Kidney concentrations and urinary excretion of mercury,zinc and copper following the administration of mercuric chloride and sodium selenite to rats

The effect of single (SC) administration of mercuric chloride (1 mg Hg/kg) alone or jointly with (PO) sodium selenite (0.39 mg Se/kg) on kidney disposition of mercury (Hg) and metallothionein (MT) and urinary excretion of Hg, zinc (Zn) and copper (Cu) has been studied in the female rat. The excretion of Hg and essential metals was determined every day following exposure. Daily excretion of endogenous Cu and Zn the Hg-exposed group was about threefold and fourfold, respectively, in comparison with control groups of rats. Sodium selenite prevented the urinary excretion of endogenous Cu and partly of Zn.     

Binding of mercury and selenium in subcellular fractions of rat liver and kidneys following separate and joint administration

The distribution of mercury and selenium has been examined in subcellular fractions of rat liver and kidneys in prolonged exposure to HgCl₂ and Na₂SeO₃ administered separately and simultaneously. The molar ratio of mercury and selenium concentrations in subcellular fractions of the organs examined varied considerably. Selenium displaced mercury from the soluble kidney fraction bound mainly with metallothionein to the nonhistone protein fraction of liver nuclei. The Hg-stimulated biosynthesis of metallothionein has been eliminated under the influence of selenium.This work was supported by the Polish-American agreement No 05-009-2, with National Institute for Occupational Safety and Health, PHS, USA     

Concomitant administration of sodium 2,3-dimercapto-1-propanesulphonate (DMPS) and diphenyl diselenide reduces effectiveness of DMPS in restoring damage induced by mercuric chloride in mice

The effect of combined therapy with diphenyl diselenide (PhSe)₂ and sodium 2,3-dimercapto-propane-1-sulphonate (DMPS) against alterations induced by mercury (Hg²⁺) was evaluated. Mice were exposed to mercuric chloride (HgCl₂) (1 mg/kg, subcutaneously) for two weeks. After that, mice received (PhSe)₂ (15.6 mg/kg), or DMPS (12.6 mg/kg), or a combination of both for one week. Thiobarbituric acid-reactive substances (TBARS), ascorbic acid and Hg²⁺ levels and glutathione S-transferase (GST) and catalase (CAT) activities were carried out in kidney. Hematological parameters, plasmatic billirubin, uric acid, urea and creatinine levels as well as lactate dehydrogenase (LDH) activity were determined. (PhSe)₂ or DMPS restored the increase in LDH activity and TBARS, bilirubin, uric acid, urea and creatinine levels caused by HgCl₂. The levels of erythrocytes, hemoglobin and hematocrit reduced by HgCl₂ exposure were restored by (PhSe)₂ or DMPS administration in mice. Leukocyte and platelet counts modified by HgCl₂ exposure were restored by (PhSe)₂ or DMPS therapy. DMPS restored the increase in Hg²⁺ levels induced by exposure to HgCl₂. Concomitant administration of (PhSe)₂ and DMPS reduced the effectiveness of DMPS in restoring damage induced by HgCl₂. Combined therapy with (PhSe)₂ and DMPS was less effective than isolated therapies in restoring the damage induced by HgCl₂ in mice.     

Differences in distribution and excretion of selenium and cadmium or mercury after their simultaneous administration subcutaneously in equimolar doses

Forty-eight hours after the simultaneous administration of either 1.8 moles Se (as Na₂SeO₃) to 200 g male rats with equivalent doses of Cd (as CdCl₂) or 0.5 moles Se with equivalent doses of Hg (as HgCl₂) the retention of selenium at the subcutaneous injection site was affected only when it was given in a single injection with the heavy metal. The retention of cadmium was increased only if selenium was injected separately and the retention of mercury was increased both in single and separate injections. When there was an increase in retention at the site of injection, this made up less than 8% of the dose for selenium and mercury and 3% for cadmium and thus could not explain either changes in distribution or the reported protective effects by one metal against the other. The shift in the distribution pattern of one metal caused by the other metal was similar, and independent of whether they were injected in single or separate injections. However the shift in the distribution of interacting metals showed some differences indicating that interaction could not be mediated through the formation of a stable complex between selenium on the one hand and mercury or cadmium on the other.Supported partly by International Atomic Energy Agency, Grant Number 1530/RB     

