Influence of selenium dose on mercury distribution and retention in suckling rats

It is well known that metal–metal interactions in the body are age‐dependent. We studied the influence of increasing selenium (Se) doses on mercury (Hg) distribution and retention in the postnatal period in Hg‐exposed suckling rats. Seven‐day‐old Wistar pups were pretreated with three different oral doses of Se as sodium selenite (6.45, 12.9 and 19.4 µmol Se kg^?1 b.w.) over 3 days. This was followed by simultaneous Se (as sodium selenite) and Hg (as mercury chloride) oral administration over 4 days. The molar ratio between Se and Hg given to pups was 1:1, 2:1 and 3:1, respectively. Mercury and Se were measured in brain, kidneys, liver, plasma, erythrocytes and urine of pups on the day after the last administration by atomic absorption spectrometry. Results showed that in all samples Se concentrations rose almost proportionally to the dose of Se given to pups. Mercury concentration in organs, plasma and urine decreased with higher oral doses of Se. However, Hg concentration in erythrocytes increased with increasing Se dose. There was evidently a redistribution of Hg from plasma to erythrocytes at higher ratio of Se:Hg. Approximately equimolar doses of Se and Hg are necessary to produce maximum uptake of Hg by plasma and liver and minimum retention of Hg in the kidney and erythrocytes. Copyright © 2009 John Wiley & Sons, Ltd.     

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.     

On the influence of zinc on mercury/selenium interaction

Pretreatment with zinc does not change the wholebody retention and elimination of mercury, either when mercury is given alone, or when mercury and selenium are given simultaneously in single doses. Distributional effects are observed, however, as higher retention levels of mercury are seen in kidneys, liver and spleen after pretreatment with zinc. The clearance rate of both elements remains unaffected, indicating that zinc does not truly interact with mercury and selenium.The zinc effect is probably due to a higher initial retention of mercury, especially in the kidneys.This work has been carried out under contract no. 171-77-1 ENV.DK of the E.C. Environmental Research Programme     

Wholebody elimination of 75SeO2-3 and 203HgCl2 administered separately and simultaneously to mice.

A study of wholebody elimination of mercury (203HgCl2) and selenium (75SeO2-3) given separately or simultaneously in single doses by intraperitoneal injections to mice has been performed. The conclusion of this study can be summarized as follows: there seems to exist a homeostatic mechanism for selenium, but not for mercury; increased retention is observed for both elements when administered simultaneously. Maximum retention of 1 element is observed, when the other is given in excess or equimolar ratio to the other. Excess mercury provokes a pattern of selenium retention similar to that found in case of selenium deficiency. The wholebody molar ratio of mercury and selenium tends towards 1. When this happens, mercury as well as selenium are eliminated at a rate different from what is seen when the elements are administered separately. Selenium therefore seems to play a direct role in metabolism of inorganic mercury.     

Transplacental and Lactational Exposure to Mercury in Hamster Pups after Maternal Administration of Methyl Mercury in Late Gestation

Abstract: Pregnant Syrian golden hamsters were given a single oral dose of ²⁰³Hg-labelled methyl mercury (MeHg), 1.6 μmol/kg body weight, on day 12 of gestation. The uptake, retention and tissue distribution of ²⁰³Hg in the dams and pups was studied by γ-counting during the following three weeks. The average transplacental transfer of ²⁰³Hg was 1.1% of the administered dose per pup, corresponding to 11% of the administered dose to a whole litter. This was considerably more than in our previous studies when the dams were treated on gestational day 2 (1.3%) or 9 (4.6%). The amount of ²⁰³Hg transferred to each pup in utero was independent of the litter size. The average additional transfer of ²⁰³Hg to a litter via milk was 1.7% of the administered dose. In the pups, the content of ²⁰³Hg in the liver and brain decreased, while the content in the kidneys and pelt increased during the second and third week. The highest amount of ²⁰³Hg was generally found in the pelt, which indicated that unweaned hamster pups primarily excrete MeHg by binding to hair. The chemical form of mercury in the liver and kidneys of the pups was determined by ion-exchange separation of inorganic Hg and MeHg followed by γ-counting. The amount of inorganic Hg in the liver of the pups remained constant throughout the experiment, while it increased in the kidneys after one week due to the demethylation of MeHg. The inorganic Hg in the liver of newborn pups was probably due to maternal demethylation of MeHg and transplacental transfer of inorganic Hg. This hypothesis was supported by the observed transplacental transfer of inorganic Hg in pregnant dams administered ²⁰³HgCl₂ on day 12 of gestation.     

