metallothionein and Cadmium-Poisoning

Cadmium is a toxic element to which man can be exposed at work or in the environment. Cd's most salient toxicological property is its exceptionally long half-life in the human body. Once absorbed, Cd accumulates in the human body, particularly in the liver. The cellular actions of Cd are extensively documented, but the molecular mechanisms underlying these actions are still not resolved. The liver manages the cadmium to eliminate it by a diverse mechanism of action. Still, many cellular and physiological responses are executed in the task, leading to worse liver damage, ranging from steatosis, steatohepatitis, and eventually hepatocellular carcinoma. The progression of cadmium-induced liver damage is complex, and it is well-known the cellular response that depends on the time in which the metal is present, ranging from oxidative stress, apoptosis, adipogenesis, and failures in autophagy. In the present work, we aim to present a review of the current knowledge of cadmium toxicity and the cellular response in the liver.

Topics: Cadmium; Cadmium Poisoning; Fatty Liver; Humans; Liver; Liver Neoplasms; Male; Metallothionein; Oxidative Stress

The incidence of serious poisoning caused by occupational cadmium exposure has declined over the past four decades due to improvements in the work environment. However, long-term low-level exposure to cadmium needs to be addressed. For workers in industries that handle cadmium, it is necessary to consider the daily cadmium intake from contaminated foods such as cereals and rice in addition to the occupational exposure, since workers might be exposed to higher levels of cadmium from a combination of these sources. Cadmium accumulates in the renal cortex by the long-term exposure along with increased concentrations of metallothionein, an important protein for protection from cadmium toxicity. However, some individuals have lower metallothionein levels despite increased cadmium accumulation in the kidneys. This article describes the strategy method for analyzing individual susceptibility to cadmium toxicity and genetic polymorphisms of metallothionein, with reference to the current status of occupational cadmium exposure.

Topics: Biomarkers; Cadmium Poisoning; Gene Expression Profiling; Genetic Predisposition to Disease; Humans; Japan; Kidney Cortex; Metallothionein; Occupational Exposure; Polymorphism, Genetic

Topics: Amino Acid Sequence; Animals; Cadmium; Cadmium Poisoning; Gene Deletion; Heavy Metal Poisoning; Humans; Metallothionein; Metals, Heavy; Molecular Sequence Data; Protein Binding; RNA, Messenger

Topics: Binding, Competitive; Cadmium; Cadmium Poisoning; Chelating Agents; Hexoses; Metallothionein; Structure-Activity Relationship; Thiocarbamates

Author's work on the adaptation and protection systems against chemical substances, such as drugs, food additives, heavy metals, pesticides and environmental pollutants, in the living body during the past thirty five years was reviewed. Using the induction of heme and drug metabolizing enzymes (especially heme oxygenase) and of metallothionein in the liver of animals as a biological index, the adaptation and protection of these substances to the body were discussed. This is because that heme oxygenase is a heat shock protein which is induced by various environmental factor, and that metallothionein also has a wide variety of biological functions, and was identified as an acute phase protein in the first phase defense system against environmental stresses. The research under mRNA levels as more sensitive index will advance in the near future.

Topics: Adaptation, Physiological; Animals; Cadmium Poisoning; Enzyme Induction; Heme Oxygenase (Decyclizing); Humans; Inactivation, Metabolic; Liver; Metallothionein

Metallothioneins are attractive substances. One of the features of these proteins is the inducibility in response to heavy metals, to a great variety of metabolites and to stress factors. In mammalia, their synthesis may be induced by interleukin-6 in response to inflammation. Metallothionein could prevent renal toxicity of cDDP without compromising its anticancer activity. However, metallothionein is also implicated in the resistance to cDDP. There are now good evidences that metallothionein is involved in many diseases, such as inflammatory bowel disease, toxemia of pregnancy, liver disease, etc.

Topics: Animals; Antidotes; Cadmium Poisoning; Free Radical Scavengers; Humans; Metallothionein

Cadmium-induced nephrotoxicity develops at cadmium concentrations in the renal cortex of 10-300 micrograms/g wet weight. The actual concentration at which it develops depends on a number of factors, e.g., exposure route, chemical species of cadmium administered, rate of administration and simultaneous exposure to other metals. The role of these factors can be explained by a mechanism of cadmium nephrotoxicity in which both extracellular and intracellular metallothionein binding play an essential role. In reindeer used for human food, cadmium was shown to be bound to metallothionein-like proteins. If cadmium bound to such proteins enters the blood plasma via the gastrointestinal tract, this is of special toxicological significance. Metallothionein-bound cadmium in the plasma of experimental animals is efficiently transported to the kidney. Tubular dysfunction in the kidney following a normally tubulotoxic dose of cadmium bound to metallothionein was prevented by preinduction of metallothionein synthesis by small non-toxic doses of cadmium.

Topics: Animals; Cadmium; Cadmium Poisoning; Food Contamination; Kidney Diseases; Kidney Tubules; Metallothionein; Protein Binding; Reindeer; Tissue Distribution

Topics: Adult; Animals; beta 2-Microglobulin; Biomarkers; Body Burden; Cadmium; Cadmium Poisoning; DNA-Binding Proteins; Electron Probe Microanalysis; Heat-Shock Proteins; Humans; Metallothionein; Middle Aged; Proteinuria; Rats; Retinol-Binding Proteins; Spectrophotometry, Atomic

Topics: Animals; Buthionine Sulfoximine; Cadmium; Cadmium Poisoning; Glutathione; Humans; Metallothionein; Methionine Sulfoximine; Mice

The increasing environmental and occupational exposure of populations to cadmium creates the need for biological indicators of cadmium exposure and toxicity. The advantages and disadvantages of monitoring blood cadmium, urinary, fecal, hair, and tissue cadmium, serum creatine, beta 2-microglobulin, alpha 1-anti-trypsin and other proteins, and urinary amino acids, enzymes, total proteins, glucose, beta 2-microglobulin, retinol-binding protein, lysozyme, and metallothionein are discussed. It is concluded that urinary cadmium, metallothionein and beta 2-microglubulin may be used together to assess cadmium exposure and toxicity.

Topics: alpha 1-Antitrypsin; Amino Acids; beta 2-Microglobulin; Blood Proteins; Cadmium Poisoning; Creatinine; Environmental Exposure; Enzymes; Feces; Glycosuria; Hair; Humans; Metallothionein; Muramidase; Proteinuria; Retinol-Binding Proteins

The increasing environmental and occupational exposure of populations to cadmium creates the need for biological indicators of cadmium exposure and toxicity. The advantages and disadvantages of monitoring blood cadmium, urinary, fecal, hair, and tissue cadmium, serum creatinine, beta 2-microglobulin, alpha 1-antitrypsin and other proteins, and urinary amino acids, enzymes, total proteins, glucose, beta 2-microglobulin, retinol-binding protein, lysozyme, and metallothionein are discussed. It is concluded that urinary cadmium, metallothionein and beta 2-microglobulin may be used together to assess cadmium exposure and toxicity.

Topics: Alkaline Phosphatase; alpha 1-Antitrypsin; Amino Acids; Animals; Aspartate Aminotransferases; beta 2-Microglobulin; Blood Proteins; Body Burden; Cadmium; Cadmium Poisoning; Clinical Enzyme Tests; Creatinine; Environmental Exposure; Feces; Glycosuria; Hair; Humans; Kidney; L-Lactate Dehydrogenase; Metallothionein; Muramidase; Proteinuria; Retinol-Binding Proteins

Topics: Aging; Body Fluids; Cadmium; Cadmium Poisoning; Edetic Acid; Humans; Kidney Diseases; Kidney Glomerulus; Lead Poisoning; Mercury Poisoning; Metallothionein; Nephritis, Interstitial

Topics: Animals; Animals, Newborn; Cadmium; Cadmium Poisoning; Calcium; Drug Interactions; Female; Fetus; Growth; Humans; Infant, Newborn; Intestinal Absorption; Metallothionein; Pregnancy; Smoking; Teratogens; Vitamin D Deficiency

Cadmium is a heavy metal, which is recently known to be hazardous to man. Cadmium workers have been observed to suffer from renal dysfunction and lung emphysema after long-term exposure to cadmium. However, since Itai-Itai disease, osteomalacia provoked in Toyama prefecture of Japan, was designated as a disease caused by cadmium in 1968, much attention has been paid to the health effects of residents in cadmium-polluted areas. The author described here recent progress and perspectives on cadmium health effect studies, cadmium analysis in biological samples; absorption, distribution and excretion of cadmium; health effects of residents in cadmium-polluted area; survey on the health status of Itai-Itai disease patients; beta 2-microglobulinuria; intestinal tract impairment and bone metabolism; effects on bone; effects on the liver; early diagnosis of cadmium effects; effects on future generations; carcinogenicity; critical concentration of cadmium; metallothionein; recommendations for future studies. One-hundred and sixty references are cited in this review.

Topics: Animals; beta 2-Microglobulin; Bone and Bones; Cadmium; Cadmium Poisoning; Haplorhini; Humans; Intestinal Mucosa; Liver; Metallothionein; Mice; Neoplasms; Rabbits; Rats

Topics: Animals; Cadmium; Cadmium Poisoning; Copper; Dose-Response Relationship, Drug; Female; Humans; Intestinal Absorption; Intestinal Mucosa; Kidney; Male; Metallothionein; Molybdenum; Pregnancy; Pregnancy Complications; Sulfur; Zinc

Topics: Amino Acid Sequence; Animals; Biological Evolution; Cadmium; Cadmium Poisoning; Copper; Humans; Metalloproteins; Metallothionein; Molecular Weight; Species Specificity; Terminology as Topic; Zinc

Topics: Adult; Age Factors; Aged; Anemia, Hypochromic; Animals; Cadmium; Cadmium Poisoning; Calcium; Copper; Diet; Female; Humans; Iron; Male; Metalloproteins; Metallothionein; Middle Aged; Pregnancy; Selenium; Zinc

Topics: Animals; Cadmium; Cadmium Poisoning; Environmental Exposure; Fishes; Food Analysis; Food Contamination; Fresh Water; Humans; Kidney Diseases; Metallothionein; Seawater

This work aimed to evaluate the effects of zinc (Zn) relating to cadmium (Cd)-induced toxicity and the role played by MTF-1. This transcription factor regulates the expression of genes encoding metallothioneins (MTs), some Zn transporters and the heavy chain of γ-glutamylcysteine synthetase. For this reason, two cell lines of mouse fibroblasts were used: a wild-type strain and a knockout strain to study the effects. Cells were exposed to complete medium containing: (1) 50 μM ZnSO

Topics: Animals; Cadmium; Cadmium Poisoning; Fibroblasts; Glutamate-Cysteine Ligase; Glutathione; Metallothionein; Mice; Transcription Factors; Zinc

Topics: Animals; Cadmium; Cadmium Poisoning; Chelating Agents; Copper; Female; Liver; Metallothionein; Rats

Cadmium (Cd) is toxic non-essential heavy metal that precipitates adverse health effects in humans and animals. Chelation therapy, the typical treatment for cadmium toxicity, has certain safety and efficacy issues to treat long term cadmium toxicity, in particular. Recent studies have shown that essential trace elements can play important roles in obviating experimental Cd toxicity. This study organizes and reviews the prototypical evidences of the protective effects of essential trace elements against Cd toxicity in animals and attempts to point out the underlying mechanisms. Zinc, selenium, iron, and combinations thereof are reported to be active. The major mechanisms elucidated inter alia are-induction of metallothionein (MT) synthesis and Cd-MT binding (for zinc), modulation of oxidative stress and apoptosis, interference in cadmium absorption and accumulation from body-thereby maintenance of essential metal homeostasis and cytoprotection. Based on the findings, essential trace elements can be recommended for the susceptible population. The application of these trace elements appears beneficial for both the prevention and remediation of long-term Cd toxicity operative via multiple mechanisms with no or minimal adverse effects as compared to the conventional chelation therapy.

Topics: Animals; Cadmium; Cadmium Poisoning; Chelating Agents; Heavy Metal Poisoning; Metallothionein; Selenium; Trace Elements; Zinc

Cadmium (Cd), a substance with one of the most critical health hazard indices, can cause damage to both the blood and kidneys and accumulates in the body at last. The present work studied the toxicological effects of Cd and the therapeutic effects of metallothionein (MT) and vitamin E (VE) on the trunk kidney and blood of freshwater grass carp (Ctenopharyngodon idellus). Grass carp were divided into three groups: Cd + phosphate-buffered saline (PBS) group, Cd + VE group, and the Cd + MT group. Fish were injected with CdCl

Topics: Animals; Apoptosis; Cadmium; Cadmium Poisoning; Carps; Kidney; Leukocyte Count; Metallothionein; Muramidase; Protective Agents; Vitamin E

Metallothioneins (MTs) are known to protect cells against oxidative stress, especially providing protection against cadmium (Cd) toxicity. To date, besides liver and kidney, the expression profiles of MT members have not been thoroughly determined in a full-spectrum of organs, especially under low-dose exposure settings. Furthermore, their diagnostic value has not been evaluated in reflecting the Cd exposure in diverse organs. In the present study, we unearthed the expression profiles of five MT members in diverse organs from mice upon low-dose Cd exposure. Compared to most organs, the deposition of Cd in cartilage has been overlooked in the past, implying the potential Cd toxicity to the joint. In contrast to MT1 and MT2 (MT1/2), the expression levels of MT3, MTL5 and MT4 were minimal with or without Cd treatment. Distinct from Cd mass, the levels of MT1/2 were similar in heart and lung to that of kidney. Our study signified the rationale of MT1/2 induction in recognizing Cd exposure extent in diverse organs including liver, kidney, heart and lung. Importantly, MT1/2 expression was induced in liver and lung cells even upon low-dose Cd exposure. Thus, our combined data unraveled the expression of MT members across various organs in Cd-exposed mice, and pinpointed their diagnostic value in characterizing Cd poisoning.

Topics: Animals; Cadmium; Cadmium Poisoning; Metallothionein; Metallothionein 3; Mice

Cadmium (Cd

Topics: Albumins; Animals; beta 2-Microglobulin; Cadmium; Cadmium Poisoning; Cell Line; Kidney Tubules, Proximal; Lipocalin-2; Low Density Lipoprotein Receptor-Related Protein-2; Metallothionein; Protein Binding; Rats; Receptors, Cell Surface

Cadmium (Cd) is produced mainly as a by-product of zinc mining. In Thailand, the largest zinc mine is located in the Mae Sot district, Tak Province. Samples of Monopterus albus were collected from paddy fields in 4 sites, three downstream and one upstream from the zinc mine. The upstream site was considered to be uncontaminated while the three downstream sites were considered to be contaminated with Cd. Studies on the accumulation level of cadmium were conducted on the liver of the fish using the atomic absorption spectrophotometer technique. The metallothionein (MT) gene expression level in the liver, as a potential biomarker for long-term Cd exposure in their natural habitat, was also assessed. The level of hepatic MT gene expression was performed by quantitative real-time PCR. The result showed that Cd accumulation in the liver was much higher in swamp eels collected from the downstream sites when compared to those collected from the upstream site. The hepatic MT level in the upstream site was 0.75-fold, while the other three downstream sites were 0.36-, 4.44- and 0.94-fold. There is no parallel correlation between hepatic cadmium levels and hepatic MT gene expression. This study then suggests that MT gene expression biomarkers might be not suitable for swamp eels with prolonged exposure to Cd.

Topics: Animals; Cadmium; Cadmium Poisoning; Eels; Fish Proteins; Fresh Water; Liver; Metallothionein; Thailand; Water Pollution, Chemical

Cadmium (Cd) is a highly hepatotoxic heavy metal, which is widely dispersed in the environment. Acute Cd hepatotoxicity has been well studied in experimental animals; however, effects of prolonged exposure to Cd doses on the liver remain unclear. In the present study, to evaluate chronic Cd hepatotoxicity, we examined specimens from cases of itai-itai disease, the most severe form of chronic Cd poisoning. We compared 89 cases of itai-itai disease with 27 control cases to assess Cd concentration in organs. We also examined 80 cases of itai-itai disease and 70 control cases for histopathological evaluation. In addition, we performed immunohistochemistry for metallothionein, which binds and detoxifies Cd. Hepatic Cd concentration was higher than Cd concentration in all other organs measured in the itai-itai disease group, whereas it was second highest following renal concentration in the control group. In the liver in the itai-itai disease group, fibrosis was observed at a significantly higher rate than that in the control group. Metallothionein expression was significantly higher in the itai-itai disease group than that in the control group. Prolonged exposure to low doses of Cd leads to high hepatic accumulation, which can then cause fibrosis; however, it also causes high expression of metallothionein, which is thought to reduce Cd hepatotoxicity.

Topics: Aged; Aged, 80 and over; Autopsy; Cadmium; Cadmium Poisoning; Case-Control Studies; Chemical and Drug Induced Liver Injury, Chronic; Chi-Square Distribution; Environmental Pollutants; Female; Humans; Immunohistochemistry; Liver; Liver Cirrhosis; Metallothionein; Middle Aged; Predictive Value of Tests; Up-Regulation

An experiment was conducted to invest effects of chronic cadmium poisoning on Zn, Cu, Fe, Ca, and metallothionein gene expression and protein synthesis in liver and kidney in rats. Forty rats, 6 weeks old, were randomly allocated into two groups. A group was given CdCl(2) (1 mg/KgCd(2+)) by intraperitoneal injection once a day. The other group was treated with normal saline in the same way. Liver and kidney were collected for analysis at the end of the third week. Results showed that Cd exposure increased Cd (P<0.01) and Zn (P<0.01) content both in liver and kidney. Fe and Ca concentration had a considerable increase in kidney (P<0.01), while both had different degree reduction in liver. Discrepancies between MT mRNA and protein were observed in liver and kidney. In liver, both MT mRNA and protein had a significant increase (P<0.01), while in kidney, only MT gene increase was checked. Meanwhile, the expression levels of MT-1 mRNA and MT-2 mRNA were distinct between liver and kidney. The present study indicated that changes in tissue Cd and Zn levels tended to reflect MT mRNA expression, but bear no clear relationship with MT protein. There did not have a strict dose-dependent relationship among Cd content, MT gene expression, and MT protein synthesis. What is more, changes of Zn, Fe, Cu, and Ca had a certain interaction with both MT mRNA and protein.

