[Cadmium toxicity. Cadmium and hypertension].
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Cadmium↗
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Molecular characterization of a novel, cadmium-inducible gene from the nematode Caenorhabditis elegans. A new gene that contributes to the resistance to cadmium toxicity.
Cadmium is an environmental contaminant that is both a human toxicant and carcinogen. To inhibit cadmium-induced damage, cells respond by increasing the expression of genes that encode stress-response proteins. We previously reported the identification of 48 cadmium-inducible mRNAs in the nematode Caenorhabditis elegans. Here we describe a new cadmium-responsive gene, designated cdr-1, whose rate and level of inducible expression parallel those of the C. elegans metallothioneins. The CDR-1 mRNA contains an open reading frame of 831 bp and encodes a predicted 32-kDa, integral membrane protein. Following cadmium exposure, cdr-1 is transcribed exclusively in intestinal cells of post-embryonic C. elegans. In vivo, the CDR-1 protein is targeted specifically to the intestinal cell lysosomes. cdr-1 transcription is significantly induced by cadmium but not by other tested stressors. These results indicate that cdr-1 expression is regulated by cadmium and in a cell-specific fashion. Inhibition of CDR-1 expression renders C. elegans susceptible to cadmium toxicity. In conclusion, cdr-1 defines a new class of cadmium-inducible genes and encodes an integral membrane, lysosomal protein. This protein functions to protect against cadmium toxicity.
Amino Acid Sequence↗
Molecular basis of cadmium toxicity.
Cadmium has been shown to manifest its toxicity in human and animals by mainly accumulating in almost all of the organs and kidney is the main target organ where it is concentrated mainly in cortex. Environmental exposure of cadmium occurs via food, occupational industries, terrestrial and aquatic ecosystem. At molecular level, cadmium interferes with the utilization of essential metals e.g. Ca, Zn, Se, Cr and Fe and deficiencies of these essential metals including protein and vitamins, exaggerate cadmium toxicity, due to its increased absorption through the gut and greater retention in different organs as metallothionein (Cd-Mt). Cadmium transport, across the intestinal and renal brush border membrane vesicles, is carrier mediated and it competes with zinc and calcium. It has been postulated that cadmium shares the same transport system. Cadmium inhibits protein synthesis, carbohydrate metabolism and drug metabolizing enzymes in liver of animals. Chronic environmental exposure of cadmium produces hypertension in experimental animals. Functional changes accompanying cadmium nephropathy include low molecular weight proteinuria which is of tubular origin associated with excess excretion of proteins such as beta 2 microglobulin, metallothionein and high molecular weight proteinuria of glomerular origin (excretion of proteins such as albumin IgG, transferrin etc.). Recent data has shown that metallothionein is more nephrotoxic to animals. Cadmium is also toxic to central nervous system. It causes an alterations of cellular functions in lungs. Cadmium affects both humoral and cell mediated immune response in animals. Cadmium induces metallothionein in liver and kidney but under certain nutritional deficiencies like protein-calorie malnutrition and calcium deficiency, enhanced induction and greater accumulation of cadmium metallothionein has been observed.
Aging↗
[Molecular mechanisms of plant resistance to cadmium toxicity].
Cadmium (Cd) is a non-essential trace element for plants, and has strong toxicity at low concentrations. It can suppress the elongation growth of plant cell, inhibit oxidative mitochondrial phosphorylation, induce oxidative stress, inhibit the activities of several antioxidative enzymes, affect photosynthesis by inhibiting ferrous reductase or damaging photosynthesis apparatus, and cause the alteration of chromatin and the change of plasma membrane ATPase activity. In response to Cd stress, the cells of cadmium-resistant plant species can produce a number of proteins such as phytochelatins, metallothioneins and stress proteins to detoxify Cd ions, and efficiently repair Cd damage. The plant cells can also resort to other defense systems to detoxify Cd ions, e.g., the immobilization of Cd by cell wall, exclusion of Cd through the action of plasma membrane, compartmentalization of Cd by vacuolar, and release of plant glands. The phytochelatin synthase (PCS) genes of Arabidopsin, wheat and Schizosaccharomyces pombe had been identified by using different approaches, and the metallothioneins (MT) in plants was also identified recently. By introducing animal MT genes, transgenic plants could increase the resistant ability to Cd toxicity. Subjected to Cd, plant cells often start to synthesize stress proteins such as heat shock proteins, and the plants having been transformed the stress protein genes could enhance their resistant capacity to Cd ions. It was reported that zinc (Zn) ion-transporting proteins could also transport Cd ion. Some minor genes not conferring tolerance on their own could modify the major gene (s), and enhance Cd tolerance. Cd detoxification in wild type plants could be a complex phenomenon, probably under polygenic control to Cd, while acute Cd stress seemed to be a simpler mechanism, apparently involving only one or a few specific major genes.