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     

Effect of various amounts of selenium on the metabolism of mercuric chloride in mice

Male ddY mice were given one injection of (1) mercury (mercuric chloride) simultaneously with various doses of selenium (sodium selenite), (2) mercury alone, or (3) various doses of selenium alone. The interaction between mercury and selenium in the liver and kidneys at 1, 5, 24, 120, and 240 hr after administration was investigated. The concentrations of mercury in the liver of mice receiving mercury and selenium simultaneously were higher than those after administration of mercury alone, while the concentrations of mercury in the kidney decreased markedly over a 1-120 hr period after administration, depending on the dose of selenium administered simultaneously with mercury. Clearly, selenium had a different effect on the accumulation of mercury in the liver and kidneys. Subcellular distribution studies revealed that mercury and selenium which were administered simultaneously were incorporated into the crude nuclear and mitochondrial fractions as stable complexes. The transport of these complexes to the kidneys seems to be limited. In addition, gel filtration of supernatant fractions of liver and kidney through a Sephadex G-75 column indicated that the proportion of mercury bound to metallothionein fraction decreased depending on the dose of selenium administered simultaneously with the mercury. This reduction was attributed to the decreased synthesis of mercury-thionein due to a reduction in the activity of Hg2+ which results from binding between mercury and selenium in the cells.     

Metabolism of Mercury in Hamster Pups Administered a Single Dose of 203Hg-Labeled Methyl Mercury

Abstract: Golden Syrian hamster pups were administered a single subcutaneous dose of ²⁰³Hg-labeled methyl mercury (MeHg), 0.4 nmol/g body weight, seven days after birth, and were sacrified 2, 7, 14, 21 or 28 days later. The excretion of ²⁰³Hg followed a biphasic elimination pattern with an average half-time of 8.7 days for the rapid component. The slow component had a much longer half-time and probably reflects binding of ²⁰³Hg to growing hair. The concentration of ²⁰³Hg in the liver, kidneys and brain two days after administration was 0.44, 0.38 and 0.19 nmol/g, respectively. The retention of ²⁰³Hg was higher in the kidney than in the liver and the brain. The content of inorganic ²⁰³Hg in the liver and kidneys increased the first weeks after administration, demonstrating that hamsters are able to demethylate MeHg before two weeks of age.     

Effect of rubratoxin B on adenosine triphosphatase activities in the mouse.

Half the animals in groups of selenium-deficient and control rats were given mercury in the drinking water for 6 weeks. The other half of the animals in both groups received tap water ad libitum. Selenium-deficient rats gained significantly less weight when given mercury, but weight gain of controls was unaffected by mercury administration. In another experiment with rats given mercury for 8 weeks, serum creatinine and renal histology were normal in selenium-deficient and control rats. Selenium-deficient rats injected with ²⁰³HgCl₂ 12 days after mercury was added to their drinking water excreted up to 10% of the ²⁰³Hg in the urine in the first 24 hr whereas control animals excreted less than 2%. This trend continued for several days and was shown to be due primarily to a loss of ²⁰³Hg from the kidney in the selenium-deficient rats. The control kidneys contained 4 times as much mercury as the kidneys in selenium-deficient rats at the end of the experiment, and the mercury content appeared to be increasing further. Selenium-deficient kidneys, however, had achieved maximum mercury accumulation by 13 days. Despite the large differences in mercury accumulation due to selenium status, in both groups about 80% of kidney ²⁰³Hg was found in the soluble fraction. Also, regardless of selenium status, about 90% of the soluble fraction ²⁰³Hg was found in a symmetrical peak on gel filtration which probably represents metallothionein. Thus a major effect of selenium status on the metabolism of inorganic mercury seems to be in facilitating the accumulation of mercury by the kidney. Since most of the kidney mercury is bound to metallothionein, selenium may mediate the binding of mercury to this protein or be a permissive factor in the induction of metallothionein by mercury.     

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.This work was supported by the Section of Medical Sciences of the Polish Academy of Sciences (Agreement 537/VI)     

Mercury-selenium interaction: distribution and excretion of 203Hg2+ in rats after simultaneous administration of selenite or selenate

In female rats intravenously injected with 203HgCl2 (0.6 mg Hg2+ per kg body wt.) the effect of intraperitoneal administration of selenite or selenate (0.525 mg Se per kg body wt.) on distribution and excretion of 203Hg was studied. The content of 203Hg was lower in kidney and higher in liver and blood in the groups treated with selenate or selenite when compared with rats which received only mercury. The brain content of 203Hg was significantly increased in rats injected with selenite. Both selenium compounds injected immediately after mercury significantly decreased urinary as well as biliary excretion of 203Hg. A transient increase in the rate of biliary excretion of 203Hg during the first 2 h after administration was observed in rats treated with selenate. This finding seems to support the idea that the reduction of selenate to selenite in the body is not rapid but takes at least several hours.     