Topics: Animals; Cadmium; Cadmium Chloride; Cadmium Poisoning; Calcium; Copper; Enzyme-Linked Immunosorbent Assay; Gene Expression; Immunohistochemistry; Injections, Intraperitoneal; Iron; Kidney; Liver; Metallothionein; Metals, Heavy; Rats; Real-Time Polymerase Chain Reaction; RNA, Messenger; Toxicity Tests, Chronic; Zinc

The toxic effect of cadmium varies with sex in experimental animals. Previous studies have demonstrated that pretreatment of male Fischer 344 (F344) rats with the female sex hormone progesterone markedly enhances the susceptibility to cadmium, suggesting a role for progesterone in the sexual dimorphism of cadmium toxicity. In the present study, we attempted to further elucidate the mechanism for sex differences in cadmium-induced toxicity in F344 rats. A single exposure to cadmium (5.0 mg Cd/kg, sc) was lethal in 10/10 (100 %) female compared with 6/10 (60 %) male rats. Using a lower dose of cadmium (3.0 mg Cd/kg), circulating alanine aminotransferase activity, indicative of hepatotoxicity, was highly elevated in the cadmium treated females but not in males. However, no gender-based differences occurred in the hepatic cadmium accumulation, metallothionein or glutathione levels. When cadmium (5.0 mg Cd/kg) was administered to young rats at 5 weeks of age, the sex-related difference in lethality was minimal. Furthermore, although ovariectomy blocked cadmium-induced lethality, the lethal effects of the metal were restored by pretreatment with progesterone (40 mg/kg, sc, 7 consecutive days) or β-estradiol (200 μg/kg, sc, 7 consecutive days) to ovariectomized rats. These results provide further evidence that female sex hormones such as progesterone and β-estradiol are involved in the sexual dimorphism of cadmium toxicity in rats.

Topics: Animals; Cadmium; Cadmium Poisoning; Dose-Response Relationship, Drug; Estradiol; Female; Glutathione; Hepatic Insufficiency; Kidney; Liver; Male; Metallothionein; Ovariectomy; Progesterone; Rats; Rats, Inbred F344; Renal Insufficiency; Sex Characteristics; Survival Analysis; Tissue Distribution

Cadmium (Cd) toxicity of the kidney varies between individuals despite similar exposure levels. In humans Cd is mainly bound to metallothioneins (MT), which scavenge its toxic effects. Here we analyzed whether polymorphisms in MT genes MT1A and MT2A influence Cd-related kidney damage.. In a cross-sectional study N=512 volunteers were selected from three areas in South-Eastern China, which to varying degree were Cd-polluted from a smelter (control area [median Cd in urine U-Cd=2.67 μg/L], moderately [U-Cd=4.23 μg/L] and highly [U-Cd=9.13 μg/L] polluted areas). U-Cd and blood Cd (B-Cd) concentrations were measured by graphite-furnace atomic absorption spectrometry. MT1A rs11076161 (G/A), MT2A rs10636 (G/C) and MT2A rs28366003 (A/G) were determined by Taqman assays; urinary N-Acetyl-beta-(D)-Glucosaminidase (UNAG) by spectrometry, and urinary β2-microglobulin (UB2M) by ELISA.. Higher B-Cd (natural log-transformed) with increasing number of MT1A rs11076161 A-alleles was found in the highly polluted group (p-value trend=0.033; all p-values adjusted for age, sex, and smoking). In a linear model a significant interaction between rs11076161 genotype and B-Cd was found for UNAG (p=0.001) and UB2M concentrations (p=0.001). Carriers of the rs11076161 AA genotype showed steeper slopes for the associations between Cd in blood and natural log-transformed UB2M (β=1.2, 95% CI 0.72-1.6) compared to GG carriers (β=0.30, 95% CI 0.15-0.45). Also for UNAG (natural log-transformed) carriers of the AA genotype had steeper slopes (β=0.55, 95% CI 0.27-0.84) compared to GG carriers (β=0.018, 95% CI -0.79-0.11).. MT1A rs11076161 was associated with B-Cd concentrations and Cd-induced kidney toxicity at high exposure levels.

Topics: Adult; Aged; Aged, 80 and over; beta 2-Microglobulin; Cadmium Poisoning; China; Cross-Sectional Studies; DNA; Environmental Pollutants; Female; Genotype; Humans; Kidney Diseases; Logistic Models; Male; Metallothionein; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide

Organisms are able to detoxify accumulated metals by, e.g. binding them to metallothionein (MT) and/or sequestering them in metal-rich granules (MRG). The different factors involved in determining the capacity or efficiency with which metals are detoxified are not yet known. In this work we studied how the sub-cellular distribution pattern of cadmium, copper and zinc in whole tissue of zebra mussels from clean and polluted surface waters is influenced by the total accumulated metal concentration and by its physiological condition. Additionally we measured the metallothionein concentration in the mussel tissue. Metal concentration increased gradually in the metal-sensitive and detoxified sub-cellular fractions with increasing whole tissue concentrations. However, metal concentrations in the sensitive fractions did not increase to the same extent as metal concentrations in whole tissues. In more polluted mussels the contribution of MRG and MT became more important. Nevertheless, metal detoxification was not sufficient to prevent metal binding to heat-sensitive low molecular weight proteins (HDP fraction). Finally we found an indication that metal detoxification was influenced by the condition of the zebra mussels. MT content could be explained for up to 83% by variations in Zn concentration and physiological condition of the mussels.

Topics: Animals; Cadmium Poisoning; Cell Fractionation; Copper; Dreissena; Environmental Monitoring; Heavy Metal Poisoning; Inactivation, Metabolic; Metallothionein; Metals, Heavy; Statistics, Nonparametric; Subcellular Fractions; Water Pollutants, Chemical; Zinc

Previously, we reported that Wistar-Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced lethality and hepatotoxicity compared to Fischer 344 (F344) rats. Since the testes are one of the most sensitive organs to acute Cd toxicity, we examined possible strain-related differences in Cd-induced testicular toxicity between inbred WI and F344 rats. Rats were treated with a single dose of 0.5, 1.0 or 2.0 mg Cd/kg, as CdCl(2), sc and killed 24 h later. Cd at doses of 1.0 and 2.0 mg/kg induced severe testicular hemorrhage, as assessed by pathological and testis hemoglobin content, in F344 rats, but not WI rats. After Cd treatment (2.0 mg/kg), the testicular Cd content was significantly lower in WI rats than in the F344 rats, indicating a toxiokinetic mechanism for the observed strain difference. Thus, the remarkable resistance to Cd-induced testicular toxicity in WI rats is associated, at least in part, with lower testicular accumulation of Cd. When zinc (Zn; 10 mg/kg, sc) was administered in combination with Cd (2.0 mg/kg) to F344 rats, the Cd-induced increase in testicular hemoglobin content, indicative of hemorrhage, was significantly reduced. Similarly, the testicular Cd content was significantly decreased with Zn co-treatment compared to Cd treatment alone. Thus, it can be concluded that the testicular Cd accumulation partly competes with Zn transport systems and that these systems may play an important role in the strain-related differences in Cd-induced testicular toxicity between WI and F344 rats.

Topics: Animals; Cadmium; Cadmium Poisoning; Dose-Response Relationship, Drug; Drug Combinations; Hemoglobins; Kidney; Liver; Male; Metallothionein; Rats; Rats, Inbred F344; Rats, Wistar; Species Specificity; Spectrophotometry; Testis; Zinc

The biochemical mechanisms of Chlorella vulgaris protection against cadmium (Cd)-induced liver toxicity were investigated in male Sprague-Dawley rats (5 weeks of age, weighing 90-110 g). Forty rats were randomly divided into one control and three groups treated with 10 ppm Cd: one Cd without Chlorella (Cd-0C), one Cd with 5% Chlorella (Cd-5C), and one Cd with 10% Chlorella (Cd-10C) groups. The rats had free access to water and diet for 8 weeks. Body weight gain and relative liver weight were significantly lower in the Cd-0C group than in Cd-5C and Cd-10C groups. Rats in the Cd-0C group had significantly higher hepatic concentrations of Cd and metallothioneins (MTs) than in the Cd-5C or Cd-10C group. The hepatic MT I/II mRNA was expressed in all experimental rats. MT II was more expressed in the Cd-5C and Cd-10C groups than in the Cd-0C group. Morphologically, a higher level of congestion and vacuolation was observed in the livers of the Cd-0C group compared to those of the Cd-5C and Cd-10C groups. Therefore, this study suggests that C. vulgaris has a protective effect against Cd-induced liver damage by reducing Cd accumulation and stimulating the expression of MT II in liver. However, the details of the mechanism of C. vulgaris on liver toxicity remains to be clarified by further studies.

Topics: Animals; Body Weight; Cadmium; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Chlorella vulgaris; Dietary Supplements; Hepatocytes; Hyperemia; Liver; Liver Diseases; Male; Metallothionein; Organ Size; Powders; Rats

The present study was designed to evaluate whether treatment with quercetin exerts any beneficial effect on cadmium (Cd)-induced hepatotoxicity in order to establish the possible protective mechanisms of quercetin. Wistar rats were distributed in four experimental groups: control, Cd, quercetin, and Cd+quercetin. Hepatic toxicity was evaluated by measuring plasma concentrations of markers of hepatic injury. The activity of antioxidant enzymes in liver was also measured. Hepatic expression of metallothioneins (MT), and endothelial nitric oxide synthase (eNOS) was assayed by Western and Northern blot. Our results demonstrated that Cd administration induced an increased marker enzyme activity in plasma. This effect was not inhibited by quercetin. However, the administration of quercetin softened Cd-induced oxidative damage. MT levels in liver were substantially increased when the animals received Cd and quercetin. Hepatic eNOS expression was significantly increased after treatment with Cd and quercetin, being this increase higher than in animals receiving Cd alone. In conclusion, in this experimental model, quercetin was not able to prevent the Cd-induced liver damage although the animals that received both, Cd and quercetin showed a marked improvement in oxidative stress and an increase in the MT and eNOS expression. These results suggest that other mechanisms different to oxidative stress could be involved in hepatic damage.

Topics: Animals; Biomarkers; Blotting, Northern; Blotting, Western; Cadmium; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Liver; Liver Function Tests; Male; Metallothionein; Nitric Oxide Synthase Type III; Oxidative Stress; Quercetin; Rats; Rats, Wistar; RNA; Thiobarbituric Acid Reactive Substances

Cadmium (Cd), a widely distributed toxic trace metal, has been shown to accumulate in liver after long- and short-term exposure. Cd (2 mg/kg/day CdCl2) was intraperitoneally given to rats for eight days. Vitamin C (250 mg/kg/day) + vitamin E (250 mg/kg/day) + sodium selenate (0.25 mg/kg/day) were given to rats by oral means. The animals were treated by anti-oxidants one hour prior to treatment with Cd every day. The degenerative changes were observed in the groups given only Cd and anti-oxidants + Cd. Metallothionein (MT) immunoreactivity increased in cytoplasm of hepatocytes of the rats given Cd when compared with controls. In a number of cells with Cd and anti-oxidants treatment, immunoreactivity increase was more than in the group given Cd only and nuclear MT expression was also detected. Cell proliferation was assessed with proliferating cell nuclear antigen (PCNA) immunohistochemistry. PCNA expressions increased in all groups more than in the controls. Anti-oxidants treatment increased cell proliferation. In the animals administered with Cd, an increase in serum aspartate (AST) and alanine (ALT) aminotransferases, liver glutathione (GSH) and lipid peroxidation (LPO) levels were observed. On the other hand, in the rats treated with anti-oxidants and Cd, serum AST and ALT, liver glutathione and LPO levels decreased. As a result, these results suggest that combined anti-oxidants treatment might be useful in protection of liver against Cd toxicity.

Topics: Animals; Antioxidants; Ascorbic Acid; Cadmium; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Hepatocytes; Lipid Peroxidation; Liver Diseases; Male; Metallothionein; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Selenic Acid; Selenium Compounds; Vitamin E

In this study, the effects of combined antioxidants treatment against cadmium toxicity were investigated microscopically, immunohistochemically, and biochemically in small intestine of Sprague Dawley rats. The rats were subdivided into four groups as intact control, cadmium was administrated, and both control and cadmium groups treated with ascorbic acid, alpha-tocopherol, and selenium. Metallothionein expression was localized in the base of intestinal glands in control rats and similar expression was observed with antioxidants treatment. In cadmium-administrated rats, metallothionein expression was detected in surface epithelium, longitudinal muscle layer, meissner, and myenteric plexuses, but not in the base of intestinal gland. On the other hand, in the rats treated with antioxidants and cadmium, immunreactivity increased in the surface epithelium and in the base of intestinal glands according to cadmium-administrated rats but not changed in the plexuses and longitudinal muscle layer. Biochemically, lipid peroxidation levels increased and glutathione levels decreased significantly in intestine of the cadmium group compared to the control. Treatment with antioxidants in cadmium-administrated rats led to a decrease in lipid peroxidation levels and a significant increase in glutathione levels. As a result, the combination of ascorbic acid, alpha-tocopherol, and selenium shows a protective effect against cadmium toxicity in small intestine.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Cadmium; Cadmium Poisoning; Drug Synergism; Glutathione; Intestine, Small; Lipid Peroxidation; Male; Metallothionein; Random Allocation; Rats; Rats, Sprague-Dawley; Selenium

Ultrastructural changes in the kidneys of rats after acute cadmium exposure and the effects of exogenous metallothionein (MT) were studied by transmission electron microscopy. Thirty-six adult Wistar rats were divided into three groups. Cadmium chloride (CdCl2) (3.5 mg/kg/day) was injected subcutaneously in the first group. In the second group, 30 micromol/kg MT was administered in addition to CdCl2. Control rats received 0.5 ml subcutaneous saline solution. Four rats from each group were killed on days 1, 3, 5, and 7 after administration of the compounds. Kidney tissues were taken and fixed in 2.5% glutaraldehyde solution for electron microscopic observations. Tissue damage in kidney increased as time passed since the administration of CdCl2 in the first group. Degeneration in the proximal and distal tubules was observed. Increased apoptosis was seen in the proximal tubules epithelium, especially on day 7. Peritubular capillaries became dilated, there was degeneration of the endothelial cells, and the amount of intertubular collagen fibers was increased. On day 1, irregular microvilli in the proximal tubules, deepening of the basal striations, and myelin figures; on day 3, multiple vesicular mitochondria and regions of edema around tubules; on days 5 and 7, increased apoptotic cell in the proximal tubules and widened rough endoplasmic reticulum of the endothelial cells of glomerular capillaries were observed. We observed that the structural alterations that increased depending on the day of Cd administration decreased after exogenous MT administration, the dilation of the peritubular capillaries persisted, and there were degenerated proximal tubules. It was established that cadmium chloride was toxic for kidney cortex and caused structural damage. Exogenous MT partly prevents CdCl2-induced damage.

Topics: Animals; Apoptosis; Cadmium Chloride; Cadmium Poisoning; Kidney; Kidney Tubules, Proximal; Male; Metallothionein; Microscopy, Electron, Transmission; Rats; Rats, Wistar

The effects of cadmium (Cd) on gene expression were examined in four organs (gills, liver, skeletal muscles and brain) of the zebrafish. Adult male fish were subjected to three different water contamination pressures over periods of 7 and 21 days: control medium (C(0): no Cd added) and two contaminated media (C(1): 1.9 +/- 0.6 microg Cd l(-1), and C(2): 9.6 +/- 2.9 microg Cd l(-1)). Fourteen genes involved in antioxidant defences, metal chelation, active efflux of organic compounds, mitochondrial metabolism, DNA repair and apoptosis were selected and their expression levels investigated by quantitative real-time PCR. Cadmium concentrations were determined in the four organs and metallothionein (MT) protein levels investigated in brain, liver and gills. Although skeletal muscle was a poor Cd-accumulating tissue, many genes were up-regulated at day 7: mt1, cyt, bax, gadd and rad51 genes. Three additional genes, c-jun, pyc and tap, were up-regulated in muscles at day 21 whereas bax, gadd and rad51 had returned to basal levels. Surprisingly, mt1 and c-jun were the only genes displaying a differential induction after 21 days in liver, although this organ accumulated the highest cadmium concentration. In brain, only mt1, mt2 and c-jun genes were up-regulated after 21 days. In gills, the highest response was observed after 7 days, featuring the differential expression of oxidative stress-response hsp70 and mitochondrial sod genes, along with genes involved in mitochondrial metabolism and metal detoxification. Then, after 21 days, the expression of almost every genes returned to basal levels while both mt1 and mt2 genes were up-regulated.

Topics: Animals; Brain; Cadmium Poisoning; Gene Expression; Gills; Liver; Male; Metallothionein; Muscle, Skeletal; Up-Regulation; Zebrafish; Zebrafish Proteins

The present report is an attempt to investigate the influence of intraperitoneal and dietary cadmium exposure on the distribution of cadmium accumulation and induction of metallothionein gene expression in different tissues of the lizard Podarcis sicula. Cadmium accumulation in liver, kidney, ovary, brain and intestine was measured by atomic absorption spectrometry. Metallothionein gene induction was determined by dot blot analyses on the total RNA extracted from the same organs. Our data indicate that cadmium exposure results in significant cadmium uptake, but the patterns of this uptake varies with organ and exposure route. After a single intraperitoneal treatment, concentrations of cadmium and metallothionein transcript are positively correlated in kidney, liver and ovary. Following a dietary cadmium treatment, a positive correlation between the increase of metallothionein mRNA and cadmium accumulation is found in intestine, ovary and kidney, while no correlation is present in liver and brain.

