cell types are considered as main targets for cadmium toxicity. Still, the diversity of pathways affected by cadmium exposure points to a more general threat to basic cellular functions. The poor efficiency of cellular export systems for cadmium explains the long residence time of the element in mammals. Therefore, proper disposal and educated uses of this technologically appealing, but biologically malicious, element should be favored in the future. The comprehensive knowledge of cadmium biological effects is indeed a necessary step to protect human and animal populations from environmental and anthropological exposures.     

Closing the Loop on Cadmium - An Assessment of the Material Cycle of Cadmium in the U.S. (11 pp)

Goal, Scope and Background In this study, the major flows of cadmium in the U.S. economy are quantified and the primary sinks are identified to gauge the need for additional policy to minimize the potential human health and ecosystem risks associated with these flows. Because of the concurrent occurrence of cadmium and zinc in ore, we also consider the relevant portions of the material cycle of zinc. Methods We estimated the flows of cadmium through U.S. manufacturing using a mass balance approach with data provided by the U.S. Geological Survey's Minerals Yearbook. Cadmium emissions factors were created using facility specific information found in the U.S. Toxics Release Inventory and were used to model future losses. Data gaps were filled through review of relevant literature. We modeled the import and sales of nickel-cadmium batteries with rechargeable battery usage trends and estimates of market share by battery chemistry. Results and Conclusion Primary cadmium in the U.S. is almost exclusively produced as a co-product of zinc. Almost all zinc and cadmium mined in the U.S. is exported to foreign smelters as ore concentrate. We estimate that the bulk of cadmium consumed in the U.S. economy (~90%) is imported in the form of nickel-cadmium rechargeable batteries. These batteries can be divided into the larger wet-cells and portable rechargeable batteries (PRB). The collection rate for the recycling of large wet cells was found to be high (80%) while the collection rate for PRBs is low (5-20%). The Rechargeable Battery Recycling Corporation (RBRC) is responsible for the collection of these batteries which are recycled exclusively by the International Materials Reclamation Company (INMETCO). The remaining PRBs are generally disposed of in municipal solid waste (MSW) landfills. This study provides a detailed substance flow analysis of U.S. stocks and flows of cadmium in products, however additional research is needed to better quantify the associated exposures and risks. Recommendation and Perspective Based on our analysis, we make four recommendations. First we suggest that if cadmium is to be used, it should be used in long-lived products that can be easily collected and recycled with minimal losses. Second, continued cadmium use should be coupled with renewed efforts on the part of policy-makers to encourage the collection and recycling of cadmium-bearing products. At present, consumers do not see the environmental cost associated with the proper disposal of the cadmium content of NiCd batteries. Policy options for improving recycling rates include collecting deposits and providing rewards for the return of spent batteries, taxing or otherwise discouraging discarding PRBs in municipal solid waste, and providing incentives for extended producer responsibility. Third, we highlight the importance of the connection between zinc mining and the supply of cadmium in designing an effective policy to manage the risks associated with cadmium. Fourth, we recommend that policy measures be taken to provide the necessary data required to improve our understanding of the flow of cadmium into the U.S. in the form of product imports and the amount of cadmium lost or disposed of by recycling processes.     

Cadmium and zinc content of fish from an industrially contaminated lake

Eleven species of fish from an industrially-contaminated lake were analysed for whole body cadmium and zinc content by atomic absorption spectrophotometry. Cadmium and zinc content of fish were species related, and most species accumulated these trace metals to levels significantly higher than background. Maximum concentrations detected were 13.60 μg Cd g⁻¹ (dry wt) in a bluegill and 820 μg Zn g⁻¹ in a redear sunfish. Cadmium content was much more variable than zinc content. Distributions of concentrations of both cadmium and zinc in fish were lognormal, and concentrations of both metals tended to decrease in higher trophic levels. Zinc concentrations significantly decreased as total length increased in three species.     

