Effects of interaction between 65Zn, cadmium, and copper in rats.

Distribution and retention of zinc in the presence of cadmium and copper was studied in rats exposed repeatedly to these metals. The experiment was performed on white rats of the Wistar strain. The animals were divided into four groups/five rats each: 1) 65ZnCl2; 2) 65ZnCl2 + CdCl2; 3) 65ZnCl2 + CuCl2; and 4) control group. Rats were administered sc every other day for two weeks: 65ZnCl2-5 mg Zn/kg; CdCl2-0,3 Cd/kg; and CuCl2-2 mg Cu/kg. The zinc content was measured in rat tissues by gamma-counting. Effect of Cd and Cu on subcellular distribution of zinc in the kidney and liver and on the level of metallothionein were also examined. Whole body retention of zinc under the influence of cadmium was lower than that observed in animals treated with zinc alone. However, copper increased twofold the whole body retention of zinc. Cadmium elevated the accumulation of zinc only in the kidneys nuclear fraction and liver soluble fraction. In the kidneys and liver, copper elevated the accumulation of zinc, in the nuclear, mitochondrial, and soluble fractions. The level of metallothionein-like proteins (MT) in the kidneys after a combined supply of zinc and copper was significantly increased with respect to the group of animals treated with zinc alone. These results indicated complex interactions between cadmium, copper, and zinc that can affect the metabolism of each of the metals.

The effect of cadmium pretreatment on the disposition and excretion of methylmercury and trace elements (zinc, copper) in rats.

Cadmium chloride (Cd) was injected s.c. into male rats at a dose rate of 3 mg Cd/kg 3 times a week for 4 weeks. The animals were maintained for administration of methylmercury (203 Hg) chloride at a dose of 3 mg CH3Hg/kg given p.o. 3 times a week for 2 weeks, followed by 3 weeks of recovery period. Animals were sacrificed 24 h after the final dose of MeHg, or 5 weeks after cessation of Cd administration. Cd-pretreatment significantly decreased total Hg concentration in the kidney and RBC and almost completely inhibited demethylation of MeHg in the kidney (from 32% to 3% of inorganic Hg). Cd-pretreatment did not affect urinary excretion of total Hg, but significantly increased daily excretion of total Hg in feces. MeHg given alone significantly increased renal but not hepatic copper levels and decreased copper in the plasma and brain. In Cd-pretreated rats, both renal and hepatic copper concentration were in the normal ranges. Zinc levels in Cd-pretreated rats significantly increased in the kidney, liver and brain but decreased in plasma (compared to control and MeHg-alone treated animals). From these results it can be concluded that Cd-pretreatment may decrease MeHg toxicity by increasing the fecal mercury excretion and by inhibiting the formation of inorganic mercury in the kidney, which is a more potent renal toxin than MeHg.

The fate of Cd, Cu, Ca, Zn, and Fe in rat during the recovery period following cessation of repeated exposure to Cd.

Cadmium was administered subcutaneously to male Wistar rats, 0.1 mL/rat in 0.9% saline 3 times a wk for 4 wk at 3 mg Cd/kg. Saline was administered to control animals in an equivalent manner, without Cd. After the end of the dosing period, the distribution and excretion of Cd, Cu, Ca, Zn, and Fe were observed in some organs and excreta for 35 d (1, 7, 14, 21, 28, and 35 d). Cadmium dosing caused significant disturbances in the metabolism of Zn, Cu, Fe, and Ca, especially during the recovery period. Growth in Cd-dosed animals did not accelerate, even after 5 wk of recovery. There was evidence of mobilization of some elements among organs. Accumulation of Cd occurred in liver, kidney, and spleen during dosing, and during the recovery period it was retained in kidney and testes (for 2 wk) and cleared steadily in liver and RBC (for 5 wk), but increased in spleen (first 3 wk). The pattern of Cd excretion was closely associated with the binding of Cd with metallothioneins in kidney and liver for the first 21 and 7 d, respectively. This was associated with the excretion of Cd-metallothioneins (Cd-MT) in urine from d 1 to 21 during recovery. Cadmium caused higher Ca accumulations in testes and liver, which were probably associated with the lesions observed in these organs. Significant increases of Cu (in kidney d 7) and Fe (in liver) were observed during recovery. Furthermore, significant reductions of Cu and Fe were found in plasma, spleen, and RBC (after 5 wk) and kidney, spleen, and testes (on d 7), and blood (after 5 wk).