Simultaneous administration of sodium selenite and mercuric chloride decreases efficacy of DMSA and DMPS in mercury elimination in rats

Two chelating agents meso-2,3-dimercaptosuccinic acid (DMSA) and sodium 2,3-dimercapto-propane-1-sulphonate (DMPS) were tested for their efficiency in mercury removal from the body of rats in the presence and in the absence of selenium. Female Wistar rats were given a single intraperitoneal injection of mercuric chloride or an equimolar mixture of mercuric chloride and sodium selenite (1.5 micromol/kg body weight). The chelating agents were given orally, in excess (500 micromol DMSA/kg body weight; 300 micromol DMPS/kg body weight), 30 min after the administration of mercury and selenium. The animals were euthanized 24 h after the treatment and mercury in the kidney, liver, and 24 h urine was determined using cold vapour atomic absorption spectrometry (CV-AAS). The simultaneous administration of mercuric chloride and sodium selenite led to a redistribution of mercury in the organs, so that accumulation of mercury in the kidneys was decreased and in the liver increased. Selenite also caused decrease in the level of urinary mercury excretion. Both chelating agents were effective in mercury removal from the body, by increasing its urinary excretion. However, when animals were simultaneously treated with mercury and selenite, the rise of mercury excreted in the urine due to the treatment with chelating agents was lower when compared to animals receiving mercury without selenite. It is concluded that sodium selenite decreases the efficiency of DMSA and DMPS in mercury removal from the body of rats.     

Effects of cadmium treatment on selenium-dependent and selenium independent glutathione peroxidase activities and lipid peroxidation in the kidney and liver of rats maintained on various levels of dietary selenium

Rats fed a basal, low-selenium diet, or this diet supplemented with 0.1 ppm and 1.0 ppm selenium and treated with cadmium, showed significant reductions in the activity of the selenoenzyme glutathione peroxidase in kidney and liver. Cadmium treatment resulted in a significant increase in the activity of selenium-independent glutathione peroxidase activity in the liver of selenium-supplemented rats. Selenium-independent glutathion peroxidase activity was significantly reduced in the kidney of rats fed the basal low-selenium diet. There was no significant increase in lipid peroxidation in any of the groups studied. Cadmium concentrations in the kidney and liver of these animals ranged from about 250 to 700 g Cd/g tissue, dry weight.Supported by NIEHS Center Grant ES-00159 and a Grant from the Selenium-Tellurium Development Association     

N-乙酰半胱氨酸和亚硒酸钠对镉亚慢性毒性的影响

目的探讨N-乙酰半胱氨酸(N-acetyl cysteine,NAC)和亚硒酸钠(Na2SeO3)对亚慢性染镉大鼠肝肾毒性的影响及其机制。方法32只Wistart大鼠随机分为4组,每组8只,第1组为对照组,第2组为单位染镉组,第3、4组为干预组。大鼠连续6周皮下注射7μmol/kg氯化镉,然后干预组分别腹腔注射1 mmol/kg NAC和10μmol/kg Na2SeO3,共2周;测定大鼠尿N-乙酰-β-苷酶(NAG)、碱性磷酸酶活力(ALP)和肝、肾皮质谷胱甘肽(GSH)、丙二醛(MDA)含量及谷胱甘肽过氧化物酶(GSH-Px)活力。结果亚慢性染镉使大鼠肝、肾皮质和尿镉含量显著升高,尿ALP、NAG和蛋白含量显著升高,肝、肾皮质GSH含量显著升高,GSH-Px活力显著降低。与单纯染镉组比较,NAC处理组尿镉、NAG和蛋白含量显著下降,肝、肾皮质GSH显著降低;Na2SeO3处理组尿镉、ALP及肝、肾皮质GSH含量显著下降,GSH-Px活力显著升高。结论NAC和Na2SeO3对镉致肾损伤的恢复具有促进作用,其机制可能与NAC或Na2SeO3改变体内GSH含量和GSH-Px活力有关。     

