Effect of N-benzyl-D-glucamine dithiocarbamate on distribution and excretion of cadmium in rats

The effect of sodium N-benzyl-D-glucamine dithiocarbamate (NBG-DTC) on the distribution and excretion of cadmium in rats exposed to cadmium and the chemical form and intestinal reabsorption of cadmium compound excreted in the bile were studied. Rats were injected intraperitoneally with 109CdCl2 (1 mg Cd and 10 microCi 109Cd/kg) and 24 h later, they were injected with NBG-DTC (400 or 1200 mumol/kg). The biliary excretion of cadmium was remarkably increased by intraperitoneally injection of NBG-DTC, while there was only a small increase in urinary excretion of cadmium. Such an enhancement effect of NBG-DTC on the biliary excretion of cadmium was much larger at the high dose (1200 mumol/kg) of NBG-DTC. The treatment with NBG-DTC significantly decreased the cadmium content in the liver at the dose of 1200 mumol/kg and did not result in the undesirable redistribution of cadmium to the tissues, such as brain, testes, heart and lung. In addition, it was found that the cadmium compound excreted in the bile was mainly characterized as cadmium-NBG-DTC and which was not reabsorbed from the intestinal tracts.     

Protection against cis-diamminedichloroplatinum-induced nephrotoxicity in rats by N-benzyl-D-glucamine dithiocarbamate

Sodium N-benzyl-D-glucamine dithiocarbamate (BGD) was evaluated for its efficacy as an inhibitor of cis-diamminedichloroplatinum (DDP)-induced nephrotoxicity in a rat model. Treatment with 2.0 mmol/kg of BGD immediately after DDP injection effectively prevented nephrotoxic effects of DDP, but administration of BGD -1 or 1 h after DDP afforded a small protection. Concurrent treatment with 0.5 mmol/kg of BGD could not prevent renal damage. The platinum concentrations in liver and kidney were significantly decreased by BGD treatment. The antitumor efficacy of DDP in the Walker 256 carcinoma-bearing rats was not affected by administration of BGD (2.0 mmol/kg).     

Effect of N-benzyl-d-glucamine dithiocarbamate on renal toxicity induced by cadmium-metallothionein in rats

The effect of N-benzyl-D-glucamine dithiocarbamate (BGD) on the renal toxicity induced by acute exposure to cadmium-metallothionein (Cd-MT) in rats was studied. Rats were injected intraperitoneally with BGD (400 mumol/kg) 6, 12, or 24 h after intraperitoneal injection of Cd-MT (1.78 mumol Cd as Cd-MT/kg) and thereafter they received three injections of BGD (400 mumol/kg) daily for 3 days. Urinary protein concentration and aspartate aminotransferase (AST) activity significantly increased 1 day after Cd-MT treatment and decreased to control levels at 9 days after the treatment. Urinary excretion of glucose and amino acids rose gradually reaching maximum levels 5 days after Cd-MT treatment and returned to the control levels at 9 days. BGD injection significantly reduced the increases in the urinary excretion of protein, AST, glucose and amino acid, which were produced by Cd-MT treatment. Significant increases in urine volume were observed after Cd-MT treatment. BGD injection inhibited the increase in urine volume caused by Cd-MT treatment. A long time interval (12 and 24 h) between the administrations of Cd-MT and BGD resulted in a decreased protective effect of BGD against Cd-MT-induced renal damage. Following Cd-MT injection, the major route of excretion of cadmium (Cd) was via the urine and the kidney was the major site of accumulation of Cd. BGD injection remarkably increased the urinary excretion of Cd, resulting in a significant reduction in the kidney Cd concentration. The results of this study indicate that BGD injection is effective in decreasing the Cd concentration in the kidney, resulting in the protective effect on Cd-MT-induced renal damage.     