Effects of Interaction Between Cadmium and Plumbum on Phytochelatins and Glutathione Production in Wheat （Triticum aestivum L.）

Phytochelatins (PCs) may function as a potential biomarker for metal toxicity. However, less attention has been paid to the effects of metal interactions on the production of PCs and glutathione (GSH), the most prominent cellular thiol. In the present study, the effects of interactions between cadmium (Cd) and plumbum (Pb) on the production of PCs and GSH were monitored over a period of 14 d in wheat (Triticum aestivum L.) tissues. The results showed that combination of Cd and Pb led to synergistic growth inhibition in wheat. Exposure to Cd or Pb increased levels of PCs in a concentration-, tissue-, and time-dependent manner. Cadmium was more effective that Pb in increasing PCs production. Compared with the effects of Cd or Pb alone on the production of PCs, the combination of Cd and Pb acted synergistically, resulting in an enhanced production of PCs. Cadmium also stimulated GSH production in a concentration-, tissue-, and time-dependent manner. However, Pb had no obvious effects on GSH levels. The combination of Pb and Cd antagonized GSH production over the course of the growth period. The results of the present study suggest that metal interactions should be considered in the application of PCs and GSH as potential biomarkers for the evaluation of metal toxicity.     

Cadmium toxicity: Effects on cytoskeleton,vesicular trafficking and cell wall construction

Cadmium is a well-known environmental pollutant with distinctly toxic effects on plants. It can displace certain essential metals from a wealth of metalloproteins, and thus disturb many normal physiological processes and cause severe developmental aberrant. The harmful effects of cadmium stress include, but are not limited to: reactive oxygen species overproduction, higher lipid hydroperoxide contents, and chloroplast structure change, which may lead to cell death. Plants have developed diverse mechanisms to alleviate environmental cadmium stress, e.g., cadmium pump and transporting cadmium into the leaf vacuoles. This mini-review focuses on the current research into understanding the cellular mechanisms of cadmium toxicity on cytoskeleton, vesicular trafficking and cell wall formation in plants.     

Interaction of cadmium and zinc during prenatal development in the rat

Cadmium chloride, zinc chloride, or a mixture of the two, labeled with 115m-Cd or 65-Zn was administered intraperitoneally to Wistar rats on day 9 of gestation. On day 20 fetuses of Cd-treated rats exhibited malformations, but those of rats given zinc or zinc plus cadmium did not. No radioactive cadmium was recovered in the fetuses or fetal membranes, although some was found in the placentas. Simultaneous administration of zinc did not alter the distribution of cadmium, but cadmium significantly increased the amount of zinc in the fetus and placenta. In a second experiment, cadmium or cadmium plus zinc was administered on day 9 of gestation and embryonic units were removed on days 10, 11, and 12. On day 10 cadmium was found in the embryonic unit and maternal uterus, and cadmium in both was significantly reduced by simultaneous administration of zinc. The cadmium concentration in uterus and embryonic units decreased sharply on day 11 and 12 and by day 12 did not differ in animals treated with cadmium or with cadmium plus zinc. It is concluded that cadmium reaches the placenta or embryo at an organogenetically sensitive time, and that zinc may protect the embryo by decreasing the exposure to cadmium this time.     

Cadmium accumulation and metabolism by rat liver parenchymal cells in primary monolayer culture

Primary cultures of adult rat liver parenchylmal cells, isolated by the collagenase perfusion technique and maintained as a monolayer,l were used to investigate the characteristics of hepatic cadmium accumulation and metabolism. Cadmium accumulation was found to be temperature- and concentration-dependent process that required sulfhydryl groups and was significantly stimulated by the addition of dexamethasome to the medium. Once taken up, cadmium was less available for exit-exchange processes than its biologically required congener, zinc. Moreover, cadmium influx enhanced zinc efflux. While most of the intracellular cadmium was located in the cytosol, its distribution within this fraction was altered with time. Initially the metal was bound to both high molecular weight species (>50 000) and metallothionein. As the incubation period increased, the cytosol concentration of cdmium and the percentage of this metal associated with metallothionein was likewise increased. [³H]Amino acid incorporation studies indicated that the accumulation of cadmium resulted in de novo synthesis of the 1 and 2 forms of metallothionein.     

Influence of zinc on lotic plants

SUMMARY. The toxicity of zinc to Hormidium rivulare Kütz. in laboratory culture media is decreased by rises in the levels of magnesium, calcium and phosphate, and increased by rises in pH and cadmium. The effects of all these are sufficiently marked that they may be expected to have considerable importance in the field. In contrast, assays with sodium, chloride and sulphate showed no detectable influence of these ions on zinc toxicity.
When applied at higher concentrations, calcium was always more effective than magnesium, but the reverse was sometimes true at lower concentrations. Both magnesium and phosphate were more effective in reducing zinc toxicity with zinc-tolerant populations than with zinc-sensitive ones. Cadmium was highly toxic, either alone or in combination with zinc; however, calcium had a proportionately greater effect in reducing cadmium toxicity than zinc toxicity. The toxic effects of zinc and cadmium were synergistic, and it seems probable that the presence of cadmium at levels of 0.01 mgl⁻¹ and above will usually lead to a significant increase in the toxicity of any zinc also present. Cadmium (in the absence of zinc) was 34 times more toxic than zinc to a zinc + cadmium sensitive population, and 15.5 times more toxic to a zinc + cadmium tolerant population. Because of the synergistic response, cadmium had an even greater effect in the presence of zinc.     