Topics: Acute Disease; Animals; Cadmium; Cadmium Poisoning; Chronic Disease; Female; Gene Expression; In Situ Hybridization; Lizards; Metallothionein; RNA; Spectrophotometry, Atomic; Tissue Distribution

Good knowledge of the relationship between toxic metals and biological systems, particularly the sub-cellular fraction, could be a suitable early indicator of toxic effects. These effects and the sub-cellular behaviour of cadmium were studied with a widely used species in freshwater toxicity bioassays, Daphnia magna. In spite of this very commonplace usage in ecotoxicological studies, very few data are available on its toxicant metabolism and in particular metal homeostasis. Combining multi-tools analysis, a soluble protein was found: it is heat-stable, rich in sulfhydryl groups (differential pulse polarography), characterised by a molecular mass of approximately 6.5 kDa, with a G-75 chromatographic profile corresponding to the rabbit metallothioneins monomer, with few if any aromatic-containing amino acids, it binds metals (e.g. Cd, Cu), and its concentration increases with Cd exposure. This evidence led us to hypothesise that metallothioneins (MTs) are present in D. magna. Up to 75% of the Cd body burden with Cd exposure is bound to the MTs fraction. The increase in the Cd concentration in the surrounding medium and concomitantly in daphnids induces sub-cellular reorganisation of essential metals such as Cu and Zn. The rate of metals in the soluble cellular fraction and associated with MTs increases with the Cd body burden. Monitoring sub-cellular distribution of metals after exposure in the natural environment could be very useful for ecotoxicological assessment.

Topics: Animals; Cadmium; Cadmium Poisoning; Chromatography, Gel; Copper; Daphnia; Hot Temperature; Inactivation, Metabolic; Metallothionein; Metals; Molecular Weight; Subcellular Fractions; Sulfhydryl Compounds; Zinc

The present study was carried out to evaluate the effect of exogenously administered metallothionein (MT) to rats exposed to high cadmium levels. A total of 72 rats were used in the study. The animals were divided into three groups: controls, Cd administered, and Cd+MT. Cadmium was administered by subcutaneous injection of cadmium(II) chloride at a dose of 3.5 mg/kg for 7 d. In addition to CdCl2, 30 micromol/kg MT was administered to the second group of rats (group II). Control rats received 0.5 mL physiologic serum via subcutaneous injection. Eight rats from each group were sacrificed on the 1st, 3rd, 5th, and 7th day after administration of the compounds. Liver, kidney, and blood samples were harvested. Levels of malondialdehyde (MDA), glutathione peroxidase (GSH-Px), serum ALT, AST, BUN, ALP, creatinine, and urea were measured. MDA levels in group I were observed to increase starting from d 1 compared to group II (p<0.05). Although MDA levels in group II were higher than controls (p<0.05), they were lower, especially in liver and blood, compared to group II. Erythrocyte GSH-Px activity levels were determined to decrease starting from d 1 in both groups (p<0.05). Decreases in GSH-Px activity levels in group II were less than group I. Serum creatinine levels in both groups were increased significantly compared to controls (p<0.05); the increase in group I was higher than group II. Serum ALT, AST, and ALP levels in group I increased to very high levels compared to controls, whereas increases in group II were at moderate levels (p<0.05). Although serum BUN levels were determined to be reduced, there was no significant change among the groups. Serum urea levels in both groups were higher than controls. Based on our results, it is possible to postulate that exogenous MT can act as antioxidant against Cd toxicity and lipid peroxidation.

Topics: Alkaline Phosphatase; Animals; Blood Urea Nitrogen; Cadmium Poisoning; Creatinine; Erythrocytes; Glutathione Peroxidase; Kidney; Lipid Peroxidation; Liver; Male; Malondialdehyde; Metallothionein; Rats; Rats, Wistar; Superoxide Dismutase; Transaminases

Although Antarctica is a pristine environment, organisms are challenged with contaminants either released locally or transported from industrialized regions through atmospheric circulation and marine food webs. Organisms from Terra Nova Bay also are exposed to a natural enrichment of cadmium, but to our knowledge, whether such environmental conditions influence biological responses to anthropogenic pollutants has never been considered. In the present study, the Antarctic rock cod (Trematomus bernacchii) was exposed to model chemicals, including polycyclic aromatic hydrocarbons (benzo[a]pyrene), persistent organic pollutants (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]), cadmium, and a combination of cadmium and TCDD. Analyzed parameters included chemical bioaccumulation, activity, and levels of biotransformation enzymes (cytochrome P4501A); metallothioneins and the efficiency of the antioxidant system measured as individual defenses (catalase, glutathione, glutathione reductase, glutathione S-transferases, and glutathione peroxidases); and total scavenging capacity toward peroxyl and hydroxyl radicals. Reciprocal interactions between metabolism of inorganic and organic pollutants were demonstrated. Dioxin enhanced the accumulation of cadmium, probably stored within proliferating endoplasmic reticulum, and cadmium suppressed the inducibility of cytochrome P4501A, allowing us to hypothesize a posttranscriptional mechanism as the depletion of heme group availability. Clear evidence of oxidative perturbation was provided by the inhibition of antioxidants and enhanced sensitivity to oxyradical toxicity in fish exposed to organic chemicals. Exposure to cadmium revealed counteracting responses of glutathione metabolism; however, these responses did not prevent a certain loss of antioxidant capacity toward peroxyl radicals. The pattern of antioxidant responses exhibited by fish coexposed to cadmium and TCDD was more similar to that observed for cadmium than to that observed for TCDD. The overall results suggest that elevated natural levels of cadmium in Antarctic organisms from Terra Nova Bay can limit biotransformation capability of polycyclic (halogenated) hydrocarbons, thus influencing the bioaccumulation and biological effects of these chemicals in key sentinel species.

Topics: Animals; Antarctic Regions; Antioxidants; Benzo(a)pyrene; Cadmium; Cadmium Poisoning; Cytochrome P-450 Enzyme System; Drug Interactions; Environmental Monitoring; Fishes; Glutathione; Metallothionein; Oxidative Stress; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; Spectrophotometry, Atomic

Newborns are believed to have a higher gastrointestinal uptake of inorganic cadmium (Cd) than adults. However, relevant models for investigations of absorption of dietary Cd in neonates are lacking. In the present study, piglets were exposed to 2 or 20 microg Cd/kg body weight (b wt) per day by repeated oral administrations of CdCl2 dissolved in deionized water or infant follow-up formula from days 0 to 10. Elevated and dose-dependent Cd retention in blood and tissues resulted from this low-dose Cd exposure, as determined at day 11. Follow-up formula reduced Cd uptake in comparison to deionized water. However, Cd distribution to the kidneys was higher when Cd was given in formula than in water. Metallothionein (MT) levels in liver, kidney and duodenum were six, three and two times higher, respectively compared to an un-exposed control. Differences in bioavailability and distribution of low-dose Cd given in various diets to newborns could be detected by the proposed piglet model.

Topics: Animals; Animals, Newborn; Blotting, Western; Body Weight; Cadmium; Cadmium Poisoning; Digestive System; Duodenum; Feces; Ileum; Infant Formula; Iron; Kidney; Liver; Metallothionein; Models, Animal; Swine; Zinc

The effects of metal mixture (Cd+Cu) versus single-metal exposure on total MT response and bioaccumulation were investigated in the freshwater bivalve Dreissena polymorpha. A two-month exposure period, including two levels of contamination, was chosen for each of the two metals: 5, 10 microg/L for Cu, and 2, 20 microg/L for Cd, with mixtures of, respectively, 5 microg/L Cu+2 microg/L Cd, 5 microg/L Cu+20 microg/L Cd, 10 microg/L Cu+2 microg/L Cd, and 10 microg/L Cu+20 microg/L Cd. Total MT contents were assessed by an Ag-saturation method, and metals contents were determined by atomic absorption spectrometry. Results at the whole-organism level showed a significant and early increase of total MT biosynthesis after exposure to Cd. This increase was significantly correlated with Cd bioaccumulation. By contrast, Cu did not modify total MT response, and mussels limited Cu bioaccumulation. The mixture either did not influence or only weakly influenced metal accumulation and MT response to Cu and Cd after long-term exposure. Our results suggest that the form of MT existing in D. polymorpha was not Cu-inducible. This could limit the use of MT in D. polymorpha as a biomarker of heavy metal pollution in freshwater ecosystems.

Topics: Animals; Biomarkers; Bivalvia; Cadmium; Cadmium Poisoning; Copper; Drug Interactions; Environmental Exposure; Metallothionein; Tissue Distribution; Water Pollutants

Selected toxic and essential metals (mercury, Hg; cadmium, Cd; and zinc, Zn) were determined in the liver and in the kidney collected from 13 dolphins (Stenella coeruleoalba and Tursiops truncatus) stranded along the southern coasts of Italy from 1991 to 1999. Liver samples were also analysed for their methyl mercury (MeHg) and selenium (Se) contents. For subcellular fractionation, liver and kidney samples were homogenized in Tris-HCl buffer; after centrifugation, the supernatant (cytosol) was separated from pellets (insoluble fraction), heated at 80 degrees C for 10 min and centrifuged in order to separate the precipitate containing the thermolabile high molecular weight proteins. The cytosol heat-stable fraction, including metallothionein-like proteins (MTLPs), was then purified by gel filtration chromatography on Sephadex G-75 column. The three subcellular fractions collected (insoluble fraction, thermolabile fraction and purified heat-stable fraction) were analysed for their Hg, Cd and Zn contents. The analytical results confirm previous similar studies on toothed whales in showing that: (1) in the liver, as well as in the kidney, Hg was mainly found in the insoluble fraction, therefore, metallothioneins seem to have no role in the Hg detoxification; (2) in the liver, the molar ratio between Se and inorganic Hg was very close to 1; this suggests that the final compound of MeHg detoxification could be HgSe (tiemannite); (3) in almost all the samples, Cd and Zn were detected in the purified heat-stable fraction (including MTLPs). The mechanism of Cd detoxification and Zn homeostasis is also discussed.

Topics: Animals; Cadmium; Cadmium Poisoning; Dolphins; Female; Homeostasis; Kidney; Liver; Male; Mercury; Mercury Poisoning; Metallothionein; Mortality; Tissue Distribution; Zinc

We previously reported that Wistar-Imamichi (WI) rats have a strong resistance to cadmium (Cd)-induced lethality compared to other strains such as Fischer 344 (Fischer) rats. The present study was designed to establish biochemical and histological differences in Cd toxicity in WI and Fischer rats, and to clarify the mechanistic basis of these strain differences. A single Cd (4.5 mg/kg, s.c.) treatment caused a significant increase in serum alanine aminotransferase activity, indicative of hepatotoxicity, in Fischer rats, but did not in WI rats. This difference in hepatotoxic response to Cd was supported by pathological analysis. After treatment with Cd at doses of 3.0, 3.5 and 4.5 mg/kg, the hepatic and renal accumulation of Cd was significantly lower in the WI rats than in the Fischer rats, indicating a kinetic mechanism for the observed strain differences in Cd toxicity. Thus, the remarkable resistance to Cd-induced hepatotoxicity in WI rats is associated, at least in part, with a lower tissue accumulation of the metal. Hepatic and renal zinc (Zn) contents after administration were similarly lower in WI than in Fischer rats. When Zn was administered in combination with Cd to Fischer rats, it decreased Cd contents in the liver and kidney, and exhibited a significant protective effect against the toxicity of Cd. We propose the possibility that Zn transporter plays an important role in the strain difference of Cd toxicity in WI and Fischer rats.

Topics: Alanine Transaminase; Animals; Blood Urea Nitrogen; Cadmium; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Iron; Kidney; Liver; Male; Metallothionein; Rats; Rats, Inbred F344; Rats, Wistar; Species Specificity; Zinc

Cadmium chloride (CdCl(2)) is a nephrotoxicant that causes damage to the proximal tubular epithelium. In vivo, it increases the permeability of epithelial surfaces, while in vitro, it acts on active trans-epithelial ion transport. The purpose of this study was to investigate CdCl(2) effects on a porcine renal proximal tubular epithelial cell line (LLC-PK1), and, in particular, to identify sensitive endpoints revealing damage both at the epithelial barrier level and at the molecular level. After exposure of the cells to CdCl(2), trans-epithelial resistance (TER) decreased while paracellular permeability (PCP) increased, indicating a structural alteration of the junctional complex. At the molecular level, we observed an increase in protective proteins, such as metallothioneins (MTs) and heat shock proteins (HSP70), starting from 25 microM CdCl(2), together with alterations in cytoskeleton organization. Production of reactive oxygen species (ROS) was also evident, indicating cellular oxidative stress. Our data indicate that CdCl(2) toxicity can be detected at the barrier level and at the molecular level at low concentrations, at which cytotoxicity assays are unable to show any damage. Therefore, these endpoints should prove very useful in studying heavy metal-induced acute toxicity. Exposure of the cells to higher concentrations of CdCl(2) (50 microM) revealed the initiation of apoptosis, mediated by caspase-3.

Topics: Acute Disease; Animals; Apoptosis; Biological Transport; Blotting, Western; Cadmium Chloride; Cadmium Poisoning; Cell Survival; Epithelial Cells; Flow Cytometry; HSP70 Heat-Shock Proteins; Immunohistochemistry; Kidney Diseases; Kidney Tubules, Proximal; L-Lactate Dehydrogenase; LLC-PK1 Cells; Metallothionein; Reactive Oxygen Species; Swine

In an attempt to establish a primate model of chronic cadmium (Cd) toxicosis, we ovariectomized cynomolgus monkeys and treated with CdCl2 by repeated intravenous injections for 13 to 15 months. The animals showed an increase in blood glucose from Month 10 and a decrease in blood insulin at Month 11of the Cd-treatment. Histopathological examination of the Cd-treated animals revealed islet atrophy with reduction in islet number and vacuolation of the islet cells, whereas there was no remarkable change in the acinar cells of the exocrine pancreas. In histomorphometrical examination, insulin-positive areas in the islets were significantly decreased, accompanying a relative increase of glucagon-positive areas. Large amounts of Cd accumulated in the pancreas, and metallothionein (MT), a Cd binding protein, was localized in the islets of Cd-treated animals. The present study demonstrated that the chronic intravenous injection of Cd to cynomolgus monkeys induced the accumulation of the metal in the pancreas, degeneration of islet B cells and the diabetic clinical signs. Therefore the islet B cell is one of the major targets of the chronic Cd poisoning in monkeys.

Topics: Animals; Blood Glucose; Cadmium; Cadmium Poisoning; Disease Models, Animal; Female; Glucagon; Insulin; Islets of Langerhans; Macaca fascicularis; Metallothionein; Monkey Diseases; Ovariectomy; Random Allocation

A number of reports document that Fischer 344 (F344) rats are more susceptible to chemically induced liver injury than Sprague-Dawley (SD) rats. Cadmium (CdCl2), a hepatotoxicant that does not require bioactivation, was used to better define the biological events that are responsible for the differences in liver injury between F344 and SD rats. CdCl2 (3 mg/kg) produced hepatotoxicity in both rat strains, but the hepatic injury was 18-fold greater in F344 rats as assessed by plasma alanine aminotransferase (ALT) activity. This difference in toxicity was not observed when isolated hepatocytes were incubated with CdCl2 in vitro, indicating that other cell types contribute to Cd-induced hepatotoxicity in vivo. Indeed, the sieve plates of hepatic endothelial cells (EC) in F344 rats were damaged to a greater degree than EC in SD rats. Additionally, Kupffer cell (KC) inhibition reduced hepatotoxicity in both strains, suggesting that this cell type is involved in the progression of CdCl2-induced hepatotoxicity. Moreover, enhanced synthesis of heat shock protein 72 occurred earlier in the SD rat. Maximal levels of hepatic metallothionein (MT), a protein associated with cadmium tolerance, were greater in SD rats. These protective factors may limit CdCl2-induced hepatocellular injury in SD compared with F344 rats by reducing KC activation and the subsequent inflammatory response that allows for the progression of hepatic injury.

Topics: Alanine Transaminase; Animals; Cadmium Chloride; Cadmium Poisoning; Dose-Response Relationship, Drug; Endothelium; Heat-Shock Proteins; Hepatocytes; HSP72 Heat-Shock Proteins; Kupffer Cells; Liver; Male; Metallothionein; Microscopy, Electron; Microscopy, Electron, Scanning; Rats; Rats, Inbred F344; Rats, Sprague-Dawley

Cadmium concentrations, (Cd,Zn)-metallothionein (MT) concentrations, MT synthesis and the relative amounts of cadmium bound to (Cd,Zn)-MTs were determined in gills, liver and kidney of common carp Cyprinus carpio exposed to 0, 0.5 microM (0.06 mg.l(-1)), 2.5 microM (0.28 mg.l(-1)) and 7 microM (0.79 mg.l(-1)) Cd for up to 29 days. Cadmium accumulation was in the order kidney > liver > gills. Control levels of hepatic (Cd,Zn)-MT were four times higher compared to those of gills and kidney. No increases in (Cd,Zn)-MT concentrations were observed in liver during the exposure period. In comparison with control carp, (Cd,Zn)-MT concentrations increased up to 4.5 times in kidney and two times in gills. In both these organs, (Cd,Zn)-MT concentrations were linearly related with cadmium tissue levels and with the de novo synthesis of MTs. Hepatic cadmium was almost completely bound to (Cd,Zn)-MT, while percentages of non-MT-bound cadmium were at least 40% in gills and 25% in kidney. This corresponded with a total saturation of (Cd,Zn)-MT by cadmium in kidney and a saturation of approximately 50 and 60% in gills and liver, respectively. The final order of non-MT-bound cadmium was kidney > gills > liver. Our results indicate that cadmium exposure causes toxic effects, which cannot be correlated with the accumulated levels of the metal in tissues. Although cadmium clearly leads to the de novo synthesis of MT and higher (Cd,Zn)-MT concentrations, the role of this protein in the detoxification process is clearly organ-specific and its synthesis does not keep track with cadmium accumulation.