The effects of dietary selenium on cadmium binding in rat kidney and liver

In acute studies, approximately 70–90% of cytosolic cadmium in liver and kidney has been shown to be bound to metallothionein, a low-molecular weight protein. In this study, we report on the influence of dietary selenium on the distribution of cadmium in rat kidney and liver. Contrary to the findings of most acute studies, our results indicate that only a relatively small proportion of cadmium (approximately 14% in the kidney and 44% in the liver) is bound to metallothionein when cadmium is administered for 7 weeks in the diet and via osmotic minipumps to selenium-deficient rats. Feeding rats the same diet supplemented with 1.0 ppm selenium results in no detectable cadmium-metallothionein peak in the kidney, and only about 10% of the cytosolic cadmium elutes as cadmium bound to metallothionein in the liver. In animals fed the selenium-supplemented diet, the bulk of the cadmium is recovered in the low-molecular weight fraction. Dietary selenium did not significantly affect the distribution of zinc and copper in the kidney or liver.Supported by NIEHS Center Grant ES-00159 and a grant from the Selenium — Tellurium Development Association     

沙棘油和亚硒酸钠对汞诱导的大鼠肝肾氧化损伤的影响

目的通过汞诱导大鼠肝肾氧化损伤,观察沙棘油(Sea Buckthorn Oil,SBO)和亚硒酸钠(Na2SeO3)干预效应。方法Wister大鼠随机分成对照组、单纯染汞组、SBO和Na2SeO3处理组。测定肝、肾及尿中汞含量,肝、肾中GSH、MDA、蛋白含量和SOD、GSH-PX活力。结果与单纯染汞组相比,SBO处理组尿汞含量增加(P<0.05),肝GSH-PX活力升高(P<0.01);Na2SeO3处理组肝汞增加,肾和尿汞含量下降,肝GSH-PX活力、GSH含量均升高(P<0.01),肝SOD活力和肾GSH-PX活力均增加(P<0.05),肾MDA含量下降(P<0.05)。结论沙棘油具有促进汞从肾脏排出的作用,对汞诱导的肝氧化损伤具有一定保护作用,对肾氧化损伤未表现出明显的保护作用。Na2SeO3可有效拮抗汞诱导的肝肾氧化损伤作用。     

Subacute effects of low dose lead nitrate and mercury chloride exposure on kidney of rats

Lead nitrate and mercury chloride are the most common heavy metal pollutants. In the present study, the effects of lead and mercury induced nephrotoxicity were studied in Wistar rats. Lead nitrate (LN, 45 mg/kg b.w/day) and mercury chloride (MC, 0.02 mg/kg b.w/day) and their combination were administered orally for 28 days. Four groups of rats were used in the study: control, LN, MC and LN plus MC groups. Serum biochemical parameters, lipid peroxidation, antioxidant enzymes and histopathological changes in kidney tissues were investigated in all treatment groups. LN and MC caused severe histopathological changes. It was shown that LN, MC and also co-treatment with LN and MC exposure induced significant increase in serum urea, uric acid and creatinine levels. There were also statistically significant changes in antioxidant enzyme activities (SOD, CAT, GPx and GST) and lipid peroxidation (MDA) in all groups except control group. In this study, we showed that MC caused more harmful effects than LN in rats.     

Binding of cadmium and mercury by metallothionein in the kidneys and liver of rats following repeated administration

Rats were injected subcutaneously with either cadmium chloride (0.5 mg Cd/kg) or mercuric chloride (0.5 and 0.25 mg Hg/kg) every other day over a period of 6 to 7 weeks. Levels of metals and metallothionein were determined in liver and kidneys. Both cadmium and metallothionein accumulated in these organs during the period of exposure. Mercury and metallothionein accumulated only in the kidneys. Mercury did not accumulate in the liver, nor did it cause an increase of metallothionein in the liver. The molar ratio of 1.6 (metal to metallothionein) in liver was constant for cadmium. In the kidneys this ratio varied from 1 to 3 for both metals, depending on the level of the metal; This ratio was 0.1 for liver mercury.This work was partly supported by the Polish-American agreement No. 05-009-2 with National Institute for Occupational Safety and Health, PHS, USA.     