Chronic hepatic and renal toxicity by cadmium in rats

Recently there has been an increased interest in the toxic effects from long term exposure of low levels of cadmium (Cd) in diet. Male, Sprague-Dawley rats were treated with 0, 25, 50, 75 ppm Cd mixed in diet continuously for 180 days. A significant decrease in body weight gain was observed in all Cd treated animals. Serum glucose, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvic transaminase (SGPT) were increased parallel to Cd concentration and treatment time. Measured hepatic and renal gluconeogenic enzymes, viz. glucose-6-phosphatase, fructose-1, 6-bisphosphatase and phosphoenolpyruvate carboxykinase were increased with higher Cd dose and time. Low concentration of Cd (25 ppm) had minimal effect with shorter treatment length. Fructose-1, 6-bisphosphatase was found to be very sensitive for assessing Cd-induced nephrotoxicity. Increased serum glucose level and gluconeogenic enzyme activities suggest that Cd might interfere in protein metabolism.     

Distribution and excretion of cadmium and nickel after simultaneous exposure and the effect of N-benzyl-D-glucamine dithiocarbamate on their biliary and urinary excretion.

A rat model for combined exposure to cadmium and nickel is presented that involves the administration of drinking water containing these elements over a period of 90 d. Coadministration of these two ions in drinking water leads to brain levels of both elements that are significantly higher than results from the administration of equal doses of the metals individually. The enhanced biliary excretion of cadmium in rats given sodium N-benzyl-D-glucamine dithiocarbamate (BGDTC) is almost twice as great in those animals given cadmium and nickel as in those animals given cadmium only. The excretion of nickel is reduced by the administration of this chelating agent. Although equal amounts of nickel and cadmium were administered to these animals, liver and kidney cadmium levels were approximately 100 times greater than the corresponding nickel levels. The results suggest that combined exposure to these elements may lead to enhanced levels of nickel and cadmium in the brain and a level of nervous system damage not predictable from information obtained under conditions of exposure to only one of these elements.     

Effects of dithiocarbamates on testicular toxicity in rats caused by acute exposure to cadmium.

N-Benzyl-D-glucamine dithiocarbamate (BGD), N-p-isopropylbenzyl-D-glucamine dithiocarbamate (PBGD), and diethyl-dithiocarbamate (DED) were compared for their protective effects against the testicular toxicity in rats induced by acute exposure to cadmium. Rats were injected subcutaneously with 109CdCl2 (3 mg Cd and 74 kBq of 109Cd/kg) and 30 min later, they were injected intraperitoneally with the chelating agents (0.4 or 3 mmol/kg). Cadmium injection increased lipid peroxidation and concentrations of hemoglobin and Ca in the testes, decreased the testicular weight, and caused sterility. The treatment with BGD (0.4 mmol/kg) did not satisfactorily protect against the testicular toxicity of cadmium. The administration of PBGD or DED at a dose of 3 mmol/kg significantly prevented the increase in the lipid peroxidation and hemoglobin concentration in the testes, the decrease in the testicular weight, and the sterility caused by cadmium. PBGD and DED significantly decreased the cadmium concentration in the testes, but DED increased the cadmium concentration in the kidney and brain. Only DED significantly prevented the increase in the testicular Ca concentration after cadmium. These results indicate that PBGD and DED protect against the sterility caused by cadmium in rats and that the effect of DED to increase the brain level of cadmium is more dangerous than the lack of effect of PBGD to prevent the increase in the testicular Ca level. The protective effects of PBGD and DED against the cadmium-induced testicular toxicity presumably result from a decrease in the cadmium concentration in the testes.     

Critical concentration of cadmium for renal toxicity in rats

To evaluate a critical concentration concept of cadmium (Cd) toxicity on the kidney, relationships of renal Cd level with urinary excretion of various substances--i.e., metallothionein, alkaline phosphatase, lactate dehydrogenase, N-acetyl-beta-D-glucosaminidase, total protein, Cd, copper, and zinc--were studied in Cd-injected rats. At the renal Cd concentration of 100-200 micrograms/g tissue, a dramatic increase of all these substances in urine was observed, supporting the idea of the critical concentration proposed by Friberg and co-workers (1974). The significance of increase of urinary metallothionein below this level is also discussed.     