Topics: Animals; Cadmium Poisoning; Carps; Fish Diseases; Gills; Kidney; Liver; Metallothionein; Time Factors; Tissue Distribution

It is reported repeatedly that severe hepatocellular necrosis along with infiltration of neutrophils occurs after acute cadmium exposure. Neutrophils, which migrate by the gradient of chemoattractants such as interleukin-8, are believed to play an important role in inflammation at the damaged sites. To investigate whether neutrophils aggravate or repair the liver injury induced by cadmium, we checked the hepatotoxic effects of cadmium on human interleukin-8 transgenic mice (hIL-8Tg), which overexpressed IL-8 and displayed an inability of neutrophil migration resulting from both the lack of chemotactic gradient and the downregulation of l-selectin on the surface of neutrophils. A significantly lower survival rate was observed in hIL-8Tg compared with wild-type mice after subcutaneous administration of cadmium. Evident liver injury characterized by abrupt increases in plasma GOT and GPT levels was found in hIL-8Tg at 18 h after cadmium administration. Histological examinations, including H & E staining and esterase staining, revealed the infiltration of numerous neutrophils into the damaged liver tissues in wild-type mice, and the inhibition of the neutrophil migration into the liver as well as enhanced hepatocellular necrosis in hIL-8Tg. Peripheral white blood cell and polymorphonuclear cell counts increased and reached their peaks at 12 h after cadmium administration in wild-type mice, whereas the increase in blood leukocyte counts was delayed in hIL-8Tg. There was no significant difference in the amounts of cadmium accumulated in liver and kidneys between wild-type mice and hIL-8Tg. In conclusion, an acute cadmium hepatotoxic effect was exacerbated in hIL-8Tg resulting from inhibited neutrophil migration, suggesting that migrated neutrophils can prevent aggravation of liver injury by acute cadmium administration.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cadmium; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Humans; Interleukin-8; Kidney; Leukocyte Count; Liver; Male; Metallothionein; Mice; Mice, Inbred BALB C; Mice, Transgenic; Neutrophil Infiltration; Reverse Transcriptase Polymerase Chain Reaction; Selectins; Survival Analysis

Liver is a major target organ of cadmium (Cd) toxicity following acute and chronic exposure. Metallothionein (MT), a low-molecular-weight, cysteine-rich, metal-binding protein has been shown to play an important role in protection against acute Cd-induced liver injury. This study investigates the role of MT in liver injury induced by repeated exposure to Cd. Wild-type and MT-I/II knockout (MT I/II-null) mice were injected sc with a wide range of CdCl(2) doses, 6 times/week, for up to 10 weeks, and their hepatic Cd content, hepatic MT concentration, and liver injury were examined. Repeated administration of CdCl(2) produced acute and nonspecific chronic inflammation in the parenchyma and portal tracts and around central veins. Higher doses produced granulomatous inflammation and proliferating nodules in liver parenchyma. Apoptosis and mitosis occurred concomitantly in liver following repeated Cd exposure, whereas necrosis was mild. As a result, significant elevation of serum enzyme levels was not observed. In wild-type mice, hepatic Cd concentration increased in a dose- and time-dependent manner, reaching 400 microgram/g liver, along with 150-fold increases in hepatic MT concentrations, the latter reaching 1200 microgram/g liver. In contrast, in MT I/II-null mice, hepatic Cd concentrations were about 10 microgram/g liver. Despite the lower accumulation of Cd in livers of MT I/II-null mice, the maximum tolerated dose of Cd was one-eighth lower than that for wild-type mice at 10 weeks, and liver injury was more pronounced in the MT I/II-null mice, as evidenced by increases in liver/body weight ratios and histopathological analyses. In conclusion, these data indicate that (1) nonspecific chronic inflammation, granulomatous inflammation, apoptosis, liver cell regeneration, and presumably, preneoplastic proliferating nodules are major features of liver injury induced by repeated Cd exposure, and (2) intracellular MT is an important protein protecting against this Cd-induced liver injury.

Topics: Animals; Apoptosis; Cadmium; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Cytosol; In Situ Nick-End Labeling; Liver; Metallothionein; Mice; Mice, Knockout; Tissue Distribution

Here we describe targeting of the mouse metallothionein I (MT) protein to the cell surface of the heavy metal-tolerant Ralstonia eutropha (formerly Alcaligenes eutrophus) CH34 strain, which is adapted to thrive in soils highly polluted with metal ions. DNA sequences encoding MT were fused to the autotransporter beta-domain of the IgA protease of Neisseria gonorrhoeae, which targeted the hybrid protein toward the bacterial outer membrane. The translocation, surface display, and functionality of the chimeric MTbeta protein was initially demonstrated in Escherichia coli before the transfer of its encoding gene (mtb) to R. eutropha. The resulting bacterial strain, named R. eutropha MTB, was found to have an enhanced ability for immobilizing Cd2+ ions from the external media. Furthermore, the inoculation of Cd2+-polluted soil with R. eutropha MTB decreased significantly the toxic effects of the heavy metal on the growth of tobacco plants (Nicotiana bentamiana).

Topics: Animals; Bacterial Adhesion; Bacterial Outer Membrane Proteins; Cadmium; Cadmium Poisoning; Cell Division; Cupriavidus necator; DNA; Escherichia coli; Gene Transfer Techniques; Industrial Waste; Metallothionein; Metals, Heavy; Mice; Neisseria gonorrhoeae; Nicotiana; Plants, Toxic; Protein Engineering; Serine Endopeptidases; Soil Microbiology; Soil Pollutants

This study examined the effects of simultaneous exposure to saline and cadmium (Cd) on organ mass and histology of a bird with salt glands, the Pekin duck, Anas platyrhynchos. Three mixed-sex groups, each containing 6 birds, ate duck pellets containing 0, 50, or 300 microg Cd/g, respectively, for 4 1/2 mo and drank 300 mM NaCl. Only females on the high-Cd diet lost body mass. Ingestion of Cd reduced heart mass in females. There was increased mass of Harderian and salt glands in both sexes. Mass of kidneys and liver increased only in males, and the gut mass (also length) increased more in males. Cadmium ingestion also induced (1) inflammation of renal interstitium and degenerative tubular changes, (2) marked degenerative changes in testes, (3) increased heart water content, (4) decreased cytoplasmic volume of liver cells, (5) reduced proportion of basophilic granular cells in chromaffin tissue of the adrenal glands, and (6) in the ileum, increased heterophilia in the lamina propria and, only in females, the apoptosis to mitosis ratio in crypt cells of the epithelium. The ducks' outward appearance gave no indication that ingesting large amounts of cadmium for 4 1/2 mo produced deleterious effects, but the physiological consequences were profound. Both sexes had greatly reduced gonadal mass and the males produced no sperm. The higher dietary level greatly hypertrophied the liver, kidneys, and gut only in males. The cadmium-induced changes in organs, particularly in the gonads, kidneys, and adrenal glands, should greatly impair the health and reproductive capacity of these ducks.

Topics: Animals; Bird Diseases; Body Weight; Cadmium; Cadmium Poisoning; Digestive System; Ducks; Eating; Female; Male; Metallothionein; Organ Size; Salt Gland; Sodium Chloride; Water-Electrolyte Balance

Metallothionein (MT) is known to play a predominant role in the protection of cells from cadmium (Cd) toxicity. To investigate other factors involved in Cd resistance, we established Cd-resistant cell lines from simian virus 40-transformed MT null fibroblasts. Cd-resistant MT null cells, Cd-rA7 and Cd-rB5, developed approximately 10-fold resistance to Cd compared to parental cells, but showed no cross-resistance to Zn, Cu, Hg, Ni, As, cisplatin or H2O2. Accumulation of Cd in the resistant cells was 13-18% of that of parental cells after treatment with Cd for 24 h. A short-term experiment revealed that the rate of Cd incorporation into the Cd-resistant cells was suppressed, and the rate of Cd release was enhanced in the resistant cells compared with that of parental cells. These results indicate that the altered transport of Cd, slow uptake and rapid release, may confer resistance to Cd on the Cd-resistant cells established from MT null fibroblasts.

Topics: Animals; Cadmium; Cadmium Poisoning; Cell Line, Transformed; Cell Survival; Cytoprotection; Drug Resistance; Fibroblasts; Metallothionein; Mice

Thiamin or methionine supplementation was equally and moderately effective in preventing the accumulation of cadmium in soft organs and alterations in a few selected biochemical indices during concomitant administration. Adequate intake of sulfur amino acid following methionine supplementation might increase the bioavailability of glutathione, facilitating the prevention of the binding of cadmium to different compartments and consequently reversing cadmium-induced biochemical disorders. In the case of thiamine the possibility of formation of a readily excretable complex between cadmium and thiamine or an increase in the body's resistance to cadmium might be the beneficial factor.

Topics: Absorption; Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Cadmium; Cadmium Poisoning; Drug Interactions; gamma-Glutamyltransferase; Kidney; Liver; Male; Metallothionein; Methionine; Rats; Rats, Wistar; Thiamine

Previous work has indicated that testosterone pretreatment protects against cadmium-induced toxicity in male rats while other data indicate that pretreatment of mice with testosterone offers no such protection against cadmium. Since cadmium toxicity may vary widely with species and strain, we examined the effect of testosterone pretreatment on cadmium toxicity in two strains of mice, one that is sensitive (C3H) and one that is resistant (C57) to cadmium toxicity. A single sc injection of 20 micromol CdCl2/kg to C3H mice or 45 micromol CdCl2/kg to C57 mice proved very toxic, causing 50%, and 44% mortalities, respectively. However, when C57 mice were pretreated with testosterone (5 mg/kg, s.c., at - 48, - 24, and 0 h) prior to cadmium (45 micromol/kg), complete resistance to cadmium-induced lethality developed. Testosterone had no effect on cadmium-induced lethality in C3H mice. Testosterone prevented extensive hepatocellular damage caused by cadmium in C57 mice and also significantly reduced cadmium-induced elevations in serum lactate dehydrogenase (LDH) activity and blood urea nitrogen (BUN), which are indicators of hepatic and renal function, respectively. The toxicokinetics of cadmium were apparently not affected by testosterone pretreatment, as the distribution of cadmium to liver in either strain was unchanged by the steroid. Cadmium-induced metallothionein (MT) levels in liver and kidney of C57 mice were increased in testosterone-pretreated mice given the higher doses of metal but no such enhancement of MT synthesis occurred in C3H mice. This increase in MT may provide some level of protection against cadmium toxicity in the C57 mice. These results indicate that testosterone pretreatment prevents toxicity of cadmium in male C57 mice, possibly through enhancement of MT synthesis, but has no effect in male C3H mice.

Topics: Animals; Antidotes; Cadmium; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Kidney; L-Lactate Dehydrogenase; Liver; Liver Diseases; Male; Metallothionein; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Species Specificity; Testosterone; Urea

Cadmium (Cd) chloride was intravenously injected at doses of 0.05 and 0.5 mg/kg/day in ovariectomized rats for 50 weeks, and the chronic Cd exposure-induced nephrotoxicity and anemia were investigated. The rats treated with 0.05 mg/kg Cd showed no apparent hematological, urinary, and histopathological abnormalities. In the 0.5-mg/kg group, renal tubular disorders became marked at 16 weeks, and cortical fibrosis with glomerular dysfunction appeared at 50 weeks. Anemia occurred at 12 weeks in the 0.5-mg/kg group and became increasingly marked with time. The mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were decreased at 12 and 25 weeks; however, the decreases of MCV and MCH disappeared at 50 weeks. A slight decrease in mean corpuscular hemoglobin concentration was noted at 50 weeks. The blood chemistry from the same group revealed a decrease in plasma iron levels and an increase in total iron binding capacity throughout the administration period. The erythropoietin (EPO) level was increased as the hemoglobin level decreased at 12 weeks, whereas the EPO level was not elevated even when the hemoglobin level was decreased at 50 weeks. These findings showed that renal anemia also occurred in addition to the iron deficiency anemia at 50 weeks.

Topics: Anemia; Animals; Body Weight; Cadmium; Cadmium Poisoning; Drinking; Erythropoietin; Female; Ferritins; Hemoglobins; Injections, Intravenous; Kidney; Kidney Diseases; Liver; Metallothionein; Ovariectomy; Rats; Rats, Sprague-Dawley; Urine

This study examined the expression of metallothionein (MT) isoforms in the lungs of Lewis rats exposed to Cadmium (Cd) aerosols. With the use of isoform-specific oligonucleotide probes and Northern hybridization analysis, we demonstrated that a dramatic, rapid, and coordinate increase occurred in pulmonary MT-1 mRNA and MT-2 mRNA following Cd inhalation exposure. MT mRNAs levels reached a maximum at 2 h post-exposure and remained above control levels at 96 h after exposure. A considerable lag between the time of maximal elevations in MT mRNAs and MT protein accumulation was observed and suggested that regulatory mechanisms in addition to transcriptional control could be involved. MT expression (protein and mRNA) and Cd lung burden were directly related to aerosol Cd concentration. In situ hybridization and immunohistochemistry studies showed good correlation between the localization of MT protein and MT mRNAs. However, staining for MT protein and MT mRNA was not uniformly distributed in the lung. MT was particularly prominent within the alveolar compartment. Even within this area, however, heterogeneity of MT expression was evident. Experiments were subsequently conducted to determine whether prior exposure to Cd modulates the transcriptional activity of MT genes such that there is a greater elevation in gene expression upon reexposure to Cd. Surprisingly, animals pretreated with Cd exhibited a smaller incremental increase in MT mRNA levels in response to subsequent Cd exposure than controls with no prior treatment. Moreover, MT mRNA levels were elevated to a similar extent regardless of whether animals were exposed to Cd aerosols for 1, 2, or 3 weeks (3 h/day; 5 days/week). MT protein and lung Cd burden, on the other hand, exhibited an increasing linear trend as a function of exposure number. In summary, this study has demonstrated that: (1) the lung responds to Cd inhalation exposure by increasing MT mRNA and MT protein levels; (2) MT expression is prominent within alveolar cells but not all cells are MT positive; and (3) Cd-pretreatment does not increase the transcriptional potential of MT genes when the animal is subsequently reexposed to Cd.

Topics: Administration, Inhalation; Aerosols; Animals; Blotting, Northern; Blotting, Southern; Cadmium; Cadmium Poisoning; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Gene Expression Regulation; Immunohistochemistry; In Situ Hybridization; Lung; Male; Metallothionein; Oligonucleotide Probes; Pulmonary Alveoli; Rats; Rats, Inbred Lew; RNA, Messenger; Stereoisomerism; Transcription, Genetic

Topics: Analysis of Variance; Animals; Aspartate Aminotransferases; Cadmium; Cadmium Poisoning; Copper; Injections, Subcutaneous; Liver; Liver Function Tests; Male; Metallothionein; Mice; Mice, Inbred ICR; Random Allocation; Specific Pathogen-Free Organisms; Testis; Thiobarbituric Acid Reactive Substances; Zinc

Topics: Animals; Cadmium Poisoning; Cell Line; Cloning, Molecular; Fish Diseases; Fishes; Gene Deletion; Metallothionein; Metals; Transfection; Water Pollutants, Chemical

Metallothionein is a low molecular mass protein inducible mainly by heavy metals, having high affinity for binding cadmium, zinc and copper. In the present study we investigated the expression of metallothionein in regenerating liver, at different time intervals, in cadmium pretreated partially hepatectomized rats. Liver metallothionein is highly expressed during regeneration induced by partial hepatectomy in rats, providing zinc within the rapidly growing tissue. Cadmium pretreatment caused inhibition of the first peak of liver regeneration, while metallothionein expression was markedly more prominent in the liver residues of cadmium-pretreated rats. These results demonstrate that although metallothionein able to bind temporarily metal ions as zinc and cadmium has been highly expressed, the liver regenerative process was inhibited possibly due to the effects of cadmium on other pivotal events necessary to the DNA replication.

Topics: Animals; Cadmium; Cadmium Chloride; Cadmium Poisoning; Chlorides; Disease Models, Animal; DNA; Hepatectomy; Immunohistochemistry; Linear Models; Liver; Liver Regeneration; Male; Metallothionein; Protein Binding; Rats; Rats, Wistar; Spectrophotometry, Atomic; Thymidine Kinase; Zinc

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Binding, Competitive; Cadmium; Cadmium Poisoning; Chromatography, Gel; Environmental Exposure; Female; Humans; Kidney Cortex; Kidney Medulla; Liver; Male; Metallothionein; Middle Aged; Reference Values; Spain

We inactivated the mouse metallothionein (MT)-I and MT-II genes in embryonic stem cells and generated mice homozygous for these mutant alleles. These mice were viable and reproduced normally when reared under normal laboratory conditions. They were, however, more susceptible to hepatic poisoning by cadmium. This proves that these widely expressed MTs are not essential for development but that they do protect against cadmium toxicity. These mice provide a means for testing other proposed functions of MT in vivo.

Topics: Alanine Transaminase; Alleles; Amino Acid Sequence; Animals; Aspartate Aminotransferases; Base Sequence; Cadmium Poisoning; DNA; Female; Liver; Male; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; Mutagenesis, Insertional; Protein Biosynthesis; Transcription, Genetic

Some studies have indicated that cadmium-induced lethality and selective injurious effects to specific tissues, such as testes or liver, can be prevented by pretreatment with the antioxidant L-ascorbic acid (ascorbic acid). However, the basis of this tolerance is unclear. We examined the effects of ascorbic acid pretreatment on cadmium toxicity in male Fischer (F344/NCr) rats. Cadmium treatment alone (25 mumol CdCl2/kg, s.c.) proved lethal, causing a 93% mortality within 72 h, but in rats pretreated with ascorbic acid (2 g/kg, s.c. 24, 12 and 1 h) cadmium-induced lethality was nearly prevented. Hepatic lesions, including hepatocellular necrosis, induced by cadmium were at least partially ameliorated by ascorbic acid pretreatment. Ascorbic acid pretreatment had no effect on cadmium-induced testicular lesions nor on cadmium content in testes, liver, kidney and urine. Ascorbic acid alone modestly increased hepatic metallothionein (MT), but not renal MT and had no effect on induction of hepatic or renal MT by cadmium. In contrast to liver and kidney, testicular cadmium-binding protein (TCBP) in rats exposed to cadmium alone decreased markedly. Moreover, the level of TCBP decreased unexpectedly in ascorbic acid pretreated rats as compared with control. These results indicate that ascorbic acid pretreatment decreases the toxicity of cadmium in the rat without markedly modifying its toxicokinetics or markedly stimulating MT synthesis.