Intervention of selenium on apoptosis and Fas/FasL expressions in the liver of fluoride-exposed rats

Fluorosis is a major public health problem in numerous areas around the world, including China. To alleviate this problem, selenium has been used. In this study, we aimed to investigate the influence of selenium on apoptosis in fluorosis-affected rat livers and determine the optimal selenium concentration in drinking water to fight fluorosis. The protein levels of Fas in NaF and NaF + Se (0.375 and 0.75 mg/L) groups as well as FasL in NaF, Se (0.75 and 1.5 mg/L), and NaF + Se (0.375 mg/L) groups were significantly increased compared with those in the control group. The mRNA levels of Fas in NaF and Se (1.5 mg/L) groups as well as FasL in NaF and NaF + Se (0.375 mg/L) groups were significantly increased. The protein levels of Fas in NaF + Se (1.5 mg/L) group and FasL in three NaF + Se groups were significantly decreased compared with those in the NaF group. The mRNA levels of Fas in the three NaF + Se groups and FasL in NaF + Se (0.75 and 1.5 mg/L) groups were significantly decreased. Compared with the control group, activity of GSH-Px, and SOD in the NaF group decreased obviously and MDA content increased obviously; activity of SOD in 1.5 mg/L Se group decreased obviously. Compared with the NaF group, activity of GSH-Px in NaF + Se (1.5 mg/L) group significantly increased, and MDA content decreased obviously. Thus, fluoride induced apoptosis in the liver, thereby causing liver damage in the rats. Selenium could alleviate fluorosis-induced liver injury. In particular, selenium at 1.5 mg/L is considered the optimum concentration against fluorosis.     

Changes in distribution of mercury and selenium in soluble fractions of rabbit tissues after simultaneous administration

The existing states of mercury and selenium in the blood and in soluble fractions of perfused rabbit liver and kidney were studied by gel filtration on Sephadex G-200 1 hr or 24 hr after intravenous injection of mercuric chloride and/or sodium selenite. Both mercury and selenium in the plasma and stroma-free hemolysate were found to exist in the high-molecular weight fraction following simultaneous injection of mercuric chloride and sodium selenite. Patterns in gel filtration of the plasma and the stroma-free hemolysate did not show any significant change between 1 hr and 24 hr after the administration. A similar tendency as described above was obtained with the liver-soluble fraction at 24 hr after injection of mercuric chloride and sodium selenite. A possible role of the high-molecular weight complex, which is quickly formed by the interaction of mercury and selenium in blood stream, in decreasing the acute renal toxicity of inorganic mercury is discussed.     

Antioxidant enzyme activity and lipid peroxidation in liver and kidney of rats exposed to microcystin-LR administered intraperitoneally.

The effect of acute exposure of intraperitoneal injection of microcystin-LR (MCLR) on antioxidant enzymes and lipid peroxidation has been studied in liver and kidney of rats. Rats were treated with two doses, i.e. 100 and 150 microg of pure MCLR/kg body weight or saline solution. The enzyme activities of glutathione peroxidase (GSH-Px), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT) in the liver were significantly decreased in MCLR-treated rats. The decrease of GR activity in the liver was 60%, followed by GSH-Px, SOD and CAT. Similarly, a decrease in the antioxidant enzymes was found in the kidney of MCLR-treated rats, such as GSH-Px (27-31%), GR (22%), SOD (42%) and CAT (25-28%). Concomitantly, significant increases in lipid peroxidation levels were recorded in liver (121 and 196% for 100 and 150 microg/kg, respectively) and kidney (48 and 58% for 100 and 150 microg/kg, respectively) from MCLR-treated rats. In conclusion, acute exposure to MCLR results in a decrease in the antioxidant enzymes and an increase in lipid peroxidation in liver and kidney rats, suggesting the oxidative stress as an important role in the pathogenesis of MCLR-induced toxicity. Antioxidant enzymes were significantly consumed in the liver and a minor decrease was found in kidney, confirming the organ-specific effects of MCLR.     