Effect of taurine on toxicity of cadmium in rats

A study was undertaken to investigate the effect of taurine on the toxicity of cadmium in male Wistar rats. The rats were divided into six groups and fed different diets with or without supplement of 5% taurine and 150-300 ppm cadmium for 2 months. It was found that the body weight of rats, the ratios of liver and kidney weight to body weight, and the level of glutathione in the liver were decreased with increasing the dose of cadmium. The levels of cadmium in the liver and kidney, the levels of thiobarbituric acid-relative substances (TBARS) in the plasma and liver, the activities of aspartate transaminase (AST) and alanine transaminase (ALT) in the plasma, and the levels of blood urea nitrogen (BUN) and creatinine in the plasma of rats were increased with the increasing dose of cadmium. Hence, symptoms of cadmium toxicity in rats included loss of body weight, hepatotoxicity and nephrotoxicity. However, these toxic effects of cadmium were significantly reduced when the rats fed diet with supplement of taurine. Furthermore, the level of cadmium in the feces of rats treated with taurine and cadmium was higher than that of rats treated with cadmium alone. It indicated that taurine might play a role in reducing the toxic effect of cadmium in rats.     

Protective role of selenium against renal toxicity induced by cadmium in rats

Cadmium is an environmental toxic metal implicated in human diseases. The mechanism of its toxicity is not fully understood. Therefore, the role of cadmium in renal toxicity, and the protective role of selenium against this toxicity were investigated. Forty-five male rats were used through out the study and divided into three groups of 15. The first group received saline solution daily for 10 days. The second group, received cadmium chloride (CdCl₂) (2 mg/kg body weight) intraperitoneally daily for a period of 10 days. The third group, received sodium selenite (1 mg/kg body weight, twice a day) and CdCl₂ (once a day) for a period of 10 days. The results showed that cadmium treatment increased renal lipid peroxidation (measured as malondialdehyde, MDA) which was associated with a significant decrease in the antioxidant systems such as reduced glutathione levels and the activities of glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). On the other hand, pretreatment of rats with selenium and cadmium led to a significant decrease in MDA concentration, and increased levels of GSH and the activities of GPx and TrxR when compared with those of cadmium-treated group. The total levels of phospholipid, triglyceride, and cholesterolester classes were decreased, while free fatty acids levels were markedly increased after cadmium treatment. In addition, the total levels of both mono- and poly-unsaturated fatty acids of different lipid classes were significantly decreased, while the total saturated fatty acids was significantly increased by cadmium treatment. Pretreatment of rats with selenium, was found to protect kidney tissues of rats against the biochemical changes resulting from cadmium administration. These results suggest that cadmium causes renal toxicity by inducing lipid peroxidation, decreasing antioxidant systems, and also by altering lipid metabolism. In addition, selenium treatment could protect the kidney tissues against the toxicity of cadmium since it reduced MDA levels and increased the activities of antioxidant enzymes in these tissues. These results could be important for the further understanding of the complex mechanisms of cadmium toxicity in kidney tissues and in the development of better treatments for people and/or animals exposed to the heavy metal.     

Nervous system effects of dissolved and nanoparticulate cadmium in rats in subacute exposure

Cadmium, a toxic heavy metal with various applications in technology, can affect people both by environmental (foodborne) and occupational (inhalation) exposure and can cause nervous system damage. To model this, rats were subacutely treated either with CdCl(2) solution per os (3.0 mg kg(-1) b.w.) or nanoparticulate CdO(2) (particle size ca 65 nm) by intratracheal instillation (0.04 mg kg(-1) b.w.) alone or in sequential combination. Nervous system effects were observed at different levels of function (open field behavior, cortical electrical activity, nerve action potential) and some general toxicological indicators were also measured. Three weeks of oral plus one week of intratracheal exposure caused significant reduction of body weight gain and open field motility. Lengthening of latency of sensory evoked potentials, observed in all treated rats, was also the most significant in the group receiving oral plus intratracheal treatment. Conduction velocity of the tail nerve was likewise decreased in all treated groups. Several of the effects pointed to a potentiating interaction between the two forms of Cd. Modeling environmental and occupational Cd exposure by oral and intratracheal application in rats was feasible, with results suggesting serious negative health effects in humans suffering such a combined exposure.     

Effect of cadmium on the toxicity of lanthanons in mice and rats

Prior administration of a sublethal dose of cadmium (1 mg/kg i.p.) produced a significant reduction in mortality of male mice and a trend to improve the impaired drug-metabolising capacity in male and female rats after a toxic dose of the light lanthanon, cerium (2 mg/kg i.v.). Gel filtration studies show that cerium binds to the high molecular weight protein fraction in rat liver cytosol despite cadmium pretreatment. This finding rules out the possibility that cadmium exerts its effect through the protective system of a newly synthesized metallothionein.     