Topics: Animals; Ascorbic Acid; Base Sequence; Cadmium Poisoning; Kidney; L-Lactate Dehydrogenase; Liver; Male; Metallothionein; Molecular Sequence Data; Oligonucleotide Probes; Rats; Rats, Inbred F344; RNA, Messenger; Testis; Tissue Distribution

The dose-response relationship for environmental cadmium exposure was assessed using logistic regression analysis. The prevalence of metallothioneinuria was employed as a response variable, while age and total cadmium intake, calculated from the average cadmium concentration in rice and duration of residence in the cadmium-polluted area, were used as explanatory variables. The target population comprised of 1843 cadmium-exposed and 240 non-exposed inhabitants of Ishikawa, Japan. The individuals were divided into 96 subgroups by sex, age (4 categories), cadmium concentrations in rice (3 categories) and length of residence in the polluted area (4 categories). Only total cadmium intake had a significant association with the prevalence of metallothioneinuria. In the non-exposed subjects total cadmium intakes corresponding to 2.5% prevalence of metallothioneinuria were calculated. Based on metallothionein levels expressed as either microgram/l urine or microgram/g creatinine, the total intakes were: 2.221 or 2.207 g in men and 2.365 or 0.319 g in women, respectively. Most of these values were similar to those reported by us previously, employing simple regression analysis. It is concluded, therefore, that a maximum allowable intake of about 2 g cadmium is a reasonable estimate for preventing the cadmium-induced renal dysfunction.

Topics: Age Factors; Aged; Aged, 80 and over; Cadmium; Cadmium Poisoning; Dose-Response Relationship, Drug; Female; Food Contamination; Humans; Male; Metallothionein; Middle Aged; Oryza; Regression Analysis

The influence of dietary iron deficiency on acute nickel, lead or cadmium toxicity as reflected by the induction of hepatic, renal and intestinal metallothionein (MT), disposition of the metals, and alterations in hematological parameters was investigated in rats. The administration of cadmium induced the hepatic, renal and intestinal MT while that of nickel or lead induced hepatic MT only. However, dietary iron deficiency did not influence the cadmium induced tissue MT but enhanced the ability of nickel or lead to restore the normal synthesis of renal and intestinal MT lowered under the influence of reduced body iron status. The accumulation of lead in liver and kidney and that of cadmium enhanced in liver only, while tissue deposition of nickel remained unaffected by iron deficiency. The induction of hepatic MT by three metals appears related to the concomitant rise in the hepatic zinc, calcium and iron levels in normal rats. However, dietary iron deficiency increased the hepatic zinc in response to nickel or cadmium and that of heptic calcium in response to lead.

Topics: Animals; Cadmium; Cadmium Poisoning; Diet; Intestinal Mucosa; Intestines; Iron Deficiencies; Kidney; Lead; Lead Poisoning; Liver; Male; Metallothionein; Nickel; Rats; Rats, Inbred Strains; Trace Elements

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

Topics: Animals; Cadmium; Cadmium Poisoning; Injections, Subcutaneous; Male; Metallothionein; Rats; Rats, Wistar; Selenium; Tissue Distribution

Two epidemiological studies aimed at investigating the dose-response relationship of environmental cadmium exposure were performed in a population living in the Kakehashi River basin, a cadmium-polluted area in Japan. In the first, the average cadmium concentration in rice from each village was used as an indicator of exposure and metallothioneinuria or beta 2-microglobulinuria as an index of renal tubular dysfunction. Dose-related increases in both the latter indices were observed. The total cadmium intake resulting in both metallothioneinuria and beta 2-microglobulinuria was calculated to be approximately 2 g for both sexes. In the second study, the dose-response relationship between urinary cadmium and metallothioneinuria or beta 2-microglobulinuria was evaluated in the same population. Prevalence rates increased proportionally with increasing urinary cadmium (Cd-U). The values of Cd-U corresponding to the prevalence rates of metallothioneinuria in the non-exposed population were calculated to be 4.2 micrograms/g creatinine for men and 4.8 micrograms/g creatinine for women; for beta 2-microglobulinuria the corresponding figures were 3.8 micrograms/g creatinine for men and 4.1 micrograms/g creatinine for women.

Topics: Aged; beta 2-Microglobulin; Cadmium; Cadmium Poisoning; Dose-Response Relationship, Drug; Female; Food Contamination; Humans; Japan; Kidney Diseases; Kidney Tubules; Male; Maximum Allowable Concentration; Metallothionein; Middle Aged; Oryza

Fulvotomentosides (Ful) is the total saponins of Lonicera fulvotomentosa. In the present study, we examined the effects of Ful on cadmium (CdCl2)-induced acute liver injury in mice. Ful pretreatment (150 mg.kg-1, sc x 3 d) remarkably decreased CdCl2 (3.7 mg Cd.kg-1, iv)-induced liver damage as indicated by serum activities of alanine aminotransferase and sorbitol dehydrogenase. Distribution of Cd to 12 organs and hepatic subcellular fractions was determined 2 h after Cd challenge. Ful pretreatment did not produce a marked shift in the distribution of Cd to various organs, but markedly altered the hepatic subcellular distribution of Cd, with more Cd bound to metallothionein (MT) in the cytosol, less in the nuclear, mitochondrial, and microsomal fractions. Ful pretreatment produced a dose-dependent increase in hepatic MT as determined by the Cd.hemoglobin assay. In conclusion, Ful protected against Cd hepatotoxicity by inducing MT, which binds Cd in the cytosol and lowers the amount of Cd available to other critical organelles and proteins.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Liver; Male; Metallothionein; Mice; Oleanolic Acid; Saponins; Tissue Distribution

It is well established that zinc can decrease the carcinogenicity and toxicity of cadmium. In some tissues this may be due to the induction of metallothionein (MT). Therefore, in the present investigation, the effect of zinc pretreatment on cadmium-induced DNA strand damage was determined. The alkaline elution technique was used to assess DNA single strand damage (SSD) in cultured cells derived from rat hepatocytes (TRL-1215), a cell line previously shown to have an active MT gene. The ability to detect SSD in TRL-1215 was established following exposure to gamma-irradiation. Exposure to increasing doses of gamma-irradiation (150-600 rad) resulted in a dose-dependent increase in SSD. Exposure of TRL-1215 cells to CdCl2 for 1 hr at 37 degrees C, using concentrations from 5 to 250 microM, failed to induce detectable SSD in these cells; however, exposure to 500 microM CdCl2 resulted in significant SSD. A time-dependent increase in SSD was demonstrated following a 2 hr continuous exposure to 500 microM CdCl2. Pretreatment of cells with 80 microM zinc acetate, 18 hr prior to exposure to 500 microM CdCl2, resulted in markedly reduced SSD when compared to non-pretreated cells. Zinc pretreatment increased the level of MT gene expression as well as MT protein production. The decrease in DNA strand damage associated with cadmium exposure was not due to a decrease in cadmium accumulation by zinc pretreated cells. In fact, cellular cadmium burden was increased over 2-fold following zinc pretreatment. In addition to protection against cadmium genotoxicity, zinc pretreatment also reduced the cytotoxicity associated with a 2-hr, 500 microM cadmium exposure. These data indicate that zinc pretreatment reduces cadmium genotoxicity, possibly through alterations in MT gene expression.

Topics: Animals; Cadmium Poisoning; Cells, Cultured; DNA Damage; Liver; Metallothionein; Rats; Rats, Inbred F344; Zinc

Pregnant Sprague-Dawley rats were intraperitoneally injected with physiological saline solution (vehicle) or cadmium chloride (CdCl2) at 2.5 mg kg-1 body wt. on days 8, 10, 12 and 14 of gestation. Offspring were examined for renal alkaline phosphatase activity (ALP) on postnatal days (PND) 3 and 12, and for kidney metallothionein (MTh) and for liver, kidney and entire gastrointestinal tract 109Cd content at birth and on PND 3 and 12. No effects were observed on neonatal survival or on body, liver and kidney weights of pups up to PND 12. Newborns born and fed by mothers exposed to CdCl2 during pregnancy exhibited a significant decrease in ALP activity on PND 3. Conversely, no significant changes were observed in newborns lactated by surrogate non-treated mothers. Renal MTh increased with age but was not influenced by maternal treatment. Traces of 109Cd were present in the liver at birth (5-7 ng). Thereafter, 109Cd was mainly found in the gastrointestinal tract of newborns lactated by their biological mothers (610-690 ng on PND 12), with a marginal uptake in the liver (10-12 ng on PND 12). 109Cd was not detectable in the kidneys at any age (less than 4 ng). These results show that prenatal exposure to Cd cannot be the sole aetiological agent in the induction of the subtle and transitory changes in renal biochemistry observed in offspring born and fed by female rats intraperitoneally injected with 2.5 mg CdCl2 kg-1 body wt. on days 8, 10, 12 and 14 of gestation. The results also contradict the role of a direct effect on the kidney.

Topics: Alkaline Phosphatase; Animals; Animals, Newborn; Body Weight; Cadmium Poisoning; Cadmium Radioisotopes; Female; Kidney; Lactation; Liver; Male; Metallothionein; Organ Size; Pregnancy; Rats; Rats, Inbred Strains

The effect of alpha-mercapto-beta-(2-furyl) acrylic acid (MFA, 200 mg/kg, oral) administered 30 min or 24 h post cadmium (1 mg/kg, i.p.) exposure on cadmium toxicity, was investigated in rats. The Cd induced hepatic metallothionein was reduced by MFA treatment parallel to the depletion of hepatic Cd. However, in renal tissue, MFA caused only redistribution of metal from the particulate to the soluble fraction. Hepatic and renal Zn and renal Cu were significantly increased on Cd exposure. MFA therapy, however, lowered the hepatic Zn and increased the renal Cu levels. The action of MFA appears to be via metal chelation rather than by MT induction.

Topics: Acrylates; Animals; Antidotes; Cadmium Poisoning; Kidney; Liver; Metallothionein; Rats; Time Factors

Topics: Aluminum; Alzheimer Disease; Cadmium; Cadmium Poisoning; Chromium; Gold; Humans; Mercury; Metallothionein; Protein Binding; Selenium; Trace Elements; Zinc

An epidemiological study to examine the dose-response relationship for environmental cadmium exposure was performed in 1843 cadmium-exposed and 240 non-exposed inhabitants of the Kakehashi River basin in Ishikawa, Japan. The average cadmium concentration in rice from each village was employed as an indicator of cadmium exposure and the individuals were grouped according to the length of residence in the polluted area. Metallothioneinuria was used as an index of renal tubular dysfunction produced by the chronic exposure to cadmium. A dose-related increase in metallothioneinuria was observed. The chronic total cadmium intake resulting in metallothioneinuria in this population was calculated to be approximately 2 g for both men and women. The cumulative lifetime dose of 2 g cadmium over a 50-year period, means an average daily intake of 110 micrograms. Thus, these values may be regarded as the maximum allowable lifetime and daily intake limits, respectively for chronic dietary exposure to cadmium.

Topics: Administration, Oral; Aged; beta 2-Microglobulin; Cadmium; Cadmium Poisoning; Dose-Response Relationship, Drug; Environmental Exposure; Female; Food Contamination; Humans; Japan; Male; Metallothionein; Middle Aged; Oryza; Radioimmunoassay

Early response to the exposure of cadmium includes the enhancement in lipid peroxidation with the concomitant impairment in antioxidative defence mechanism. This investigation deals with the delayed response of cadmium induced stimulation of endogenous defence response against its oxidative damage. The administration of cadmium led to an increase in the hepatic enzymatic and nonenzymatic defence armory in a dose dependent manner 72 hrs post its administration. This includes respectively an increase in the activities of superoxide dismutase, glutathione peroxidase, glucose-6-phosphate dehydrogenase and in the levels of glutathione, metallothionein and zinc. Cadmium administration also stimulated serum ceruloplasmin activity in a dose dependent manner. These changes are accompanied by the concomitant decrease in the peroxidative damage to lipids. Our results suggest the development of a delayed adaptive/defence response as a result of exposure to cadmium.

Topics: Animals; Antioxidants; Cadmium; Cadmium Poisoning; Ceruloplasmin; Female; Glutathione; Glutathione Peroxidase; Lipid Peroxidation; Metallothionein; Rats; Superoxide Dismutase; Zinc

The present investigation examines the possibility that Cd and ethanol have a significant toxicological interaction. This examination was warranted as exposure to either chemical is known to compromise human health. Inasmuch as both chemicals affect the morphology, biochemistry, and physiology of liver, it seemed reasonable to consider liver as a possible site of interaction. Specifically, the hypothesis that ethanol alters the hepatotoxic action of Cd was evaluated. Accordingly, male rats were injected iv with hepatotoxic (3.0 mg/kg) or lethal (4.5 mg/kg) dosages of Cd, 24 hr after single-dose ethanol administration (7 g/kg, po). Cd-induced hepatotoxicity was assessed by measuring the activities of alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase in serum collected 10 hr after Cd injection. Lethality was assessed by recording the number of survivors over a 7-day period. Prior exposure to ethanol substantially reduced the lethal and hepatotoxic properties of Cd. Two mechanisms were evaluated in an effort to explain ethanol-induced suppression of Cd hepatotoxicity. Ethanol pretreatment was postulated to: (1) enhance Cd excretion in bile thereby decreasing hepatic Cd content and/or (2) reduce the interaction between Cd and target sites in liver such as organelles and cytosolic high-molecular-weight (HMW) proteins. The first proposed mechanism was incorrect as the biliary excretion of Cd was nearly abolished and the concentration of Cd in whole liver increased (33%) as a result of ethanol exposure. The second proposed mechanism was a plausible explanation of ethanol-induced suppression of Cd hepatotoxicity because ethanol pretreatment decreased (approximately 60%) the content of Cd in nuclei, mitochondria, and endoplasmic reticulum, and nearly eliminated the association of Cd with cytosolic HMW proteins. Reduction in the concentration of Cd in potential target sites of intoxication was caused by a metallothionein-promoted sequestration of Cd in cytosol.

Topics: Animals; Bile; Cadmium; Cadmium Poisoning; Chromatography, Gel; Enzyme Induction; Ethanol; Liver; Male; Metallothionein; Rats; Rats, Inbred Strains

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.

Topics: Animals; Cadmium Poisoning; Cricetinae; Female; Kidney; Liver; Male; Maternal-Fetal Exchange; Mesocricetus; Metallothionein; Pregnancy; Thiocarbamates

Urinary cadmium (Cd), N-acetyl-beta-D-glucosaminidase (NAG), metallothionein (MT), beta 2-microglobulin (BMG), and blood cadmium were determined in 79 workers who had been employed at a Cd pigment factory in Japan. The workers who had been dealing with Cd pigment manufacturing processes were estimated to be exposed to cadmium pigment dust at a maximum concentration of 3.0 micrograms/m3/8 h for about 20 years. The urinary Cd level ranged from 0.2 to 9.7 micrograms/g creatinine with a geometric mean of 1.02 micrograms/g creatinine. Pearson's correlation coefficients between logarithm of urinary Cd and that of NAG, MT, and BMG in urine were 0.45, 0.62, and 0.05, respectively. The correlation coefficients between blood Cd and urinary NAG, MT, and BMG were 0.21, 0.40, and -0.074, respectively. When partial correlation coefficients were calculated to exclude the contribution of age factor, urinary Cd turned out to be significantly correlated with urinary MT (r = 0.55) and NAG (r = 0.52). The present results indicate that urinary Cd is more closely associated with urinary MT and NAG than with BMG, and suggest that MT and NAG could be good indicators of Cd absorption in a Cd-exposed population whose mean urinary Cd level is relatively low, or less than 10 micrograms/g creatinine.

Topics: Acetylglucosaminidase; Adult; Air Pollutants, Occupational; beta 2-Microglobulin; Cadmium; Cadmium Poisoning; Hexosaminidases; Humans; Metallothionein; Occupational Diseases; Proteinuria

The pre- and post-treatment with calcium trisodium diethylene-triaminepentaacetic acid (CaNa3DTPA) was investigated for their efficacy to mobilize cadmium (Cd) from various tissues and hepatic metallothionein (MT) in Cd-exposed rats. Pretreatment with CaNa3 DTPA significantly reduced the hepatic and renal Cd absorption while, post Cd treatment with CaNa3 DTPA was effective in reducing renal and brain Cd. Pretreatment with CaNa3DTPA significantly increased the Cd induced hepatic metallothionein (MT) level, MT-bound Cd, Zn and Cu contents while, post treatment with CaNa3DTPA reduced the hepatic MT, MT-bound Cd compared to Cd alone treated rats.

Topics: Animals; Cadmium; Cadmium Poisoning; Female; Liver; Metallothionein; Pentetic Acid; Rats; Tissue Distribution

Topics: Atrophy; Biopsy; Cadmium Poisoning; Humans; Infant; Kidney Tubules; Male; Metallothionein

alpha-Mercapto-beta-(2-furyl) acrylic acid (MFA), alpha-mercapto-beta-(2-hydroxyphenyl) acrylic acid (MHA), beta-1,2-phenylene di-alpha-mercaptoacrylic acid (1,2-PDMA) and beta-1,4-phenylene di-alpha-mercapto acrylic acid (1,4-PDMA) were compared to sodium N-benzyl-D-glucamine dithiocarbamate (NBG-DTC) an effective cadmium chelator, for their ability to mobilize Cd and influence the Cd induced tissue metallothionein (MT) in rats administered 109CdCl2, 72 hr earlier. MFA was almost as effective as NBG-DTC but more effective than MHA in enhancing urinary and faecal excretion of Cd, reducing tissue and blood levels of Cd and in lowering Cd induced increase in hepatic and renal MT contents. 1,2-PDMA and 1,4-PDMA were effective only in reducing the hepatic burden of Cd. The resuls do not indicate any direct relationship between the efficacy of alpha-mercapto-beta-aryl acrylic acids to decorporate body Cd and their lipophilic-hydrophilic character or number-arrangement of their sulfhydryl groups.