Backlighting the European Indium Recycling Potentials

With increased understanding of the effects of human activities on the environment and added awareness of the increasing societal value of natural resources, researchers have begun to focus on the characterization of elemental cycles. Indium has captured significant attention due to the potential for supply shortages and nonexistent recycling at end of life. Such a combination of potentially critical features is magnified for countries that depend on imports of indium, notably many European countries. With the aims of analyzing the dynamics of material flows and of estimating the magnitude of secondary indium sources available for recycling, the anthropogenic indium cycle in Europe has been investigated by material flow analysis. The results showed that the region is a major consumer of finished goods containing indium, and the cumulative addition of indium in urban mines was estimated at about 500 tonnes of indium. We discuss these results from the perspective of closing the metal cycle in the region. Securing access to critical raw materials is a priority for Europe, but the preference for recycling metal urban mines risks to remain only theoretical for indium unless innovations in waste collection and processing unlock the development of technologies that are economically feasible and environmentally sustainable.     

Microbial leaching of metals from sulfide minerals

Microorganisms are important in metal recovery from ores, particularly sulfide ores. Copper, zinc, gold, etc. can be recovered from sulfide ores by microbial leaching. Mineral solubilization is achieved both by 'direct (contact) leaching' by bacteria and by 'indirect leaching' by ferric iron (Fe(3+)) that is regenerated from ferrous iron (Fe(2+)) by bacterial oxidation. Thiobacillus ferrooxidans is the most studied organism in microbial leaching, but other iron- or sulfide/sulfur-oxidizing bacteria as well as archaea are potential microbial agents for metal leaching at high temperature or low pH environment. Oxidation of iron or sulfur can be selectively controlled leading to solubilization of desired metals leaving undesired metals (e.g., Fe) behind. Microbial contribution is obvious even in electrochemistry of galvanic interactions between minerals.     

The tissue disposition and urinary excretion of cadmium, zinc, copper and iron, following repeated parenteral administration of cadmium to rats.

The effect of repeated parenteral administration of cadmium (0.75, 1.5 and 3.0 mg/kg) on tissue disposition and urinary excretion of cadmium, zinc, copper and iron has been studied in the male rat. Cadmium, zinc and copper accumulated in liver and kidney, but the concentration of iron did not alter significantly. The kidney weight relative to body weight showed a dose-related increase in weight of 25--65%. Excretion of cadmium in the urine increased directly with dosage and the increase was most significant when kidney damage had probably occurred. Administration of cadmium also resulted in dose-related increases in the urinary excretion of zinc, copper and iron. The cadmium concentration of blood increased with dosage of cadmium, and the plasma concentrations of zinc and copper were also raised but plasma iron concentration was diminished.     

Interplay of the Czc system and two P-type ATPases in conferring metal resistance to Ralstonia metallidurans

Cadmium and zinc are removed from cells of Ralstonia metallidurans by the CzcCBA efflux pump and by two soft-metal-transporting P-type ATPases, CadA and ZntA. The czcCBA genes are located on plasmid pMOL30, and the cadA and zntA genes are on the bacterial chromosome. Expression of zntA from R. metallidurans in Escherichia coli predominantly mediated resistance to zinc, and expression of cadA predominantly mediated resistance to cadmium. Both transporters decreased the cellular content of zinc or cadmium in this host. In the plasmid-free R. metallidurans strain AE104, single gene deletions of cadA or zntA had only a moderate effect on cadmium and zinc resistance, but zinc resistance decreased 6-fold and cadmium resistance decreased 350-fold in double deletion strains. Neither single nor double gene deletions affected zinc resistance in the presence of czcCBA. In contrast, cadmium resistance of the cadA zntA double mutant could be elevated only partially by the presence of CzcCBA. lacZ reporter gene fusions indicated that expression of cadA was induced by cadmium but not by zinc in R. metallidurans strain AE104. In the absence of the zntA gene, expression of cadA occurred at lower cadmium concentrations and zinc now served as an inducer. In contrast, expression of zntA was induced by both zinc and cadmium, and the induction pattern did not change in the presence or absence of CadA. However, expression of both genes, zntA and cadA, was diminished in the presence of CzcCBA. This indicated that CzcCBA efficiently decreased cytoplasmic cadmium and zinc concentrations. It is discussed whether these data favor a model in which the cations are removed either from the cytoplasm or the periplasm by CzcCBA.     