Effect of oral and inhalation exposure to cadmium on the oestrous cycle in rats

Female rats were administered by gavage an aqueous solution of CdCl2 for 14 weeks, 5 days per week, at doses of 0.04, 0.4, 4 and 40 mg Cd/kg/day or exposed by inhalation to CdO for 20 weeks (5 h per days, 5 days per week) at concentrations of 0.02, 0.16 and 1 mg Cd/m3. A pronounced increase in the mean duration of the oestrous cycle mainly due to lengthening of dioestrus was noted already 6 weeks after treatment of females given per os 40 mg Cd/kg or exposed to a concentration of 1 mg Cd/m3. No changes in the mean duration of the oestrous cycle were found in other experimental groups, although in the 0.16 mg Cd/m3 group an increased percentage of females with oestrous cycles lasting over 6 days was shown 18 weeks after exposure. Since Cd-induced lethality and decrease in body weight gain were observed in females given by gavage 40 mg Cd/kg or exposed by inhalation to a concentration of 1 mg Cd/m3, it is concluded that exposure to cadmium does not affect the sexual cycle unless other overt signs of Cd-toxicity are induced.     

Effect of repeated exposure to lindane and cadmium on lindane metabolism in rats

The effects of daily administration of cadmium and lindane for 35 days on the metabolism of lindane in rats were investigated. The results indicate that cadmium induces a significant inhibition of lindane metabolism, since the group dosed with lindane plus cadmium had a significantly higher concentration of lindane in plasma and tissues than the group dosed with lindane alone. The inhibition in the metabolic rate of lindane is associated with the cadmium-induced alterations in the disposition of essential trace elements, Zn, Cu and Fe, in the liver.     

Failure to produce hypertension in rats by chronic exposure to cadmium

Groups of ten male and ten female Sprague-Dawley rats were exposed for 92 and 84 wk, respectively, to increasing concentrations of cadmium (as the chloride) in their drinking-water. The exposure levels of Cd used were 0, 5, 12·6 and 31·5 ppm Cd, and 5 ppm Cd plus certain trace metals. Blood pressure was measured in unanaesthetized animals at regular intervals (46 times in females, 49 times in males) by an indirect method to which the animals were kept conditioned. At the end of the experiments blood pressure was also determined directly under sodium pentobarbital anaesthesia. Although the weight of the kidneys, Cd residues and the severity of histological alterations in the kidneys increased in a dose-related manner, the blood pressure and pulse rate were not significantly affected in any of the experimental groups. There was a dose-dependent decrease in water consumption; all other parameters remained unaffected.     

Effects of chronic exposure to cadmium on renal cytochrome P450-dependent monooxygenase system in rats

The aim of this study was to evaluate the effects of chronic exposure to cadmium (Cd) on the renal cytochrome P450-dependent monooxygenase system. For this purpose, male Wistar rats were intoxicated with Cd administered in drinking water at a concentration of 5 or 50 mg Cd/l for 6, 12 and 24 weeks. Concentrations of cytochrome P450 and cytochrome b₅ as well as activities of NADPH-cytochrome P450 reductase and NADH-cytochrome b₅ reductase were determined in the kidney microsomal fraction. Protein content of CYP1A1, CYP2E1 and CYP3A1 cytochrome P450 isoforms was evaluated as well. In the rats exposed to 5 mg Cd/l, the concentration of cytochrome P450 decreased (by 41%) after 24 weeks of the experiment. The activity of NADPH-cytochrome P450 reductase decreased (by 24%) after 6 and 12 weeks, whereas after 24 weeks it remained unchanged, compared with the control group. Moreover, a decrease in the concentration of cytochrome b₅ (by 25, 15 and 26% at 6, 12 and 24 weeks, respectively) and the activity of its NADH reductase (by 26 and 31% at 6 and 24 weeks, respectively) was noted in these animals. At the exposure to 50 mg Cd/l, the concentrations of cytochrome P450 and cytochrome b₅ and the activities of their corresponding reductases were decreased at each time-point. Western blot analysis revealed that all isoforms of cytochrome P450 studied were affected by Cd and the effect was dependent on the level and the duration of exposure. The results of this study indicate that chronic exposure to Cd in a dose- and time-dependent manner affects the kidney cytochrome P450-dependent monooxygenase system by decreasing the concentrations of cytochrome P450 and cytochrome b₅ and inhibiting the activities of their corresponding reductases. The effect of Cd on the cytochrome P450 content is associated with its ability to stimulate or inhibit of various P450 isoforms. A very important finding of this study is that Cd affects the kidney cytochrome P450-dependent monooxygenase system at relatively low exposure and low kidney Cd accumulation (2.40±0.15 g/g). As the experimental model used reflects human exposure to Cd, we conclude that Cd can affect the kidney cytochrome P450-dependent monooxygenase system in environmentally exposed humans. Previously we have reported disorders in the system in the liver of rats at the same levels of exposure as in this study. Thus, we hypothesize that the metabolism and detoxification of many substances, including xenobiotics, may be seriously affected in Cd-exposed subjects.Part of this work was presented at the EUROTOX 2001, Istanbul, Turkey, 2001     