A kinetic analysis of the interaction between methylmercury and selenium.

Guinea pigs were given radiolabelled methyl(203)mercuric chloride at a dose of 3 mg/kg p.o. alone or with an equimolar dose of sodium selenite, every second day for 3 weeks (10 doses). Whole-body mercury levels were measured during the course of the study and multi-compartment analysis carried out by computer least-squares curve fitting. Results indicated that mercury given alone behaved according to a single compartment model with half-life of 23.6 days, while in the presence of selenium a two-compartment behaviour resulted with one clearing rapidly (half-life 8.7 +/- 5.3 days) and the other clearing more slowly (half-life 40.8 +/- 13.0 days). Selenium decreased excretion of mercury in feces (2-fold) and urine (7-fold). Approximately 70% of the total mercury in the feces and 90% of that in the urine was in organic form. Tissue distribution of total, organic and inorganic mercury was determined 1, 14 and 28 days after the final dose. Selenium decreased the levels of mercury 1 day after the final dose, but produced a slower clearance after that. In all organs examined most of the mercury was in the organic form, except in the kidney which had over 70% inorganic mercury. Selenium increased the relative amounts of inorganic mercury in the liver, spleen, pancreas, large and small bowels, but not in the kidney.

Interactions of calcium, copper, iron, and zinc with methylmercury and selenium in guinea pig tissues.

Female guinea pigs were exposed to 10 doses of 3 mg/kg body weight of methylmercuric chloride with or without concomitant equimolar doses of sodium selenite. Tissue concentrations of calcium, copper, iron, and zinc were determined 1, 14, and 28 d after the final dose, in red blood cells, plasma, pancreas, spleen, kidney, liver, cerebrum, and cerebellum. Various alterations were observed, most notably a marked depression in cerebellar calcium levels, a change that did not take place in the presence of selenium. The alterations are discussed in terms of their possible relevance to mechanisms of methylmercury toxicity and selenium protection against it.

Demethylation and excretion of methyl mercury by the guinea pig.

Female guinea pigs were dosed po with 1.0 mg CH3 203Hg/kg as methylmercuric chloride, 10 times over a 3-week period. Tissue distribution, excretion, and accumulation of inorganic and organic mercury were studied. The highest concentration of mercury was found in the kidney. The greatest decreases of mercury levels were observed in the small bowel, red blood cells, liver, and cerebrum. The half-life of whole body clearance, based on a single compartment model, was 31.6 days. Mercury in the kidney, liver, and cerebrum was bound mainly by nuclear and soluble fractions. The highest ratio of inorganic to total mercury was seen in the kidney, 60% of this being as inorganic mercury. Excretion of mercury in the feces was measured throughout the experiment. The relationship of organic to inorganic mercury was relatively constant at about 1:3. Data on the effects of methyl mercury on tissue concentrations of zinc and copper show that the only change in the copper content was a marked increase in the kidney.

The effect of methylmercury on the distribution and excretion of selenium by the guinea pig.