Aminoacyltransferases↗
The vascular endothelium as a target of cadmium toxicity.
Cadmium (Cd) is an important industrial and environmental pollutant that can produce a wide variety of adverse effects in humans and animals. A growing volume of evidence indicates that the vascular endothelium may be one of the primary targets of Cd toxicity in vivo. Studies over the past 20 years have shown that Cd, at relatively low, sublethal concentrations, can target vascular endothelial cells at a variety of molecular levels, including cell adhesion molecules, metal ion transporters and protein kinase signaling pathways. The purpose of this review is to summarize the results of these recent studies and to discuss the implications of these findings with regard to the mechanisms of Cd toxicity in specific organs including the lung, liver, kidney, testis and heart. In addition the possible roles of the vascular endothelium in mediating the tumor promoting and anticarcinogenic effects of Cd are discussed.
Animals↗
DNA repair systems as targets of cadmium toxicity.
Cadmium (Cd) is a heavy metal and a potent carcinogen implicated in tumor development through occupational and environmental exposure. Recent evidence suggests that proteins participating in the DNA repair systems, especially in excision and mismatch repair, are sensitive targets of Cd toxicity. Cd by interfering and inhibiting these DNA repair processes might contribute to increased risk for tumor formation in humans. In the present review, the information available on the interference of Cd with DNA repair systems and their inhibition is summarized. These actions could possibly explain the indirect contribution of Cd to mutagenic effects and/or carcinogenicity.
Animals↗
Influence of glibenclamide on the efficacy of calcium trisodium pentetat as an antidote for cadmium toxicity.
Cadmium causes hyperglycemia, activation of hepatic and renal gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1,6-diphosphatase, increases hepatic and renal zinc, renal copper and decreases hepatic and renal iron levels in rats. Glibenclamide, a hypoglycemic agent, significantly reversed most of the Cd effects, enhanced fecal excretion of Cd and potentiated urinary and fecal elimination of Cd by calcium trisodium diethylenetriaminepentaacetate (CaNa3DTPA), a commonly used metal chelator. However, the restoration of Cd-induced alterations in carbohydrate metabolism was not related to elimination of Cd from the tissues.
Animals↗
Evidence for an interaction between p-glycoprotein and cadmium toxicity in cadmium-resistant and -susceptible strains of Drosophila melanogaster.
The role of an ATP-dependent membrane protein, p-glycoprotein (pgp), in cadmium toxicity and resistance in Drosophila melanogaster was investigated. Two strains were compared, a wild-type and a cadmium-resistant strain. Verapamil (1, 10, and 100 mciroM) was added to the larval diet of Drosophila in both the presence and the absence of 80 ppm cadmium chloride. Adult emergence of wild-type but not of cadmium-resistant flies was reduced in the presence of cadmium. Verapamil in the larval diet without cadmium had no effect on adult emergence in either strain. Verapamil in the diet spiked with cadmium significantly reduced adult emergence in both strains. This result is indicative of an interaction between the efflux of cadmium and verapamil and demonstrates that pgps have a role in regulating the toxicity of cadmium in Drosophil. These results do not rule out pgps as putative cadmium resistance genes.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Cadmium toxicity decreased by dietary ascorbic acid supplements.