Exogenous metallothionein and renal toxicity of cadmium and mercury in rats.

The relative tissue distribution and toxicity of cadmium (Cd) and mercury (Hg) in the liver and kidneys of rats when the metals are administered as either inorganic salts or complexed with MT were studied. Male Sprague-Dawley rats were injected (i.v.) with Cd or Hg inorganic salt of chloride or in a complex of MT at a dose of 0.3 mg/kg body weight. The concentration of MT and metals in plasma and urine was monitored for 7 days, at the end of which the rats were killed. Injection of both HgCl2 and Hg-MT induced the synthesis of MT only in the kidney but not in the liver, whereas CdCl2 and Cd-MT injections induced MT synthesis in both liver and kidney, respectively. Plasma MT levels increased 3 days after CdCl2 but not after HgCl2 injection, suggesting that hepatic MT may be an important source of plasma MT under our experimental conditions. Renal toxicity was observed morphologically and by an increase in blood urea nitrogen, plasma creatinine, proteinuria in rats injected with Cd-MT and both forms of Hg. Urinary MT excretion was significantly elevated in Cd-MT injected rats compared with those injected with CdCl2. However, HgCl2 and Hg-MT injected rats showed no significant difference in urinary MT excretion. The magnitude in the renal accumulation of Hg is similar after the administration of Hg-MT or HgCl2, but our findings suggest that the site of epithelial injury may be different. Injury effects of Hg-MT localized mainly in the terminal portions of the proximal convoluted tubule and the initial portions of the proximal straight tubule whereas inorganic Hg caused necrosis in pars recta segments of the proximal tubule.     

Effect of low-level lifetime exposure to cadmium on calciotropic hormones in aged female rats

The effect of low-level lifetime exposure to cadmium (Cd) on calciotropic hormones and the possible association between the Cd-induced disorders in bone metabolism and these hormones were investigated on a female rat model of human environmental exposure in areas unpolluted by this metal. For this purpose, the concentrations of 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)₂D), calcitonin (CT) and parathormone (PTH) were measured in the serum of control and Cd-exposed (1 mg Cd/l in drinking water for 24 months) female rats. Calcium (Ca) and inorganic phosphorus (P_i) serum concentrations, renal tubular reabsorption of Ca (TRCa) and phosphate (TRP) and the glomerular filtration rate (GFR) were estimated as well. Moreover, 1,25(OH)₂D, metallothionein (MT) and Cd were determined in the kidney. The exposure to Cd led to a decrease in the serum concentrations of 25OHD and 1,25(OH)₂D (by 50 and 31%, respectively) and the concentration of 1,25(OH)₂D in the kidney mitochondrial fraction (by 55%). The serum concentrations of CT and PTH increased (5.2-fold and by 29%, respectively) and those of Ca and P_i were unchanged, whereas the TRCa, TRP and GFR decreased due to the exposure to Cd. The results give evidence that the low lifetime exposure to Cd disturbs the metabolism of calciotropic hormones and damages the reabsorptive and filtrative function of the kidney in aged female rats. Numerous correlations noted between calciotropic hormones and the indices of kidney function, and indices of bone turnover and bone mineral status (bone mineral content and density) of these females indicate a relationship between these hormones and the kidney functional status and bone metabolism. The results of the present study together with our previous findings on the bone status in the experimental model allow for the conclusion that the low lifetime exposure to Cd by affecting the metabolism and proper function of calciotropic hormones may contribute to the advancement of bone damage at the elderly.     