Nitrogen and Phosphorus in the Finnish Energy System, 1900–2003

In producing power, humans move the nutrients nitrogen (N) and phosphorus (P) from their long‐term geological and biological stocks and release or emit them in soil, water, and the atmosphere. In Finland, peat combustion is an important driver of N and P fluxes from the environment to human economy. The flows of N and P in the Finnish energy system were quantified with partial substance flow analysis, and the driving forces of emissions of nitrogen oxides (NOx) were analyzed using the ImPACT model. In the year 2000 in Finland, 140,000 tonnes of nitrogen entered the energy system, mainly in peat and hard coal. Combustion released an estimated 66,000 tonnes of N as nitrogen oxides (NOx) and nitrous oxides (N2O) and another 74,000 tonnes as elemental N2. Most of the emissions were borne in traffic. At the same time, 6,000 tonnes of P was estimated to enter the Finnish energy system, mostly in peat and wood. Ash was mainly used in earth construction and disposed in landfills; thus negligible levels of P were recycled back to nature. During the twentieth century, fuel‐borne input of N increased 20‐fold, and of P 8‐fold. In 1900–1950, the increasing use of hard coal slowly boosted N input, whereas wood fuels were the main carrier of P. Since 1970, the fluxes have been on the rise. NOx emissions leveled off in the 1980s, though, and then declined in conjunction with improvements in combustion technologies such as NOx removal (de‐NOx) technologies in energy production and catalytic converters in cars.     

Isolation and Identification of a New Analogue of Aspergillic Acid Derived from Valine and Isoleucine

The biological activities of zinc and cadmium on Euglena gracilis grown in zinc deficient and sufficient media were examined- Cadmium was neither involved in the normal cell metabolism of E. gracilis under zinc deficient conditions, nor did not replace zinc, which is essential for the normal growth. More cadmium was incorporated into cells grown in zinc deficient media than in zinc sufficient ones, resulting in more toxic effects in zinc deficient media than in zinc sufficient ones. Cadmium effectively provoked abnormal cells under zinc deficient conditions, suggesting that the normal process of cell division was interrupted by cadmium.     

Cadmium concentrations in the testes, sperm, and spermatids of mice subjected to long-term cadmium chloride exposure.

BACKGROUND: Exposures to cadmium have been reported to reduce male fertility and there are several hypotheses that suggest how reduced male fertility may result from incorporation of cadmium into sperm chromatin. The purpose of this study was to determine whether mice subjected to long-term intraperitoneal cadmium exposure incorporated cadmium into their sperm chromatin. METHODS: Male mice were exposed to 0.1 mg/kg body weight cadmium in the form of CdCl2 via intraperitoneal injection once per week for 4, 10, 26, and 52 weeks and then sacrificed. The cadmium contents of the liver, testes, pooled sperm, and pooled spermatids from dosed and control animals were determined by atomic absorption spectroscopy. Cadmium and zinc contents in individual sperm and spermatid heads were determined by particle-induced x-ray emission. RESULTS: Atomic absorption spectroscopy revealed that although cadmium accumulated in the liver and testes, cadmium was not detected in pooled sperm or spermatid samples down to minimum detectable limits of 0.02 microg/g dry weight. Particle-induced x-ray emission analyses did not show the presence of cadmium in any sperm or spermatid head down to minimum detectable limits of 15 microg/g dry weight. Particle-induced x-ray emission analyses also demonstrated that phosphorus, sulfur, and zinc concentrations in individual sperm and spermatid heads were not altered by exposure to CdCl2. CONCLUSIONS: Because cadmium was not incorporated into sperm chromatin at levels above 0.02 microg/g dry weight, the data cast doubt on hypotheses that suggest that reduced male fertility may result from incorporation of cadmium into sperm chromatin.     