Feeding the environmental toxicant cadmium to young Japanese quail for 4 weeks produced growth retardation, severe anemia, low concentrations of iron in the liver, and high concentrations of cadmium in the liver. Dietary ascorbic acid supplements almost completely prevented the anemia and improved the growth rate but did not markedly alter concentrations of iron or cadmium in the liver.
Anemia↗
Acute toxicity profile of cadmium revealed by proteomics in brain tissue of Paralichthys olivaceus: potential role of transferrin in cadmium toxicity.
An analytical approach using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) separated proteins from the brain tissue of the fish Paralichthys olivaceus. Approximately 600 protein spots were detected from the brain sample when applying 600 microg protein to a 2D-PAGE gel in the pH range 3.5-10.0. Compared to a control sample, significant changes of 24 protein spots were observed in the fish tissue exposed to acute toxicity of seawater cadmium (SCAT) at 10 ppm for 24h. Among these spots, nine were down-regulated, nine were up-regulated, two showed high expression, and four showed low expression. The collected spots were identified by peptide mass fingerprinting (PMF) and database search, and they were further classified by LOC tree, a hierarchical system of support vector machines which predict their sub-cellular localization. The amount of transferrin expression in brain cells decreased linearly with the increase of SCAT concentration in seawater. Among the 24 proteins identified on a 2D-PAGE gel, 9 demonstrated a synchronous response to acute cadmium, suggesting that they might represent a biomarker profile. Based on their variable levels and trends on the 2D-PAGE gel this protein (likely to be transferrin) suggesting they might be utilized as biomarkers to investigate cadmium pollution levels in seawater and halobios survival, as well as to evaluate the degree of risk of human fatalities. The results indicate that the application of multiple biomarkers has an advantage over a single biomarker for monitoring levels of environmental contamination.
Animals↗
Zinc amelioration of cadmium toxicity on preimplantation mouse zygotes in vitro.
Zinc, at a concentration of 5 or 10 micrograms/ml medium, has been shown to protect mouse preembryos in vitro from the toxicity of cadmium at a concentration of 5 micrograms/ml medium after a simultaneous treatment of the ions from four-cell to morula or from morula to blastocyst for 24 hours. Such an amelioration indicates that cadmium toxicity is a result of the unique property of the cadmium ion and is not due to an alteration in the culture medium after the addition of an extra metallic ion. Zinc probably ameliorates cadmium-treated mouse preembryo by competing with cadmium for uptake or some other metabolic processes. In view of the well-documented competition between cadmium and zinc ions for binding sites in many other cell types, some macromolecules to which similar divalent metallic ions bind competitively may also exist in the mouse preembryo. This suggests that a protective mechanism dependent on the metal-metal interactions begins to operate in the mouse preembryo at a very early stage of differentiation before implantation.
Animals↗
Cadmium toxicity in rat pheochromocytoma cells: studies on the mechanism of uptake.
The uptake and toxicity of cadmium were compared in two rat pheochromocytoma cell lines: PC12 cells, which express voltage-sensitive calcium channels, and PC18 cells, which do not. PC12 but not PC18 cells responded to depolarization with an increase in 45Ca2+ uptake and an increase in the concentration of cytoplasmic free calcium ion, [Ca2+]i. These responses were blocked by the dihydropyridine calcium channel antagonist nimodipine and amplified by the agonist BAY K8644, drugs selective for L-type channels. Cadmium caused death of PC12 cells with an LC50 of 12 microM. Inclusion of high K+ with the agonist BAY K8644 shifted the kill curve to the left (LC50 = 6 microM). whereas nimodipine protected against cadmium toxicity (LC50 = 30 microM). In contrast, drugs acting on L-type calcium channels did not affect Cd2+ toxicity for PC18 cells (LC50 15 microM). Fura 2 was used to measure intracellular free Cd2+ by fluorescence ratio methods. Addition of 25 microM Cd2+ to both PC12 and PC18 cells caused a rise in the 340/380 fluorescence ratio attributable to the uptake of Cd2+, since it was almost completely reversed by chelating extracellular Cd2+ and adding a membrane-permeant chelator of heavy metals. Cd2+ addition resulted in a gradual increase in Fura 2 fluorescence in both PC12 and PC18 cells, but depolarization with BAY K8644 increased the apparent rate of Cd2+ uptake only for the PC12 cells. Cd2+ fluorescence appeared to be concentrated near the plasma membrane. The results confirm the potential involvement of calcium channels in cadmium transport and extend the use of intracellularly trapped fluorescent dyes to monitor intracellular free cadmium ion concentration.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Glutathione and metallothioneins as cellular defense against cadmium toxicity in cultured Chinese hamster cells.