Topics: Acrylates; Animals; Antidotes; Cadmium; Cadmium Poisoning; Chelating Agents; Feces; Female; Metallothionein; Rats; Sulfhydryl Compounds; Tissue Distribution

Topics: Animals; Cadmium Poisoning; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; In Vitro Techniques; Liver; Male; Metallothionein; Rats; Rats, Inbred Strains; Zinc

An epidemiologic investigation was carried out to study the significance of urinary excretion of metallothionein (MT) in people aged 50 years and over living in a cadmium (Cd)-polluted area in Japan. The urinary level of MT was compared with various parameters (age, urinary alpha 1-microglobulin (alpha 1-MG), beta 2-microglobulin (beta 2-MG), total protein, Cd, copper (Cu), and zinc (Zn), and relative clearances to creatinine of alpha 1-MG, beta 2-MG, phosphate and uric acid). It was found that the urinary excretion of MT is closely associated with Cd and the indices of renal dysfunction listed above. This observation was more remarkable in women than men. When subjects with signs of renal dysfunction were compared as a group to those with normal renal functions, the excreted amount of MT in the former is significantly greater. The results support the notion that the urinary excretion of MT reflects not only Cd exposure levels but also renal dysfunction caused by long-term Cd exposure.

Topics: Acetylglucosaminidase; Aged; Aged, 80 and over; Aging; Alpha-Globulins; beta 2-Microglobulin; Cadmium Poisoning; Environmental Pollutants; Female; Humans; Japan; Kidney Diseases; Male; Metallothionein; Metals; Middle Aged

A sensitive cadmium-affinity assay was developed for measurement of urinary thionein (Th) level. Acidification with HCl (2.5 M) was used to remove metal ions from purified urinary metallothionein (MTh), adsorbed on activated polystyrene tubes. It was found that the amount of 109Cd bound to standard Th (rabbit Th) was proportional to that of Th in the concentration range of 20-6000 ng/ml. The method exhibited a sensitivity below 20 ng/ml and a precision of about 5%. The results of the Cd-affinity assay were unaffected by dilution of, or addition of standard Th to urine samples. Under the latter circumstances, the Cd-affinity assay was performed with a mean analytical recovery of 100.3 +/- 4%. Addition of Cd, Zn, Hg and Cu (50 micrograms each) or glutathione and cysteine (0.1 mmol) to urine specimens (1 ml) did not interfere with the determination of Th. The mean values of urinary Th in healthy subjects were 200 +/- 53 micrograms/g creatinine (n = 9) and 256 +/- 97 micrograms/g creatinine (n = 8) for men and women respectively. The mean daily excretions of Th by non-fasting female and male healthy adult rats were 9.95 +/- 2.7 micrograms (n = 10) and 18.2 +/- 3.9 micrograms, respectively. The Cd-affinity assay succeeded in indicating Cd exposure and/or development of Cd toxicity in rats.

Topics: Animals; Cadmium Poisoning; Cadmium Radioisotopes; Female; Humans; Male; Metallothionein; Rats; Rats, Inbred Strains; Sex Factors; Species Specificity

The effect of duration of employment at a North American cadmium smelter on urinary metallothionein (MT), total protein, beta 2-microglobulin (beta 2-MG), glucose, cadmium, copper and zinc of 53 men was studied. The levels of all urinary parameters increased with the duration of employment. Smoking history did not affect any of the above parameters studied. Although age was responsible for some of the changes noted in protein, glucose and beta 2-MG levels, its effect on MT and cadmium was insignificant. All urinary parameters were significantly related with each other. The relationship of elevated urinary MT levels with respect to renal dysfunction was also examined. Subjects with abnormal renal function excreted significantly higher amounts of MT than did those with normal renal function. The results confirm not only that occupational exposure to cadmium over long periods results in renal dysfunction but also that urinary MT could be used to monitor exposure and ultimately the appearance of the renal dysfunction.

Topics: Adult; Aging; Cadmium; Cadmium Poisoning; Copper; Humans; Kidney; Male; Metallothionein; Middle Aged; Occupational Diseases; Zinc

Kidney cells were isolated from rats pretreated by daily subcutaneous doses of cadmium metallothionein (CdMT: 0.05-0.2 mg Cd/kg X 5) and from non-pretreated rats. Upon exposure to CdCl2 in vitro (0-200 micrograms Cd/ml), a concentration dependent decrease in viability was observed in the non-pretreated cells, while no such decrease occurred in the pretreated cells indicating that these cells were more resistant to the toxic action of cadmium. There was a higher in vitro uptake of Cd+2 and an increased metallothionein (MT) concentration in the pretreated cells (compared to non-pretreated cells). Subcellular distribution studies revealed that Cd was mainly recovered in the "cytosol" fraction. The higher total cadmium uptake in pretreated cells corresponded to an increase of Cd in "cytosol" and "nuclear" fractions. This observation may be explained by MT-binding of Cd in the cells and is in accordance with a possible protective effect of induced MT in the pretreated cells. In order to assess whether pretreatment-induced tolerance to cadmium toxicity--indicated by the cellular studies--could also be observed in vivo, some whole animal experiments were also performed. A dose-related proteinuria was observed in non-pretreated rats after a single subcutaneous administration of 109Cd-MT at doses of 0.05 and 0.4 mg Cd/kg. Urinary total Cd, 109Cd and MT was also increased in a dose-related fashion. Cadmium concentrations in kidney were dose related and reached 19 micrograms/g wet weight. In contrast, in animals repeatedly pretreated with CdMT according to 1), no proteinuria was observed after administration of the same single doses of 109CdMT. Total Cd. 109Cd and particularly MT-concentrations in urine were lower in such pretreated animals than in in non-pretreated ones in spite of the accumulation of higher tissue concentrations of total Cd (up to 80 micrograms/g). The pretreatment was thus shown to prevent some of the acute nephrotoxicity of CdMT, possibly by means of induction of MT synthesis.

Topics: Animals; Cadmium; Cadmium Poisoning; Electrophoresis, Agar Gel; In Vitro Techniques; Kidney Cortex; Kidney Tubules; Male; Metallothionein; Rats; Rats, Inbred Strains; Subcellular Fractions

The concentration of metallothionein in mouse tissues after administration of ascorbic acid was determined by the Cd-hem method. The concentration of metallothionein in the liver was increased significantly after an intraperitoneal injection of L-ascorbic acid at the dose of 1000 mg/kg. A simultaneous injection of cycloheximide inhibited the increase of the metallothionein concentration. Mortality of mice injected with a lethal dose of cadmium was decreased significantly by the pre-injection of L-ascorbic acid. All of these results indicate that metallothionein is induced in the liver after the administration of ascorbic acid.

Topics: Animals; Ascorbic Acid; Cadmium Poisoning; Cycloheximide; Intestine, Small; Kidney; Liver; Male; Metallothionein; Mice; Pancreas; Zinc

Gel chromatographic analysis of urine specimens obtained from three women environmentally exposed to cadmium (Cd) was carried out to study the relationship between urinary excretion of heavy metals and metallothionein (MT). In one of the three Cd-exposed women MT was detected in the fraction corresponding to molecular weight of about 10,000 (MT-F) by radioimmunoassay, and Cd and copper (Cu) peaks were also observed in the MT-F. However, in the other two Cd-exposed women no metal peak was found in the MT-F although MT alone was detected in it. When urine specimens from these subjects were treated with 2-mercaptoethanol before chromatography, appreciable amounts of Cd and Cu were recovered in the MT-F. In a sample to which dithiothreitol was added at the time of urine collection more than 60% of both Cd and Cu were recovered in the MT-F. These results support the suggestion that MT is so susceptible to oxidation that metals bound to MT can be released from it and distribute in high or low molecular weight fractions. It is also suggested that most urinary Cd and Cu is excreted with MT and that MT is directly involved in the increased excretion of these metals, especially Cu, in people environmentally exposed to Cd.

Topics: Aged; Cadmium Poisoning; Chromatography, Gel; Copper; Environmental Pollutants; Female; Humans; Metallothionein; Oxidation-Reduction; Sulfhydryl Compounds

This case report describes the natural history of chronic cadmium intoxication in a woman who was exposed to excessive cadmium in her occupation. We document the clinical, laboratory, and tissue response to the toxicant.

Topics: Adenocarcinoma; Cadmium; Cadmium Poisoning; Environmental Exposure; Female; Humans; Kidney; Liver; Lung Neoplasms; Metallothionein; Microscopy, Electron; Middle Aged; Occupational Diseases

Epithelial cells from the kidney were freshly isolated from rats pretreated by daily subcutaneous doses of CdCl2 in vivo (0.5-2 mg Cd/kg X 5). Such cells were incubated in vitro in media with different concentrations of cadmium chloride (0-200 micrograms Cd/ml). There was no inhibition of cell growth in such cells. However, in cells isolated from non-treated rats, in vitro exposure to the same concentrations of CdCl2 caused a dose dependent decrease in viability. When cells, isolated from non-treated rats were pretreated in vitro with CdCl2 (10 micrograms/ml) and subsequently exposed to cadmium chloride (0-200 micrograms/ml), a protective effect was observed, which was similar to the one observed in cells isolated from animals pretreated with CdCl2. The concentration of metallothionein in the cells treated with cadmium was increased. A lower uptake of cadmium chloride, in vitro has been observed in kidney cells pretreated in vivo or in vitro compared to nonpretreated cells. Subcellular distribution studies indicate that Cd-distribution was similar in pretreated and non-pretreated cells, but concentrations were generally lower in the pretreated cells. The decreased uptake of Cd by pretreated kidney cells is a sign of Cd-interference with cellular function. These changes are suggested as a contributing mechanism to the prevention of acute toxic effects of cadmium on the kidney.

Topics: Animals; Cadmium; Cadmium Chloride; Cadmium Poisoning; Cell Survival; Drug Resistance; Female; Kidney; Male; Metallothionein; Proteinuria; Rats; Rats, Inbred Strains; Time Factors

Recent work indicated that administration of the pyrimidine analog 5-azacytidine (AZA), either to cells in culture or to rats, results in an enhancement of expression of the metallothionein (MT) gene. Since MT is thought to play a central role in the detoxification of cadmium, the present study was designed to assess the effect of AZA pretreatment on cadmium cytotoxicity. Cultured rat liver cells (TRL 1215) in log phase of growth were first exposed to AZA (8 microM). Forty-eight hours later, cadmium (10 microM) was added. MT concentrations were then measured 24 hr after the addition of cadmium. A modest increase in MT amounts over control (1.7-fold) was detected after AZA treatment alone. Cadmium alone resulted in a 10-fold increase in MT concentrations. The combination of AZA pretreatment followed by cadmium exposure caused a 23-fold increase in MT concentrations over control. Treatment with the DNA synthesis inhibitor hydroxyurea (HU) eliminated the enhancing effect of AZA pretreatment on cadmium induction of MT, indicating that cell division is required. AZA-pretreated cells were also harvested and incubated in suspension with cadmium (250 microM, 37 degrees C) for 0 to 90 min. After incubation intracellular and extracellular fluids were separated by centrifugation through an oil layer. AZA-pretreated cells showed marked reductions in cadmium-induced cytotoxicity as reflected by reduced intracellular potassium loss, glutamic-oxaloacetic transaminase loss, and lipid peroxidation (assessed by thiobarbituric acid reactants) following cadmium exposure. AZA pretreatment had no effect on the cellular uptake of cadmium. Results suggest that AZA pretreatment induces tolerance to cadmium cytotoxicity which appears to be due to an increased capacity to synthesize MT rather than high quantities of preexisting MT at the time of cadmium exposure.

Topics: Animals; Azacitidine; Cadmium; Cadmium Poisoning; DNA; Drug Interactions; In Vitro Techniques; Liver; Metallothionein; Potassium; Rats; Rats, Inbred F344; Thymidine; Tritium; Uridine

A Cd-, Zn-, Cu-binding protein was isolated from the liver of dogfish subjected to environmental experimental contamination (50 ppm Cd). It was also found in liver from untreated fish. This protein has a high absorption at 250 nm and a low absorption at 280 nm, suggesting a mercaptide bond and a lack of aromatic amino acids. The SDS-PAGE pattern and changes in absorption spectrum on adding Cd or lowering pH are found as for mouse MT. The protein contains Cu and Zn in control and Cu, Zn and Cd in treated fish. Cd levels in the protein are significantly higher in females and significantly increase with treatment duration. Copper levels decrease after 96 hr in males and 6 days in females.

Topics: Animals; Cadmium; Cadmium Poisoning; Copper; Dogfish; Electrophoresis, Polyacrylamide Gel; Female; Hydrogen-Ion Concentration; Liver; Male; Metallothionein; Mice; Molecular Weight; Sex Factors; Sharks; Species Specificity; Water Pollutants, Chemical; Zinc

Toxicity of cadmium on Drosophila cell lines has been studied. Maximal tolerance for cadmium chloride is 10 microM. Metallothioneins are induced in Drosophila cells following cadmium addition. A stable cadmium resistant cell line (Cd R200) has been selected starting from the haploid D clone. The Cd R200 cells are diploid and display metallothionein levels 22 times higher than cells of the original line fully induced with cadmium. The 200 microM CdCl2 tolerance upper limit in Cd R200 line is overcome if L-cysteine is supplemented to the medium. It is thus possible, in the presence of 5 mM L-cysteine, to select cells able to resist 800 microM CdCl2. These cells produce 4 times more metallothioneins than Cd R200 cells.

Topics: Animals; Cadmium Poisoning; Cell Line; Chromatography, DEAE-Cellulose; Chromatography, Gel; Drosophila melanogaster; Drug Resistance; Electrophoresis, Polyacrylamide Gel; Metallothionein

Oral administration of cadmium results in the induction of metallothionein in liver of rhesus monkeys subjected to protein calorie malnutrition and calcium deficiency. Metallothionein was resolved into three iso-proteins viz. MTa, MTb & MTc which varied in their quantities and metal composition in these nutritional stress conditions. 'MTc' was the major iso-protein in protein calorie malnourished monkeys, while 'MTb' predominated in the calcium deficient group.

Topics: Animals; Cadmium; Cadmium Poisoning; Calcium; Cytosol; Liver; Macaca mulatta; Male; Metallothionein; Protein-Energy Malnutrition

Rats were injected sc with 0.5 mg Cd/kg, 6 days/week, for up to 26 weeks. Hepatic and renal function and tissue Cd and metallothionein (MT) content were determined in tissues and plasma at various times after Cd injection. Cd in liver and kidney increased linearly for the first 10 weeks of treatment, but thereafter hepatic concentrations of Cd decreased by 33% whereas the content of Cd in kidney remained constant. MT in liver and kidney increased linearly during the first 12 weeks of Cd treatment to 4400 and 2300 micrograms MT/g, respectively, but rose only slightly thereafter. Circulating concentrations of MT progressively increased beginning 2 weeks after Cd treatment and were approximately 10 times control values in rats dosed with Cd for 12 or more weeks. Plasma activities of alanine and aspartate aminotransferase exhibited a time course similar to that observed with MT, and were elevated as early as the sixth week of Cd exposure. Sharp increases in activities of these enzymes also occurred after 10 to 12 weeks of dosing. Hepatic microsomal metabolism of benzo[a]pyrene and ethylmorphine was severely attenuated beginning 4 weeks after Cd. Renal injury occurred after hepatic damage, as evidenced by decreased in vitro p-aminohippuric acid uptake beginning 8 weeks after exposure. Urine outflow increased threefold 11 weeks after Cd exposure began, while urinary protein and Cd excretion increased beginning at Week 9. These data indicate the liver is a major target organ of chronic Cd poisoning, and suggest that Cd-induced hepatic injury, via release of Cd-MT, may play an important role in the nephrotoxicity observed in response to long-term exposure to Cd.

Topics: Animals; Body Weight; Cadmium; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Kidney; Kidney Diseases; Liver; Liver Diseases; Male; Metallothionein; Organ Size; Rats; Rats, Inbred Strains; Tissue Distribution

Topics: Animals; Cadmium Poisoning; Female; Kidney; Metallothionein; Nickel; Rats

Endogenous sulfhydryl compounds serve a critical role in maintaining the function and viability of living systems. Glutathione (GSH) is the most abundant of these nonprotein thiols. During the past decade it has been demonstrated that sulfhydryls such as GSH also serve an important role in protecting vital nucleophilic sites in the liver from electrophilic attack by numerous classes of reactive chemicals. Organocompounds such as bromobenzene and acetaminophen which undergo microsomal metabolism yield reactive intermediates that are specifically inactivated by conjugation with sulfhydryls in the form of GSH. Thus, for organocompounds GSH is extremely important in protecting against toxic insults. More recently, other sulfhydryl compounds also have been found to serve a specific but as yet less defined role in protecting biological systems against chemically induced injury. Metals such as cadmium have a high affinity for sulfhydryls and the metal binding protein metallothionein binds cadmium with high affinity. The highly specific association of the metal with this sulfhydryl-enriched protein serves to effectively sequester the reactive cadmium ion. The central role of sulfhydryl equivalents in the detoxication of organo- and metallocompounds is similar; however, the mechanism by which this is achieved is fundamentally different.

Topics: Acetaminophen; Animals; Biotransformation; Bromobenzenes; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Cysteine; Cytochrome P-450 Enzyme System; Humans; Metallothionein; Metals; Microsomes, Liver; Sulfhydryl Compounds; Zinc

Changes of alkaline phosphatase in small intestine, liver, kidney, bone and serum of rats administered 100 ppm (890 nM) of Cd2+ in the drinking water were observed during a 12 months period. After 2 weeks of cadmium administration, decreases in bone and small intestine alkaline phosphatases in serum of Cd-exposed rats were observed by a polyacrylamide gradient gel electrophoresis and the alterations continued through the 9th month of administration. At one month, the activities of the alkaline phosphatase fractions, p-1 and p-2, obtained from Sephadex G-200 column gel filtration of bone extracts from Cd-exposed rats were 32% and 43% of those in the controls, respectively, whereas Cd accumulation in the bone was very low (9 nmol/g wet weight). After 3 months, osteoporotic changes of bone and erosion of submucosa layer of the small intestine were observed by light microscopy. Alkaline phosphatase in small intestine of the Cd-exposed rats was 60% of that in the controls after 3 months. At 12 months, the decreased activity of bone alkaline phosphatase in Cd-exposed rats recovered to the same level as activity in the non-exposed rats. Moreover, the activity in kidney of the Cd-exposed rats was 80% of that in the controls. However, histological conversion from osteoporotic to osteomalacic changes in bone and kidney lesions by Cd administration were not observed by light microscopy. Liver alkaline phosphatase activity of the Cd-exposed rats did not change even at 12 months, whereas 1.2 mumol of Cd per g wet weight accumulated in this organ.