The influence of methylmercury (MeHg) on the tissue and subcellular binding of selenium was determined. Adult female guinea pigs received either 75Se (as sodium selenite) or MeHg (as chloride) followed 5 h later by an equimolar dose of 75Se. Animals were sacrificed 1, 3, 7, and 13 days after administration. Pretreatment with MeHg significantly altered the organ distribution of 75Se, particularly during the first week of the study. 75Se concentrations were markedly reduced in most organs of animals receiving both 75Se and MeHg except the liver, which contained markedly elevated 75Se levels. The subcellular distribution of 75Se was also altered by MeHg. Within liver, kidney and brain, 75Se was primarily bound to nuclear and mitochondrial fractions in both treatment groups, but nuclear binding was higher in animals receiving both compounds. Within nuclear fractions, most 75Se was bound to insoluble-nonhistone proteins. In the presence of MeHg, total nuclear binding of 75Se increased, but total binding to insoluble-nonhistone proteins decreased. MeHg also reduced the total 75Se binding to high molecular weight proteins of the soluble fraction. Alterations in tissue and subcellular binding of MeHg and Se may contribute to the lower degree of toxicity observed in animals receiving both compounds.

Effect of selenium on distribution, demethylation, and excretion of methylmercury by the guinea pig.

The influence of selenium on methylmercury excretion, organ and subcellular distribution, and demethylation was studied in the guinea pig at different times following a single equimolar dose (50 miroM/kg) of CH203 3) HgCl and Na2SeO3 administered separately or concomitantly per os. Excretion of mercury through feces was the dominant clearance pathway in both groups. Selenium significantly decreased excretion of total and organic mercury in feces during the course of the study, but in the urine only on d 13. Selenium also significantly decreased the concentration of total mercury in major organs. The exception was brain on d 1, in which mercury levels were higher in the presence of selenium; however, on d 7 and 13 both cerebrum and cerebellum showed lower mercury levels as compared to the group treated with methylmercury alone. Selenium had no significant effect on the subcellular mercury distribution in the liver, kidney, and cerebrum, other than that which could be accounted for the whole organ uptake. The level of organic mercury in most of the analyzed organs was significantly decreased by the presence of selenium; however, relative proportions of inorganic to organic mercury remain unchanged. The single exception was kidney, where selenium markedly decreased the relative amount of inorganic mercury.

Effect of zinc, cadmium or copper on mercury distribution in rat tissues.

Distribution and retention of mercury in the presence of zinc, cadmium or copper was studied in rats exposed repeatedly to these metals. Whole-body retention of mercury under influence of zinc and cadmium was slightly lower than that observed in animals treated with mercury alone; however, copper decreased whole-body retention by over 50%. Combined administration of mercury and various metals changed the distribution of mercury in the subcellar fractions of kidney and liver. Zinc, cadmium and copper decreased incorporation of mercury in metallothionein-like proteins (MT) in the kidney; however, in the liver mercury was bound mainly by MT. It seems very likely that one metal may induce changes in the distribution of another by processes other than a single displacement interaction.

Effect of interaction between 65Zn, mercury and selenium in rats (retention, metallothionein, endogenous copper).

Interaction of zinc with mercuric chloride and sodium selenite was studied in the rat at the organ and subcellular levels (liver and kidneys). Zinc chloride was administered subcutaneously at dose of 5 mg Zn/kg, mercury chloride into the tail vein at a dose of 0.5 mg Hg/kg (both metals every other day during 2 weeks) and sodium selenite intragastrically, at doses of 0.1 mg Se/kg, every day. Zinc retention in the rat did not exceed 20% and was unchanged in the presence of mercury. An interaction effect was reflected by an increased whole-body retention of zinc by selenium, mercury, and selenium. In the presence of selenium no peak of metallothionein-like proteins stimulated by zinc or mercury was found in the soluble fraction of the kidneys. The metallothionein level did not differ from that typical for control group animals, too. A significant increase in the level of endogenous copper was found only in the kidneys of rats exposed to zinc in the presence of mercury and selenium.

The effects of plant-incorporated methylmercury on its distribution, excretion and demethylation patterns in the rat.

Rats were dosed once per os with either plant-incorporated or solution-radioactive methylmercury (MeHg). While whole-body retention did not change, the incorporation into some organs was approx. 2.5 X higher when administered Hg was in the plant-incorporated rather than in solution form. The only noticeable change in demethylation occurred in the cerebrum where MeHg:Hg ratios were 79:10 (plant-incorporated MeHg) and 65:24 (solution-MeHg). Between 5 to 7% of the total mercury was excreted in faeces and urine either in the inorganic (faeces) or organic (urine) forms. Mercury levels in mitochondrial and soluble fractions of cerebrum were noticeably lower with plant-MeHg than with solution-MeHg.