Failure of zinc to prevent dysmorphogenesis of cultured rat conceptuses by anti-yolk sac antiserum

Day 10 rat conceptuses were cultured for 48h in the presence of either cadmium or anti-visceral yolk sac antiserum (AVYS). Cadmium was embryotoxic at concentrations exceeding 0.25 micrograms/ml whilst AVYS caused embryonic dysmorphogenesis, particularly affecting the optic vesicles, at concentrations of 2 microliters/ml and above. The effect of pretreatment with zinc on embryotoxicity caused by cadmium or AVYS was studied. Zinc ameliorated the effects of cadmium but had no effect on AVYS-induced embryonic abnormalities. In a second set of experiments inhibition of 125I-labelled PVP uptake by the yolk sac of cultured whole conceptuses was studied. Cadmium and AVYS both inhibited uptake compared to control cultures. Zinc again ameliorated the effect of cadmium but had no action against AVYS-induced inhibition. These results are in contrast to our previous findings using isolated cultured yolk sacs in which zinc ameliorated the inhibitory effects on 125I-labelled PVP uptake of both cadmium and AVYS. These data show that in experiments using the isolated cultured yolk sac and the intact cultured conceptus, a qualitatively different response in yolk sac behaviour is observed under similar experimental conditions.     

Cadmium carcinogenesis in review

Cadmium is an inorganic toxicant of great environmental and occupational concern which was classified as a human carcinogen in 1993. Occupational cadmium exposure is associated with lung cancer in humans. Cadmium exposure has also, on occasion, been linked to human prostate cancer. The epidemiological data linking cadmium and pulmonary cancer are much stronger than for prostatic cancer. Other target sites for cadmium carcinogenesis in humans (liver, kidney, stomach) are considered equivocal. In rodents, cadmium causes tumors at several sites and by various routes. Cadmium inhalation in rats results in pulmonary adenocarcinomas, supporting a role in human lung cancer. Prostate tumors and preneoplastic proliferative lesions can be induced in rats after cadmium ingestion or injection. Prostatic carcinogenesis in rats occurs only at cadmium doses below those that induce chronic degeneration and dysfunction of the testes, a well-known effect of cadmium, confirming the androgen dependency of prostate tumors. Other targets of cadmium in rodents include the testes, adrenals, injection sites, and hematopoietic system. Various treatments can modify cadmium carcinogenesis including supplemental zinc, which prevents cadmium-induced injection site and testicular tumors while facilitating prostatic tumors. Cadmium is poorly mutagenic and probably acts through indirect mechanisms, although the precise mechanisms remain unknown.     

Biological function of metallothionein. VI. Metabolic interaction of cadmium and zinc in rats

The accumulation and depletion of cadmium in liver and kidney metallothionein (MT) and the effects of dietary zinc deficiency on cadmium metabolism were studied in rats. The accumulation of cadmium in liver MT started to plateau after 80 days, but there was a linear accumulation of this element in kidney MT over the entire 300-day experiment. Cadmium in MT fractions was depleted very slowly when rats were changed to a diet without cadmium. The accumulation of cadmium in MT also caused zinc to accumulate in this protein, even in rats fed zinc-deficient diets. However, the reverse situation was found not to be true; zinc did not cause cadmium to accumulate in MT. Dietary zinc deficiency limited the binding of injected¹⁰⁹Cd to MT of liver, but not of kidneys or testes. However, zinc-deficient rats fed cadmium in their diets metabolized cadmium similarly to zinc-supplemented rats, suggesting that zinc deficiency does not limit the ability of cadmium to stimulate MT synthesis.     

Zinc-, copper- and cadmium-binding protein in Ehrlich ascites tumour cells.

The properties of Ehrlich ascites tumour cells exposed in vivo to cadmium were investigated as a function of the zinc status of the host animals. Tumour-cell growth was inhibited by cadmium in both zinc-sufficient and zinc-deficient animals. However, cells in zinc-sufficient tumours accumulate much less cadmium than those in deficient tumours. The subcellular distributions of cadmium and zinc do not depend on zinc status. Cadmium and zinc are bound to a low-molecular-weight protein with properties similar to metallothionein. Without exposure to cadmium, a zinc- and copper-binding protein is still present that behaves like a metallothionein. This protein can rapidly bind cadmium added to Ehrlich cells in vitro. It is shown that the zinc- and copper-binding protein contains free thiol groups. Ehrlich cells isolated from cadmium-treated animals are viable and show normal incorporation of uridine into RNA, but the cellular uptake of thymidine and its incorporation into DNA are inhibited.     

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.