Topics: Alkaline Phosphatase; Animals; Bone and Bones; Cadmium; Cadmium Poisoning; Chromatography, Gel; Cytosol; Electrophoresis, Polyacrylamide Gel; Intestines; Isoenzymes; Kidney; Liver; Male; Metallothionein; Rats; Rats, Inbred Strains

After chronic exposure to low doses of CdCl2 an increase in disulphide bonds has been established in rat liver using a specific staining method for disulphide bonds and cytophotometric quantitation. This increase is dependent on doses and length of exposure time. Evidence is presented that this increase might be related to the accumulation of metallothionein or some other cadmium binding protein. Using the same staining method after long exposure to low doses of CdCl2 a large number of large dark blue stained granules were observed in the proximal tubule cells, with blue stained deposits in the lumen of the proximal and some renal medulla tubules of the kidney. Evidence is presented that this staining pattern corresponds to the destruction of the proximal tubule cell by the cadmium thionein complex.

Topics: Animals; Cadmium Poisoning; Disulfides; Electron Probe Microanalysis; Female; Histocytochemistry; Kidney; Kidney Tubules; Liver; Metallothionein; Proteins; Rats; Rats, Inbred Strains; Staining and Labeling

Induction of cadmium metallothionein (MT) in chronic cadmium exposure in Rhesus monkeys undergoing protein calorie malnutrition (PCM) and calcium deficiency has been studied. A positive correlation between cadmium content and levels of MT in kidney, liver, intestine, testis, heart and lung, has been observed. The accumulation of cadmium and synthesis of MT in these tissues was highest in monkeys subjected to cadmium exposure during calcium deficiency. Although more of cadmium is directed towards kidneys of calcium-deficient monkeys the MT-inducing ability of kidney is lower than that of liver. Monkeys on PCM diet also showed enhanced accumulation of cadmium and MT as compared to those on normal diet during cadmium exposure.

Topics: Animals; Cadmium Poisoning; Calcium; Diet; Macaca mulatta; Male; Metallothionein; Protein-Energy Malnutrition; Tissue Distribution

A low-molecular-weight cadmium-binding protein was induced in the livers of rainbow trout (Salmo gairdnerii) following a series of intraperitoneal injections of cadmium chloride. The subsequent purification and amino acid analysis of this protein showed it to be a true metallothionein. As in higher organisms, two major forms of metallothionein appeared to be present in the liver following cadmium treatment. Following a similar induction procedure total RNA was also isolated and shown to contain high levels of metallothionein-mRNA activity when assayed in a wheat-germ cell-free translation system. This activity was present in the Poly-A+-containing fraction of the total RNA. The bulk of this mRNA activity was shown to be in the 8-10S region of a sucrose gradient.

Topics: Animals; Cadmium; Cadmium Chloride; Cadmium Poisoning; Liver; Metallothionein; Protein Biosynthesis; RNA, Messenger; Transcription, Genetic; Trout

Rats were injected daily, five days/week, with 0.6 mg Cd/kg as CdCl2 for eight weeks. Groups of rats were sacrificed weekly. Urine, plasma and tissue cadmium levels, and morphology of renal cortex were studied. No abnormal effects were found until the fifth or sixth week when cadmium in kidney reached about 100 micrograms/g tissue. At this time, renal tubular lining cells showed an increase in lysosomes, microbodies and smooth endoplasmic reticulum and a low molecular weight cadmium-binding species was detectable in plasma. These changes were followed by the onset of glycosuria and proteinuria, accompanied by abnormal mitochondrial morphology. This progressed to cellular swelling and finally necrosis at the seventh and eighth weeks when cadmium concentration of the kidney reached about 200 micrograms/g of tissue. It is concluded that there are two phases in the development of cadmium induced nephropathy. Phase I is an adaptive phase characterized by some increase in smooth endoplasmic reticulum, microbodies and secondary lysosomes and the presence of metallothionein intracellularly in liver and kidney, but no detectable metallothionein in plasma and no increase in urinary cadmium. Phase II is a toxic phase characterized by detectable low molecular weight cadmium-binding species in plasma and evidence of renal tubular dysfunction followed by lethal injury to renal tubular lining cells.

Topics: Animals; Cadmium; Cadmium Poisoning; Kidney; Kidney Diseases; Liver; Male; Metabolic Clearance Rate; Metallothionein; Rats; Rats, Inbred Strains; Zinc

Metallothioneins (MT) are a group of proteins of very peculiar structure, in that 15-20 of its amino acid residues are cysteinyl. We have studied possible functions of the SH-rich MT as a detoxifying molecule by using human and murine cell lines with high amounts of Cd-induced MT. Such cells show radioresistance, they are resistant to Cd, cisplatinum, chlorambucil and gold, and the MT binds these substances firmly. The clinical relevance may be twofold. Firstly, MT may confer resistance to useful drugs such as alkylating agents. Secondly, MT may be a resistance factor to harmful effects of xenobiotics.

Topics: Animals; Cadmium Poisoning; Cells, Cultured; Chlorambucil; Cisplatin; Drug Resistance; Gold; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Metallothionein; Mice; Radiation-Protective Agents

Topics: Animals; Cadmium; Cadmium Poisoning; Humans; Kidney; Kidney Diseases; Metallothionein

Pretreatment of female mice with a small oral dose of Cd2+ (15 mg Cd2+/kg) decreased Cd2+ uptake by the liver and kidney and increased that by the small intestinal mucosa at 4 or 24 hr after challenge with a large oral dose of Cd2+ (100 mg Cd2+/kg). By 4 hr after the challenge dose, more Cd2+ taken up by the liver was bound to metallothionein (MT) in the Cd2+-pretreated mice than the water-pretreated controls (10 ml H2O/kg); but at 24 hr, the amount of Cd2+ bound to MT in the liver and kidney were lower in the former than the latter. The amount of Cd2+ not bound to MT in the liver at 4 and 24 hr after the challenge dose and that in the kidney at 24 hr were lower in the Cd2+-pretreated mice than the water-pretreated controls. These results suggested that the factor directly related to the toxic action of Cd2+ was the amount of Cd2+ not associated with MT in the liver and other organs. More Cd2+ taken up by the small intestinal mucosa at 24 hr after the challenge dose was associated with MT in the Cd2+-pretreated mice than the water-pretreated controls. The present study indicates that MT induced in the small intestinal mucosa by pretreatment prevents Cd2+ absorption by sequestering subsequently administered Cd2+, and Cd2+ taken up by the liver and kidney is bound to MT in an inert form, thus the decrease in the amount of Cd2+ not bound to MT, giving protection from the acute oral toxicity of the cation. Pretreatment 24 hr prior to the challenge dose was found to be the most effective.

Topics: Animals; Cadmium; Cadmium Poisoning; Chromatography, Gel; Drug Tolerance; Female; Intestinal Mucosa; Kidney; Liver; Metallothionein; Mice; Mice, Inbred ICR; Premedication; Proteins; Zinc

Cadmium in blood (Cd-B) and in urine (Cd-U) and metallothionein (Mt-U) and beta 2-microglobulin in urine (beta 2m-U) were measured in 94 male Cd workers. The results were examined according to the workers' current exposure to cadmium (group C, n = 73, workers currently exposed to Cd; group R, n = 21, Cd workers removed from exposure or retired) and according to their renal status (group N, n = 66, normal beta 2m-U; group I, n = 28, beta 2m-U greater than 200 micrograms/g creatinine). The interrelationships between Mt-U, Cd-U, Cd-B and years of cadmium exposure were examined in the various subgroups. The study of the correlations between these variables demonstrates that Mt-U is directly correlated with Cd-U but not with Cd-B or years of Cd exposure. The association between Cd-U and Mt-U is independent of the status of renal function and the intensity of current exposure to cadmium. Under moderate chronic exposure to cadmium, the fraction of Cd-U which is directly influenced by recent exposure (Cd-B) is small in comparison with that influenced by the cadmium body burden.

Topics: Adult; Aged; beta 2-Microglobulin; Cadmium; Cadmium Poisoning; Humans; Kidney Diseases; Male; Metallothionein; Middle Aged; Occupational Diseases; Time Factors

The utility of isolated rat hepatocytes as a model system for screening potential chelators in treatment of Cd intoxication was studied. The ability of the chelators diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 2,3-dimercaptosuccinic acid (DMSA), diethyldithiocarbamic acid (DDC), d,1-penicillamine (PEN), nitrilotriacetic acid (NTA), and 2,3-dimercaptopropanol (BAL) to decrease the cellular concentration of Cd was correlated with the previously reported effectiveness of these agents in the treatment of Cd intoxication in vivo. The results of cellular studies with either control or metallothionein-induced hepatocytes were compared to the in vivo effect of the chelators administered before or after the induction of metallothionein, respectively. The effects of DTPA, EDTA, DDC, and BAL in the hepatocyte model screening system correlated well with their reported in vivo effects. The results with NTA, PEN, and DMSA were not correlated as well but were explained by the relative differences between in vivo doses versus in vitro concentrations of the respective chelators. Therefore, the proposed model for screening potential chelators for use in cadmium intoxication appears to be a system which may prove to be an economical and rapid method to facilitate the search for efficacious chelators.

Topics: Animals; Cadmium; Cadmium Poisoning; Cells, Cultured; Chelating Agents; Drug Evaluation, Preclinical; Liver; Male; Metallothionein; Rats; Rats, Inbred Strains

Metallothionein (MT) in the livers and kidneys of rats that died after repeated injections of cadmium (Cd) was selectively oxidized to dimers of MT with time after death. In vitro experiments suggest that the dimer formation is facilitated in heavily Cd-accumulated tissues by oxygen and temperature when cell damage occurs.

Topics: Animals; Cadmium Poisoning; Chromatography, High Pressure Liquid; Female; Kidney; Liver; Metalloproteins; Metallothionein; Postmortem Changes; Rats; Rats, Inbred Strains; Spectrophotometry, Atomic

Chelator efficacy in Cd poisoning drops precipitously if therapy is not commenced almost immediately after exposure. Metallothionein (MT), a low-molecular-weight metal-binding protein with high affinity for Cd, may be important for this phenomenon. To more fully assess this role of MT in the acute drop in chelator efficacy following Cd poisoning, rats were injected iv with radioisotopic Cd (1mg/kg as CdCl2; 50 muCi/kg) followed by diethylenetriaminepentaacetic acid (DTPA; 90 mg/kg ip) at various times (0, 15, 30, 60, and 120 min) after Cd. Ther percentage of the Cd dose remaining in major organs 24 hr following Cd was determined. Although DTPA reduced Cd content in the various organs when given immediately after Cd, the chelator was ineffective at all later times. Increases in hepatic and renal MT did not occur until 2 hr after Cd, and did not coincide with the earlier drop in chelator efficacy. Blockade of MT synthesis by actinomycin D treatment (1.25 mg/kg, 1 hr before Cd) failed to prolong the chelators effectiveness. Furthermore, newborn rats have high levels of hepatic MT which had no effect on the time course of chelator effectiveness since DTPA still decreased Cd organ contents if given immediately following Cd but had no effect if given 2 hr after Cd. Therefore, if appears that MT does not have an important role in the acute decrease in efficacy of chelation therapy for Cd poisoning. The quick onset of chelator ineffectiveness may be due to the rapid uptake of Cd into tissues which makes it relatively unavailable of chelation.

Topics: Animals; Cadmium; Cadmium Poisoning; Chelating Agents; Dactinomycin; Kidney; Liver; Metalloproteins; Metallothionein; Pentetic Acid; Rats; Rats, Inbred Strains

We have confirmed the observations of Tsunoo et al. (Toxicol. Lett. 4:253, 1979) that (a) DBA/2 mice are resistant to cadmium mortality than C3H mice and (b) DBA/2 mice accumulate more 109Cd into hepatic metallothionein than do C3H mice in response to an injection of 30 mumol CdCl2/kg, a dose of CdCl2 which is lethal to C3H mice. We now report, using a nonlethal dose of 8 mumol CdCl2/kg, that the rates of both the synthesis and the degradation of cadmium-induced hepatic metallothionein are increased in C3H mice. The rate of metallothionein synthesis, measured 6 hr after cadmium administration and expressed as the percentage of injected [35S]cysteine incorporated into metallothionein/g liver, was 0.33 +/- 0.04% (SD) in C3H mice, compared to 0.19 +/- 0.06% in DBA/2 mice (significantly different rates by Students' t test. P less than 0.01). Also, at this dose, hepatic 35S-labeled metallothionein was degraded with a half-life of 22.5 +/- 0.7 hr in C3H mice, compared to 30.1 +/- 2.5 hr in DBA/2 mice (significantly different half-lives by F test, within 95% confidence limits). The increased accumulation of metallothionein in resistant DBA/2 mice compared to sensitive C3H mice after cadmium exposure appears to be due primarily to a difference in metallothionein degradation, rather than metallothionein synthesis.

Topics: Animals; Cadmium Poisoning; Female; Liver; Metalloproteins; Metallothionein; Mice; Mice, Inbred C3H; Mice, Inbred DBA; Species Specificity

1. The protective effect against Cd toxicity of prior exposure to Cd or Zn solutions at low concentration was studied. 2. Carp were bred in tap water (A), 1 ppm Cd solution (B) and 5 ppm Zn solution (C) for 14 days and then transferred into 15 ppm Cd solution. The survival ratio of carp decreased in the order: (C):(B):(A). 3. Binding capacity of Cd to high molecular and metallothionein fractions in the cytoplasmic solutions of the hepato-pancreas was studied and the binding capacity to the metallothionein fraction was stronger than that to the high molecular fraction. The authors recognized that Zn in the metallothionein fraction is substituted by Cd.

Topics: Animals; Cadmium Poisoning; Carps; Cyprinidae; Cytoplasm; Liver; Metalloproteins; Metallothionein; Pancreas; Time Factors

Topics: Animals; Cadmium; Cadmium Poisoning; Kidney; Kidney Tubules, Proximal; Metalloproteins; Metallothionein; Protein Biosynthesis; Rats; RNA

Topics: Acute Disease; Animals; Cadmium; Cadmium Poisoning; Chelating Agents; Edetic Acid; Liver; Male; Metallothionein; Mice; Mice, Inbred Strains; Pentetic Acid; Succimer; Time Factors

An indirect immunoperoxidase staining technique was employed to localize the heavy metal binding protein, metallothionein, in rat liver and kidney. Immunostaining for metallothionein was observed in all hepatocytes and most renal tubular cells. This protein was not detectable, however, in cell types such as endothelial or connective tissue cells, indicating that metallothionein synthesis or accumulation is tissue- and cell-type specific. Hepatocytes from cadmium-exposed animals showed increased staining for metallothionein. The presence of metallothionein was also seen extracellularly within the liver sinusoids and renal tubules in both normal and cadmium-exposed animals, suggesting transport and excretion, respectively, of this protein.

Topics: Animals; Cadmium Poisoning; Immunoenzyme Techniques; Kidney; Liver; Metalloproteins; Metallothionein; Rats

Metallothionein purified from the livers of rats injected with CdCl3 was cleaved by proteolysis into a 32-residue polypeptide that contained 4 bound Cd ions. Appearance of this fragment designated alpha requires prior treatment of metallothionein with EDTA to remove the Zn ions and destabilize the 3-metal cysteine cluster in the other domain. The half-molecule domain was not efficiently produced by proteolysis of native metallothionein. The Cd4-alpha fragment is asymmetric in shape, as is the parent molecule. NH2-terminal sequence analysis revealed that the alpha fragment starts at Lys 30. Since the same amino acids are released from the COOH terminus of intact thionein and the alpha fragment by carboxypeptidase Y, the alpha domain generated by digestion with subtilisin therefore comprises residues 30 through 61. The amino acid composition of the alpha polypeptide is consistent with the structure of the 4-metal cysteine cluster proposed by Otvos and Armitage ((1980) Proc. Natl. Acad. Sci. U. S. A. 77, 7094-7098). Metallothionein appears to consist of a 3-metal cysteine domain in the NH2-terminal half of the thionein molecule and the 4-metal cysteine domain in the COOH-terminal half.

Topics: Amino Acid Sequence; Amino Acids; Animals; Cadmium; Cadmium Poisoning; Edetic Acid; Kinetics; Liver; Male; Metalloproteins; Metallothionein; Peptide Fragments; Protein Binding; Protein Conformation; Rats; Rats, Inbred Strains; Spectrophotometry, Ultraviolet

Topics: Animals; Cadmium; Cadmium Poisoning; Cell Line; Cricetinae; Cricetulus; DNA; Female; Gene Expression Regulation; Kinetics; Metalloproteins; Metallothionein; Ovary; RNA, Messenger; Subcellular Fractions

Topics: Animals; Cadmium; Cadmium Poisoning; Liver; Male; Metalloproteins; Metallothionein; Metals; Mice; Mice, Inbred ICR; Rats; Rats, Inbred Strains; Zinc

Topics: Age Factors; Amino Acids; Animals; Animals, Newborn; Cadmium; Cadmium Poisoning; Liver; Male; Metalloproteins; Metallothionein; Rats; Testis; Tissue Distribution; Zinc

Topics: Animals; Cadmium; Cadmium Poisoning; Copper; Kinetics; Liver; Male; Metalloproteins; Metallothionein; Models, Biological; Molecular Weight; Rats; Rats, Inbred Strains; Tissue Distribution; Zinc

Topics: Animals; Cadmium; Cadmium Poisoning; Female; Kidney; Kidney Tubules; Lysosomes; Male; Metallothionein; Rats; Rats, Inbred Strains; Subcellular Fractions; Zinc

Topics: Amino Acids; Animals; Cadmium Poisoning; Cells, Cultured; Deoxyglucose; Epithelium; Kidney; Liver; Metalloproteins; Metallothionein; Rats

Topics: Animals; Cadmium; Cadmium Poisoning; Copper; Kidney; Kidney Tubules, Proximal; Liver; Metalloproteins; Metallothionein; Necrosis; Rats; Zinc

In order to test the possibility of metallothionein (MT) transfer from liver to kidney, experimental hepatic disorders produced by hepatotoxins were examined to study the release of MT from liver. 109Cd exposed rats were treated with carbon tetrachloride (CCl4) and the distribution of cadmium (Cd) in the body was studied. Hepatic Cd was significantly decreased corresponding to the dose of CCl4. Cd in plasma, kidney, and urine was increased remarkably in contrast with the decrease of hepatic Cd. No remarkable changes in Cd of other tissues and feces were observed. These phenomena were produced by other hepatotoxins like galactosamine and ethionine, and long-term administration of Cd, too. In every case that plasma Cd increased markedly, plasma levels of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), and lactate dehydrogenase (LDH) rose simultaneously, and a significant, positive correlation between Cd concentration and each of enzyme activities in plasma was observed. Cd in hepatic supernatant of CCl4 treated rats was bound mostly to MT fraction, and in kidney, plasma or urine, Cd was also in the form of MT. These results suggest that hepatic MT can be released into blood in the same manner as hepatic enzymes and transported to kidney and urine in some types of hepatic disorders.