Immuno- and neurotoxicological investigation of combined subacute exposure with the carbamate pesticide propoxur and cadmium in rats

In the present study, the effects of subchronic per os exposures to cadmium chloride (CdCl(2)), and a carbamate insecticide, propoxur (Pr), were investigated in male Wistar rats on general toxicological (body weight gain, relative organ weights) haematological (RBC, WBC, Ht, MCV, cell content of the femoral bone marrow) immune function (plaque forming cell (PFC) assay, delayed type hypersensitivity (DTH) reaction) and neurotoxicological (spontaneous and stimulus-evoked cortical activity, nerve conduction velocity) parameters. The animals were treated for 4, 8 and 12 weeks with 6.43 mg/kg CdCl(2), 8.51 mg/kg Pr, or with a combination of 6.43 mg/kg CdCl(2)+0.851 mg/kg Pr or 8.51 mg/kg Pr+1.61 mg/kg CdCl(2). Cadmium exposure affected the relative thymus, liver, and adrenal weight, RBC count, haematocrit and MCV, and there was an increase in nerve conduction velocity and a decrease in the cortical evoked potential latency. Pr induced a decrease in thymus weight, had some effect on the liver weight but none on the electrophysiological parameters. A significant interaction between Cd and Pr was detected by the following parameters: RBC, Ht, PFC, and nerve conduction velocity. The results indicate that combined exposures in humans may result in a shift in the apparent detection limits and/or in the LOEL of the single substances. The latter raises the necessity to reconsider exposure limits in situations where the risk of combined exposure is high.     

Immune alterations in rats following subacute exposure to tributyltin oxide

Adult male Fischer 344 rats were dosed by oral gavage with bis(tri-n-butyltin)oxide (TBTO) in peanut oil for 10 consecutive days, at dosages ranging from 1.25 to 15 mg/kg/day. Other groups of rats were dosed daily for 10 days by oral gavage with cyclophosphamide (CY) at dosages ranging from 0.75 to 6 mg/kg/day. These rats served as positive controls for the immune assays employed. The immune function parameters examined included the following: delayed-type hypersensitivity (DTH) and antibody responses to bovine serum albumin (BSA), primary antibody responses to sheep red blood cells (SRBC) and trinitrophenyl lipopolysaccharide (TNP-LPS) and enumeration of splenic lymphocyte populations. The DTH and antibody responses to BSA were not affected by TBTO exposure; however these responses were suppressed in rats dosed with CY at 6 mg/kg/day. The plaque forming cell (PFC) response to the T cell-dependent antigen SRBC was enhanced in rats dosed with TBTO at from 5 to 15 mg/kg/day. On the other hand, the PFC response to the T cell-independent antigen TNP-LPS was unaffected by TBTO exposure. Rats dosed with CY had suppressed PFC responses to SRBC and TNP-LPS at dosages of 3 and 6 mg/kg/day, respectively. Enumeration of splenic lymphocyte populations from TBTO-exposed rats revealed a reduction in OX8- but not W3/25- or IgG-positive cells. These results, as well as results from an earlier study from this lab, suggest that T lymphocytes are a primary target for TBTO-induced immune alterations and that the enhancement of the PFC response to SRBC in TBTO-exposed rats may be mediated by alterations in the suppressor (OX8-positive) T lymphocyte population.     

Effect of long-term inhalation exposure to cadmium oxide fumes on cardiac muscle ultrastructure in rats

The ultrastructure of the cardiac muscle of rats exposed 5 h daily, 5 days a week to cadmium oxide (CdO) fumes at a concentration of 0.16 mg Cd/m3 for 3 and 6 months and at a concentration of 1 mg Cd/m3 for 3 and 4 months has been evaluated. The structure of muscle cells, arterioles and capillaries remained unchanged. There were distinct alterations of the intercalated disc structure dependent upon the level and time of exposure. The damage to intercalated discs varied from the enlargement of the fissure between membranes (within unspecialized segments) to disruption of the complex junctions.