To evaluate the protective role of cell glutathione (GSH) against the toxicity of cadmium, the effect of GSH depletion on the metal toxicity was investigated and the role of glutathione was compared with that of zinc-induced metallothioneins (MTs). A 6-h incubation of cultured Chinese hamster V79 cells with 0.2 mM L-buthionine-SR-sulfoximine (BSO), a selective inhibitor of gamma-glutamylcysteine synthetase, resulted in approx. 95% depletion of GSH in the cells. The depletion of GSH did not influence the rate of cell growth, the amount of cell protein or the chromosome structure during culture for at least 24 h. Cells depleted or not depleted of GSH were challenged with (1-5).10(-5) M CdCl2 for 2 h and subsequent cell growth was evaluated. The cytotoxicity of cadmium was enhanced with increasing duration of BSO pretreatment and was correlated with the decrease of cell GSH, indicating that GSH constitutes a cellular defense against toxicity by cadmium. Inducibility of MTs by zinc was investigated in cultured V79 cells. Incubation of the cells with 1.10(-4) M zinc acetate did not result in accumulation of MTs over the control values for up to 2 h. Thereafter, however, the synthesis of MTs increased with increasing duration of zinc treatment and an approx. 9-fold increase in the amount of MTs was observed 10 h after addition of zinc. Depletion of cell GSH by BSO did not much influence the increased accumulation of MTs by zinc. In contrast, zinc at the same concentration did not influence the level of cell glutathione up to 12 h. The cytotoxicity of cadmium was markedly reduced in the cells pretreated with zinc and the protective effect of zinc was dependent upon duration of pretreatment, being parallel with the increased accumulation of MTs. Protection of cells from cadmium toxicity by zinc pretreatment was as or a little more effective in the cells depleted of GSH as in those not depleted. Thus, glutathione appears to be an intrinsic protector against cadmium toxicity, while MTs serve as an induced cellular defense that is mobilized against heavy metal stress, but takes more than 2 h to accumulate in significant amounts. Accordingly, it is suggested that GSH and MTs have cooperative protective roles against cadmium toxicity, as an initial defense for the former and a second-stage defense for the latter.
Acetates↗
Nutritional influences on metal toxicity: cadmium as a model toxic element.
The nutrient quality of the diet has been shown repeatedly to be a significant factor in modifying the response of man and animals to toxic element exposure. Deficiencies of several essential nutrients have been shown to exacerbate the effects of cadmium and supplements of such nutrients have been shown to ameliorate the toxicity. Thus the effects of exposure to a toxic element, such as cadmium, may vary, depending on interactions with other elements which are present in the diet in different concentrations.
Adolescent↗
Cadmium toxicity in the newborn rat.
Newborn rats have about a 20-fold higher concentration of metallothionein in the liver than does the adult rat. This marked increase in hepatic metallothionein does not result in a lower acute toxicity to cadmium in newborn rats; it does not markedly increase the distribution of cadmium to the liver, decrease its concentration in other tissues, or produce a slower removal of the cadmium from younger animals. The toxicity of cadmium in the newborn rat appears to be more dependent on other factors such as the development of the blood-brain barrier and the stage of development of the testes than on the amount of metallothionein in the liver. The results of this study suggest that we should probably reevaluate the role of metallothionein in producing tolerance to cadmium.
Amino Acids↗
The influence of pH on cadmium toxicity to the green alga Stichococcus bacillaris and on the cadmium forms present in the culture medium.