Arginase and kallikrein activities as biochemical indices of occupational exposure to lead.

In a group of 60 workers occupationally exposed to lead the blood and urine lead concentrations, haematocrit, ALA-D and arginase activities, and urinary 5-aminolaevulinic acid (ALA) and coproporphyrin concentrations, and kallikrein activity were determined. Correlation coefficients of -0.78 and 0.77 for Pb-B/ALA and Pb-B/arginase were found respectively for lead concentrations above 40 microgram/dl blood, and 0.83, 0.76, 0.74, and -0.64 for Pb-U/ALA, Pb-U/Cp-U, Pb-U/kallikrein, and Pb.U/kallikrein, respectively. It seems that the increase in serum arginase activity may be indicative of liver damage while the decrease in kallikrein activity may indicate kidney damage in workers exposed to lead.

Variation of the level of mercury and metallothionein in the kidneys and liver of rats with time of exposure to sodium selenite.

Sodium selenite was administered to rats before, after, and simultaneously with mercuric chloride. In all animal groups, mercury was administered intravenously in doses of 0.5 mg/kg every other day for two weeks. Selenium was given intragastrically either in a single dose of 7.0 mg Se/kg or in repeated doses of 0.1 mg Se/kg every day for weeks. It was demonstrated that, depending on the administration schedule, selenium induced significant changes in the binding of mercury by soluble fraction proteins both in the kidneys and in the liver. In every exposure, the mercury content decreased mainly in the low-molecular weight proteins, and the level of metallothionein-like proteins was diminished in the both organs. In the kidneys, the mercury content showed a correlation with the level of metallothionein (r=0.78). Amounts of mercury below 10 µg/g kidney do not stimulate metallothionein biosynthesis in this organ. A distinct interaction effect was observed in the case of a simultaneous administration of equimolar amounts of both the metals in question.

Whole-body retention of mercury and selenium and histopathological and morphological studies of kidneys and liver of rats exposed repeatedly to mercuric chloride and sodium selenite.

Distribution and retention of mercury and selenium was studied in rats exposed repeatedly to HgCl2 injections (0.5 mg Hg/kg to the tail vein every other day) and intragastrically to Na2SeO3 (0.5 mg Se/kg every day), applying combined and separate administration of these metals for 2 weeks. Whole-body retention of mercury in the presence of selenium was augmented by 20% and that of selenium in the presence of mercury by 4% with respect to the administered dose. Combined administration of mercuric chloride and sodium selenite brought about damage to the epithelial cells of renal proximal convolutions and formation of protein casts in their lumen. These changes had the same pattern as those induced by administration of mercuric chloride alone, but the intensity was lower. Submicroscopic studies revealed that repeated combined administration of sodium selenite and mercuric chloride did not completely abolish the mercury-induced mitochondrial swelling and contributed to chromatin destruction in the hepatocyte nuclei.

Activity of glutamate and malate dehydrogenases in liver and kidneys of rats subjected to multiple exposures of mercuric chloride and sodium selenite.

Rats were subjected for 2 weeks to separate and combined exposures to mercuric chloride and sodium selenite at doses of 0.5 mg Hg/kg and 0.5 mg Se/kg. The content of mercury, selenium and protein as well as the activities of glutamate dehydrogenase (GLDH) and malate dehydrogenase (MDH) were determined in homogenates, mitochondria and intramitochondrial structures of the exposed animals. It was found that both separate and combined exposures of rats to mercuric chloride and sodium selenite inhibited GLDH activity and did not affect MDH activity in the examined organs. Mercury-selenium interaction brought about a decrease in the content of mercury in the intramitochondrial structures of kidneys and an increased accumulation of both elements in the outer and inner membranes of liver mitochondria. The biochemical mechanism of mercury-selenium interaction is discussed.

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.