Topics: Animals; Cadmium; Cadmium Poisoning; Carbon Tetrachloride Poisoning; Dose-Response Relationship, Drug; Female; Kidney; Liver; Liver Diseases; Male; Metallothionein; Rats; Rats, Inbred Strains; Time Factors; Tissue Distribution

Topics: Animals; Blood Proteins; Cadmium Poisoning; Chromatography, Gel; Copper; Kidney Cortex; Liver; Male; Metalloproteins; Metallothionein; Proteinuria; Rabbits; Tissue Distribution; Zinc

Upon exposure to cadmium, the biosynthesis of metallothionein is increased in liver and kidneys. The protein sequesters a large fraction of the tissue cadmium, thereby making it less available for excretion. The primary function of the protein in cadmium metabolism, therefore, appears to be storage of the metal in a less toxic form. Low levels of metallothionein are found in plasma and urine upon cadmium exposure. The protein is cleared from the circulation and is reabsorbed by kidney. There it is rapidly degraded, releasing Cd2+ ions which are the probable cause of the proximal tubular damage. Circulating metallothionein can also induce the autoimmune response, resulting in the formation of soluble immune complexes which may deposit in glomeruli and affect their function as well. Therefore, due to its release into the circulation, the metallothionein-bound storage form of cadmium may in fact be responsible for both tubular and glomerular dysfunction observed after chronic cadmium exposure.

Topics: Animals; Cadmium; Cadmium Poisoning; Female; Humans; Kidney; Liver; Male; Metalloproteins; Metallothionein; Rats; Rats, Inbred Strains

The concentration of metallothionein (MT) in the liver of the perinatal rat is relatively high at term and 7 days after birth and then decreases to barely detectable levels by day 28. The developmental pattern MT-zinc parallels that of MT. When challenged with a single injection of cadmium chloride, the 26-day-old rat responds with a dose-related increase in hepatic MT which sequesters both cadmium and zinc. When the 5-day-old rat is similarly challenged, induction of MT occurs only at the highest dose tested (6 mg Cd/kg); however, due to the pre-existence of MT in these younger rats, cadmium administered at the lower doses still binds to the MT in a dose-related manner. Despite the induction of MT seen in both age groups following the 6.0 mg/kg dose, exposure to that level of the metal produced death in 30% of the younger animals but in only 4% of the older animals. When cadmium was administered to pregnant rats on day 19 of gestation, it was found to produce a dose-related induction of maternal hepatic MT over the following 48 hr. In contrast, maternal exposure to the metal led to a significant depression of fetal hepatic MT over the same time interval.

Topics: Animals; Body Weight; Cadmium Poisoning; Chromatography, Gel; Female; Liver; Male; Maternal-Fetal Exchange; Metalloproteins; Metallothionein; Organ Size; Pregnancy; Rats; Rats, Inbred Strains; Zinc

Topics: Animals; Cadmium Poisoning; Chromatography, High Pressure Liquid; Cytosol; Kidney Cortex; Liver; Macaca mulatta; Metalloproteins; Metallothionein; Pancreas; Tissue Distribution

Topics: Animals; Cadmium Poisoning; Metalloproteins; Metallothionein; Oligochaeta

Cadmium-binding proteins (CdBPs) in the cytosol fractions from several organs of man orally exposed to cadmium (Cd) were examined by gel chromatography. In kidney and liver most of the cadmium (76-87%) in the cytosols was bound to metallothionein, and hepatic metallothionein contained zinc also at a similar level. The pancreas cytosol also contained a metallothionein-like CdBP, although its content was only one-tenth of the hepatic one. In the thyroid gland a prominent CdBP, eluting later than that of metallothionein, was observed; this CdBP was not detectable in normal dogs, pigs, and oxen. No CdBPs were observed in other organs including heart, muscle, genital organs, aorta, and bone. These results suggest that CdBPs participate in accumulation and distribution of cadmium in man, since organs containing CdBP such as kidney, liver, pancreas, and thyroid gland show a tendency to accumulate high levels of cadmium.

Topics: Aged; Cadmium; Cadmium Poisoning; Cytosol; Food Contamination; Humans; Male; Metalloproteins; Metallothionein; Oryza; Tissue Distribution

Chelation and removal of cadmium from rats which were exposed to cadmium by multiple injections were studied in vivo after injection of two different compounds, 2,3-dimercaptopropanol (BAL) and diethylenetriamine pentaacetic acid (DTPA). Rats were injected i.p. with 1 mg of Cd/kg as 109CdCl2 daily for 4 days and 3 days after the last injection, they were treated with the chelating agents alone or in combination 5 days in a week for 2 weeks. BAL (50 mg/kg) alone or in combination with DTPA (50 mg/kg) was effective in removing cadmium from the body without increasing the level of cadmium in the kidney, the critical organ in cadmium toxicity. After treatment with BAL alone and BAL-DTPA, cadmium was excreted mainly in the feces with marked decrease in hepatic and renal concentrations of both cadmium and metallothionein. Injection of DTPA alone increased the urinary excretion of cadmium without any significant change in tissue cadmium. Although the urinary excretion of zinc was increased after injection of DTPA and also BAL-DTPA, there was no change in the tissue levels of zinc and copper. The results of this study suggest the potential use of BAL or BAL-DTPA combination as a mode of chelation of cadmium from the body under proper experimental conditions in chronic cadmium poisoning. It may be possible to prevent tubular damage in the kidney, the critical organ in cadmium toxicity by this treatment.

Topics: Animals; Cadmium; Cadmium Chloride; Cadmium Poisoning; Copper; Dimercaprol; Kidney; Male; Metalloproteins; Metallothionein; Pentetic Acid; Rats; Rats, Inbred Strains; Zinc

The significance of elevated excretion of metallothionein in urine of women living in cadmium-polluted areas of Japan was studied with respect to renal dysfunction. The relationships between the concentrations of metallothionein in urine and those of other non-specific urinary indices of renal dysfunction, i.e., total protein, glucose, beta 2-microglobulin, retinol-binding protein, alpha-amino nitrogen and proline were examined. In addition, the relationships between urinary metallothionein and urinary cadmium and copper were also evaluated. It was found that the logarithm of the metallothionein concentration in urine was significantly correlated with the logarithm of the concentrations of each of the above parameters. When subjects with signs of renal dysfunction, including "itai'itai" disease patients and patients suspected of the disease, were compared with subjects with normal renal functions, as a group, the former excreted significantly higher concentrations of metallothionein in their urine than the latter. The results suggest that the elevated excretion of metallothionein is not only an index of excessive cadmium exposure, but also of renal dysfunction caused by chronic exposure to this metal.

Topics: Aged; Cadmium Poisoning; Copper; Environmental Exposure; Female; Glycosuria; Humans; Kidney Diseases; Metalloproteins; Metallothionein; Middle Aged; Proteinuria

Metallothionein, a low molecular weight cadmium-binding protein, has been determined for the first time in urine of "itai-itai" disease patients and other Japanese women environmentally exposed to cadmium. On a group basis, the urinary metallothionein levels of "itai-itai" disease patients and suspected patients were significantly higher than that of women living in a cadmium-polluted area. Women living in a non-polluted area excreted significantly less metallothionein than women living in a cadmium-polluted area. A similar trend was observed for urinary beta 2-microglobulin, a nonspecific index of renal tubular dysfunction. However, mean levels of urinary cadmium in the "itai-itai" disease patients, suspected patients and women living in the cadmium-polluted area were similar. It is suggested that if, in addition to beta 2-microglobulin and cadmium, metallothionein is used as another index of cadmium exposure, monitoring of renal tubular dysfunction caused by cadmium may be more effectively carried out.

Topics: Aged; beta 2-Microglobulin; Cadmium; Cadmium Poisoning; Environmental Exposure; Female; Humans; Kidney Diseases; Metalloproteins; Metallothionein; Middle Aged

The concentrations of zinc, copper, iron, manganese, magnesium, and phosphorus in the kidneys were determined for control female rats of five different ages (4, 8, 12, 16, and 20 weeks old). The concentration of copper increased with age and it was attributed to three metallothionein peaks on a SW 3000 column. Parenteral administration of Cd-thionein caused swelling of kidneys to different degrees, depending on the age of the rats; the youngest rats were affected most. The concentrations of cadmium and the six metals in the kidneys at 12 hr and 7 days after injection were determined and compared with controls. The distribution among protein fractions of cadmium, zinc, and copper, which are related to metallothionein, were examined by gel permeation chromatography. The elution profiles of the three metals changed not only with the ages of the rats but also with time after injection. The changes were correlated with the copper content in the metallothioneins and with swelling of the kidneys. The changes also correlated with native metallothionein levels.

Topics: Aging; Animals; Cadmium Poisoning; Female; Kidney; Metalloproteins; Metallothionein; Metals; Rats

Topics: Cadmium Poisoning; Humans; Metalloproteins; Metallothionein

Distribution profiles of cadmium (Cd) in the cytosols of livers prepared from repeatedly Cd-injected rats (3.0 mg Cd/kg body weight, 4 times a week for 1, 2, 3, or 4 weeks) were characterized by high-performance liquid chromatography with a flame atomic absorption spectrophotometer (HPLC-AAS). The accumulation of Cd and decrease of relative zinc (Zn) to Cd ratio in metallothionein were accompanied by the change of distribution profile of Cd in the cytosol fraction. Cd distributed to the heat-unstable high molecular weight proteins was assumed to be non-selectively bound free Cd and a toxic chemical form. Two kinds of heat-stable Cd-binding proteins other than metallothionein increased with the accumulation of Cd; one was metallothionein dimers, and the other was thought to be Cd-binding proteins of shorter amino acid chain than metallothionein and related to metallothionein.

Topics: Animals; Cadmium; Cadmium Poisoning; Carrier Proteins; Cytosol; Female; Liver; Metalloproteins; Metallothionein; Molecular Weight; Rats

Free and membrane-attached polysomes were isolated from the liver of normal and cadmium-treated rats, and were translated using L-[35S]cysteine and a nuclease-treated reticulocyte lysate system. The translation products were analyzed for radioactive metallothionein by immunoprecipitation with antibodies to rat cadmium metallothionein followed by sodium dodecyl sulfate--polyacrylamide gel electrophoresis. In both normal and cadmium-treated rats, radioactive metallothionein was produced by free polysomes but not by membrane-attached polysomes. Cadmium treatment did not increase the in vitro ability of polysomes to synthesize metallothionein. As a control, the translation products of these two classes of polysomes were also analyzed for radioactive albumin and it was confirmed that membrane-attached polysomes produce albumin but do not synthesize metallothionein. The cell-free synthesis of metallothionein by free polysomes was also demonstrated by isolation of nascent metallothionein by Sephadex gel filtration and DEAE-cellulose chromatography. In adult rat liver there are two forms of metallothionein and both were produced in vitro by free polysomes.

Topics: Albumins; Animals; Cadmium; Cadmium Poisoning; Liver; Male; Metalloproteins; Metallothionein; Polyribosomes; Protein Biosynthesis; Rabbits; Rats; Reticulocytes

The urinary excretion of Cd, Cu, and Zn was measured in rats injected with 0.5 mg/kg Cd, sc, 6 d/wk for u to 25 wk. Gel chromatographic analysis for these urinary metals were also carried out. The Cd excretion slightly increased at first, followed by a rapid increase with concurrent appearance of proteinuria around 6 wk. During these early weeks, excretion of Cu in the urine showed a more pronounced increase and reached a plateau level (three to four times the control value). Zn excretion showed a sharp increase accompanied by proteinuria, following a slight increase, and reached about 10 times the control value. A linear relation was obtained between Cd and both Cu and Zn in the urine before proteinuria appeared. Metallothionein (MT) in the urine was associated only with Cu before the appearance of proteinuria. Cu-MT increased with increasing excretion of urinary Cu. Cd-containing MT first appeared in the urine after on onset of proteinuria, but it was still rich in Cu at first. Fron 10 wk, urinary MT showed an excess increase and contained much Cd than Cu. Zn-MT was not observed in the urine. Most of the urinary Zn was recovered from the lower-molecular-weight fractions. The results suggest that MT is directly involved in urinary excretion of Cu in the absence of renal damage and in the excretion of Cd as well as Cu after the appearance of toxicity in Cd-exposed rats.

Topics: Animals; Cadmium; Cadmium Poisoning; Chromatography, Gel; Copper; Male; Metalloproteins; Metallothionein; Rats; Rats, Inbred Strains; Zinc

Topics: Animals; Cadmium Poisoning; Chromatography, Ion Exchange; Copper; Male; Metalloproteins; Metallothionein; Rats; Zinc

Topics: Adult; Body Fluids; Cadmium Poisoning; Humans; Metalloproteins; Metallothionein; Middle Aged; Occupational Diseases

Repeated s.c. injections of cadmium chloride into rats (3 mg Cd/kg body weight, 4 times a week) caused acute and transitory tubular necrosis after 2 to 3 weeks; recovery was observed after 4 weeks despite continued loading. Kidney copper decreased for the first 3 weeks and was slightly increased after 4 weeks. Distribution profiles of cadmium (Cd), zinc (Zn), copper (Cu) on an SW column revealed that elution profiles of kidney metallothionein changed from typical kidney with high copper content to typical liver metallothioneins with tubular necrosis and restoration.

Topics: Animals; Cadmium; Cadmium Poisoning; Copper; Female; Kidney; Kidney Diseases; Metalloproteins; Metallothionein; Necrosis; Rats; Rats, Inbred Strains; Zinc

Topics: Aging; Animals; Cadmium Poisoning; Fertility; Male; Metallothionein; Organ Size; Rats; Testicular Diseases; Testis

Topics: Animals; Cadmium; Cadmium Poisoning; Carrier Proteins; Cricetinae; Cross Reactions; Horses; Humans; Liver; Metalloproteins; Metallothionein; Radioimmunoassay; Rats; Species Specificity; Zinc

Topics: Animals; Cadmium; Cadmium Poisoning; Cytosol; Liver; Metalloproteins; Metallothionein; Molecular Weight; Protein Binding; Species Specificity; Trout

The effects of dosage and of cadmium pretreatment on the binding of cadmium in rat bile were studied. With increasing dose a higher cumulative biliary excretion of Cd was observed and a higher percentage of the Cd was excreted in a low-molecular-weight form. On the other hand, after cadmium pretreatment, a decrease in the cumulative biliary excretion of cadmium was observed but a greater percentage of that excreted into the bile was bound to high molecular weight compounds.

Topics: Animals; Bile; Cadmium; Cadmium Poisoning; Female; Metallothionein; Molecular Weight; Rats; Time Factors

Topics: Amino Acid Sequence; Animals; Cadmium Poisoning; Liver; Metalloproteins; Metallothionein; Mice; Rabbits; Species Specificity

Topics: Animals; Cadmium; Cadmium Poisoning; Female; Fetus; Kidney; Liver; Maternal-Fetal Exchange; Metalloproteins; Metallothionein; Pregnancy; Zinc

Topics: Animals; Cadmium; Cadmium Poisoning; Humans; Kidney; Liver; Mercury; Metalloproteins; Metallothionein; Organ Specificity; Protein Biosynthesis; Rabbits; Rats; Species Specificity; Transcription, Genetic; Zinc

The effects of dietary cadmium on copper and zinc metabolism in animals are described. Emphasis is given to situations involving chronic exposure to low levels of cadmium, to the identification of population groups most at risk, and to the protective effect of dietary supplementation with copper and zinc. The mechanism of the interaction between the metals and the involvement of metallothionein are discussed.

Topics: Animals; Cadmium Poisoning; Ceruloplasmin; Copper; Diet; Female; Kidney; Metallothionein; Pregnancy; Sheep; Vitamin D; Zinc

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

Topics: Animals; Cadmium; Cadmium Poisoning; Calcium; Calcium, Dietary; Carrier Proteins; Dose-Response Relationship, Drug; Intestinal Mucosa; Intestine, Small; Male; Metallothionein; Rats

The mechanisms by which cadmium (Cd) stimulates the synthesis of hepatic and renal metallothionein were investigated in rats. In the liver the incorporation of 35S and 14C labels from cystine showed a lag period of about 2 h and maximum incorporation into metallothionein took place 8--12 h after injection of 30 mumol CdCl2/kg. The incorporation of the labels into renal metallothionein was faster than into the hepatic protein; the lag period was less than 1 h and maximum incorporation occurred 4--5 h after the Cd injection. Cycloheximide inhibited the amino acid incorporation into both hepatic and renal metallothionein. Actinomycin D treatment, however, inhibited hepatic metallothionein synthesis only. These results suggested that at the dose level employed Cd regulated the biosynthesis of metallothionein in the liver at the transcriptional level and in the kidney at the translational level.

Topics: Animals; Cadmium; Cadmium Poisoning; Cycloheximide; Dactinomycin; Kidney; Kinetics; Liver; Male; Metalloproteins; Metallothionein; Organ Specificity; Rats; Subcellular Fractions

Topics: Animals; Cadmium; Cadmium Poisoning; Intestinal Mucosa; Intestine, Small; Kidney; Kinetics; Liver; Male; Metalloproteins; Metallothionein; Organ Specificity; Rats; Testis; Time Factors