Cadmium toxicity to the green alga Stichococcus bacillaris was investigated in media of pH 3-9. A significant decrease of cadmium toxicity occurred in both the acidic and alkaline ranges of pH. In media of pH 3 and 9, cadmium did not affect the dry mass content substantially. Maximum toxicity of cadmium was noticed at pH 6-7. Voltametric investigations showed a significant effect of pH on electrochemically measured cadmium content in the culture media. Hydrolysis of the medium components and formation of cadmium complexes with OH(-) ions caused a considerable decrease in amounts of electrochemically measured cadmium in the alkaline range of pH.
Journal Article↗
Defense mechanisms against cadmium toxicity I. A biochemical and histological study of the effects of pretreatment with cadmium on the acute oral toxicity of cadmium in mice.
Resistance to the lethal action of Cd2+ produced in mice was maintained for 6 to 24 hr after pretreatment with 1/10 of the challenge Cd2+ doses as shown by an increased oral LD50. Pretreatment 24 hr prior to the challenge doses was most effective. In addition, 1/20 to 1/7 of the challenge doses was necessary to acquire the tolerance to the acute oral toxicity of Cd2+. The largest effect was found for pretreatment with 1/7 of the challenge doses. Acute liver injury at 24 hr after challenge with a large dose of Cd2+ (100 mg Cd2+/kg, p.o.) was markedly reduced by pretreatment with a small dose of the cation (15 mg Cd2+/kg, p.o.) 24 or 48 hr prior to the challenge dose as shown by a marked reduction in serum GOT and GPT activities and the reversal of histopathological changes. The elevated serum urea nitrogen at 4 hr after the Cd2+ challenge was reduced by pretreatment 6 to 24 hr prior to the challenge dose. In spite of the increased urea nitrogen 4 hr after the Cd2+ challenge, no morphological alterations were observed in the kidney at 24 hr. Serum Alp activity was not significantly influenced by the Cd2+ challenge. Glucose in serum was increased by the administration of a small dose of Cd2+, but was unaffected by a large dose. Decreases in hepatic RNA and DNA concentrations at 24 hr after the Cd2+ challenge were prevented by pretreatment 24 or 48 hr prior to the challenge dose. Potentiation of hexobarbital sleep time was observed at 6 or 24 hr after a small dose of Cd2+. Nevertheless, further potentiation at 24 hr after the Cd2+ challenge (75 mg Cd2+/kg, p.o., in this case) was reduced by pretreatment 24 hr prior to the challenge dose. A major target organ for the acute oral toxicity of Cd2+ was the liver rather than the kidney.
Animals↗
Influence of chemical and environmental stressors on acute cadmium toxicity.
Previous investigations have demonstrated that the cytosolic protein metallothionein (MT) is induced not only by exposure to certain heavy metals but also by a variety of other factors, including environmental stress. While MT synthesis has been observed with exposure to cold temperatures, there is a paucity of data concerning the influence of cold on heavy-metal toxicity. The present investigation focused on the influence of metal and cold pretreatments on the acute toxicity of cadmium. Mortalities of 80% and 100% were observed for mice orally administered challenge doses of 100 mg Cd/kg and 150 mg Cd/kg, respectively. To determine a protective cadmium pretreatment dose, animals were administered 2.5, 5, 10, 20, 25, and 50 mg Cd/kg 24 h prior to cadmium challenge. In animals pretreated with 10 mg Cd/kg, mortalities of 20% and 70% were observed with the respective challenge doses. Immediately following cold stress (4 degrees C, 12 h), mortalities of 30% and 90% were observed with cadmium challenge doses of 100 and 150 mg Cd/kg, respectively. Significant correlations were demonstrated between induced hepatic MT concentrations and cadmium pretreatment (r = 0.99), as well as cold pretreatment (r = 0.87). Results of this investigation indicate that stressors, such as cold, influence the acute toxicity of cadmium to the same magnitude as metal pretreatment. This induced tolerance to cadmium was attributed, in part, to the induction of MT synthesis. Furthermore, the induced levels of MT resulting from cold stress may confound the simplistic approach of using MT as a biological monitor of occupational exposure to cadmium.
Animals↗