Biochemical and histological effects of five weeks ingestion of Zamzam water on the liver and kidneys of Wistar rats

Zamzam water is a natural alkaline water which has become alkaline as a result of the natural environment. It comes from what is considered as one of the oldest springs in the world. The water contains high concentrations of alkaline minerals as well as trace and heavy metals. The aim of the current study is to evaluate the effects of five weeks ingestion of Zamzam water on the liver and kidney functions of rats. Adult female Wistar rats weighing 150–200 g were divided into two groups, with 15 rats in each. The control group was supplied daily by bottled water and the Zamzam water group was supplied daily by 500 ml of Zamzam water for five weeks. The rats were weighed weekly and, at the end of the experiment, blood samples were collected from all rats for the biochemical determination of serum levels of aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), urea, creatinine, albumin, and uric acid, using calorimetric methods. Liver and kidney tissues were fixed in 10% neutral buffered-formalin solution and further embedded in wax blocks for routine hematoxylin and eosin (H&E) staining and were examined for histopathological changes using a light microscope. The results of the current study showed that there was a significant increase (P < 0.05) in the weight of the Zamzam group when compared to the control group after five weeks of ingestion. Liver and kidney function tests did not show any significant difference when compared with the controls (P > 0.05). In addition, histological examination of the liver and kidney tissues did not show any toxicological changes. In conclusion, the results showed that the ingestion of Zamzam water did not alter serum levels of kidney function tests and liver enzymes; and did not result in a noticeable change in the liver and kidney histology. Thus, the high concentrations of elements in Zamzam water do not induce hepatotoxicity or nephrotoxicity and the water is considered safe for long-term consumption.     

Profile of nonprotein thiols,lipid peroxidation and delta-aminolevulinate dehydratase activity in mouse kidney and liver in response to acute exposure to mercuric chloride and sodium selenite

The effects of mercury (Hg(2+)) and selenite (Se(4+)) on delta-aminolevulinic acid dehydratase (delta-ALA-D) activity, 2-thiobarbituric acid reactive substances (TBARS) and nonprotein sulfhydryl content (NPSH) in mouse kidney and liver were investigated. Male mice were given a single i.p. injection of Hg(2+) and/or Se(4+) (25 micromol/kg) and were killed at 6, 12, 24 and 48 h after treatment. Hg(2+) inhibited renal delta-ALA-D at 6 and 12 h after treatment. Se(4+) abolished the inhibitory effect of mercury on renal delta-ALA-D at 12 h after treatment. Renal and hepatic NPSH content decreased after Hg(2+) exposure and selenite inhibited, at least in part, the Hg-induced oxidation of renal and hepatic NPSH. Se(4+) and Hg(2+), when injected alone, did not alter hepatic or renal TBARS levels; however, simultaneous exposure to these compounds increased hepatic and renal TBARS levels at 12 and 48 h after treatment, respectively. Present results suggest that selenium abolishes the interaction of Hg(2+) with sulfhydryl groups of protein and nonprotein sources.     

硒对镉致脂质过氧化与金属硫蛋白诱导合成的影响

目的 比较亚硒酸钠(Na2SeO3)与硒代蛋氨酸(SeMet)对镉(Cd)毒性的拮抗效应，探讨脂质过氧化及金属硫蛋白(MT)的诱导合成在硒(Se)拮抗Cd毒性作用中的意义，为镉中毒的防护提供依据。方法 健康雄性Wistar大鼠36只，随机分6组。I组为正常对照组，Ⅱ组为Cd中毒组，Ⅲ组为Na2SeO3组，Ⅳ组为SeMet组，V组为Cd Na2SeO3组，Ⅶ组为Cd SeMet组。Cd按100μmol／kg体重，Se(Na2SeO3及SeMet)按10μmol／kg体重的剂量隔日1次经口灌胃，其中V组和Ⅵ组按先Se后Cd交替灌胃。Se、Cd均灌胃15次。实验时间为30d。结果 单独给Cd组大鼠肝脏和肾脏MT水平升高，而血清MT出现降低；2种Se化合物均使大鼠肾脏和肝脏MT含量轻度增高，但2个Se加cd组与单独给Cd组比较，MT水平差异不显著；染Cd大鼠仅见血清脂质过氧化产物丙二醛(MDA)含量明显升高，而2种Se化合物对其没有明显影响；无论是单独给Se组(Ⅲ、Ⅳ)，还是Se加Cd组(V、Ⅵ)，大鼠全血、肝脏及肾脏GSH-Px活力均明显增高。结论 Se能在一定程度上诱导机体合成MT，但在Se拮抗Cd毒性作用中MT的诱导合成可能不起主要作用；Se能提高机体的抗氧化能力。对拮抗Cd毒性具有一定的作用；SeMet与Na2SeO3对诱导MT的合成及提高GSH-Px的活力，其效应基本相似。     

Biochemical parameters of pregnant rats and their offspring exposed to different doses of inorganic mercury in drinking water

This work investigated the effects of low and high doses of inorganic mercury in drinking water on biochemical parameters of pregnant rats and their offspring. Female Wistar rats were treated during pregnancy with 0, 0.2, 0.5, 10 or 50 μg Hg²⁺/mL as HgCl₂. Rats were euthanized on day 20 of pregnancy. Pregnant rats presented a decrease in total water intake in all doses of mercury tested. At high doses, a decrease in the total food intake and in body weight gain was observed. Pregnant rats exposed to 50 μg Hg²⁺/mL presented an increase in kidney relative weight. Mercury exposure did not change serum urea and creatinine levels in any of the doses tested. Moreover, mercury exposure did not change porphobilinogen synthase activity of kidney, liver and placenta from pregnant rats in any of the doses tested, whereas fetuses of pregnant rats exposed to 50 μg Hg²⁺/mL presented an increase in the hepatic porphobilinogen synthase activity. In general, pregnant rats presented alterations due to HgCl₂ exposure in drinking water. However, only the dose 50 μg Hg²⁺/mL appeared to be enough to cross the blood-placenta barrier, since at this dose the fetuses presented change in the porphobilinogen synthase activity.     

MRP2 and the handling of mercuric ions in rats exposed acutely to inorganic and organic species of mercury

Mercuric ions accumulate preferentially in renal tubular epithelial cells and bond with intracellular thiols. Certain metal-complexing agents have been shown to promote extraction of mercuric ions via the multidrug resistance-associated protein 2 (MRP2). Following exposure to a non-toxic dose of inorganic mercury (Hg²⁺), in the absence of complexing agents, tubular cells are capable of exporting a small fraction of intracellular Hg²⁺ through one or more undetermined mechanisms. We hypothesize that MRP2 plays a role in this export. To test this hypothesis, Wistar (control) and TR⁻ rats were injected intravenously with a non-nephrotoxic dose of HgCl₂ (0.5 μmol/kg) or CH₃HgCl (5 mg/kg), containing [²⁰³Hg], in the presence or absence of cysteine (Cys; 1.25 μmol/kg or 12.5 mg/kg, respectively). Animals were sacrificed 24 h after exposure to mercury and the content of [²⁰³Hg] in blood, kidneys, liver, urine and feces was determined. In addition, uptake of Cys-S-conjugates of Hg²⁺ and methylmercury (CH₃Hg⁺) was measured in inside-out membrane vesicles prepared from either control Sf9 cells or Sf9 cells transfected with human MRP2. The amount of mercury in the total renal mass and liver was significantly greater in TR⁻ rats than in controls. In contrast, the amount of mercury in urine and feces was significantly lower in TR⁻ rats than in controls. Data from membrane vesicles indicate that Cys-S-conjugates of Hg²⁺ and CH₃Hg⁺ are transportable substrates of MRP2. Collectively, these data indicate that MRP2 plays a role in the physiological handling and elimination of mercuric ions from the kidney.