Selenium and mercury molar ratios in commercial fish from New Jersey and Illinois: Variation within species and relevance to risk communication

There is an emerging consensus that people consuming large amounts of fish with selenium:mercury ratios below 1 are at higher risk from mercury toxicity. As the relative amount of selenium increases compared to mercury, risk may be lowered, but it is unclear how much excess selenium is required. It would be useful if the selenium:mercury ratio was relatively consistent within a species, but this has not been the case in our studies of wild-caught fish. Since most people in developed countries and urban areas obtain their fish and other seafood commercially, we examined selenium:mercury molar ratios in commercial fish purchased in stores and fish markets in central New Jersey and Chicago. There was substantial interspecific and intraspecific variation in molar ratios. Across species the selenium:mercury molar ratio decreased with increasing mean mercury levels, but selenium variation also contributed to the ratio. Few samples had selenium:mercury molar ratios below 1, but there was a wide range in ratios, complicating the interpretation for use in risk management and communication. Before ratios can be used in risk management, more information is needed on mercury:selenium interactions and mutual bioavailability, and on the relationship between molar ratios and health outcomes. Further, people who are selenium deficient may be more at risk from mercury toxicity than others.     

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     

Methyl mercury: acute toxicity, tissue distribution and decay profiles in the guinea pig

Acute toxicity studies with methyl mercuric chloride showed that the guinea pig was quite susceptible to methyl mercury intoxication. LD50 values were 5.5 mg Hg/kg ip and 16.5 mg Hg/kg po. One to 2 weeks after dosing, several animals began to display signs of neurotoxicity.Tissue distribution and pharmacodynamic studies with radiolabeled methyl mercuric chloride ([²⁰³Hg]CH₃HgCl) at 1 and 10 mg Hg/kg revealed that while most tissues decreased in mercury concentration from day 1 to day 7, cerebrum, cerebellum and muscle showed a delayed uptake of the alkyl mercurial. In CNS tissue the concentration of mercury decreased in the order cerebrum > cerebellum > spinal cord. Kidney and liver consistently contained the highest levels of mercury, and plasma the lowest, during the 49-day sampling period. One week after dosing the blood: brain ratios were less than 1. The tissue concentration of mercury was generally directly proportional to the dose administered; however, mercury levels in the gall bladder were significantly higher than anticipated on 5 of the 7 sacrifice days.Most of the tissues displayed a biphasic decay profile with a half-life of 2–3 days for the initial rapid phase of decline. This initial phase was followed by a slower tissue excretion rate for which the mean half-life for mercury was 15 ± 0.9 days and 15 ± 0.8 days for the low and high dose, respectively. The similarity of these values again indicates no dose-related effects.     

The effect of 2,3-dimercaptopropane sodium sulfonate on mercury retention in rats in relation to age

The effectiveness of DMPS (sodium 2,3-dimercaptopropane-1-sulfonate) in reducing inorganic mercury retention was studied in 2-, 6-, and 28-week-old albino rats. ²⁰³Hg was administered IP. The chelating agent DMPS was administered by IP injection at a dose of 250 mol/kg body weight three times, 1 day after ²⁰³Hg administration and at 24 h intervals thereafter. The whole body retention determined 1, 2, 3, and 6 days after ²⁰³Hg administration showed that DMPS decreased the body retention of mercury in all age groups, being about twice as effective in adult compared to suckling rats. The reduced effectiveness was due to the reduced efficacy of DMPS in reducing kidney retention in young animals. In other organs the effectiveness of DMPS was not age dependent. These and previous results obtained with different chelating agents and other metals indicate that age might be an important factor in chelation therapy in general.     

The kinetics of methylmercury administered repeatedly to rats

Female rats (65–75 days old) were given orally 0.84 or 3.36 mg Hg/kg as methylmercury chloride (MeHgCl) 5 times a week for 13 and 3 weeks, respectively. The proportion of inorganic to total mercury remained as low as 6% in whole animal though it increased to above 40% in the kidneys.Differences in organ half times and the negative correlation with time for blood to liver, brain and kidney mercury ratios indicated more than one compartment for MeHg⁺. Brain had 26 days half time with a 32% final equilibrium concentration in relation to the body concentrations. Brain concentrations of mercury reported on rats dosed repeatedly with MeHg⁺ agreed with these values which justifies their use when experiments are planned to give a certain brain MeHg⁺ concentration.Half time for the whole body was 34 days but pathological changes — weight loss, tubular damage, slow gastrointestinal passage — disturbed the accumulation curves in the higher dose group. Blood to kidney ratio and uptake of MeHg⁺ by kidneys also changed significantly.     

Mercury toxicokinetics—dependency on strain and gender

Mercury (Hg) exposure from dental amalgam fillings and thimerosal in vaccines is not a major health hazard, but adverse health effects cannot be ruled out in a small and more susceptible part of the exposed population. Individual differences in toxicokinetics may explain susceptibility to mercury. Inbred, H-2-congenic A.SW and B10.S mice and their F1- and F2-hybrids were given HgCl₂ with 2.0 mg Hg/L drinking water and traces of ²⁰³Hg. Whole-body retention (WBR) was monitored until steady state after 5 weeks, when the organ Hg content was assessed. Despite similar Hg intake, A.SW males attained a 20-30% significantly higher WBR and 2- to 5-fold higher total renal Hg retention/concentration than A.SW females and B10.S mice. A selective renal Hg accumulation but of lower magnitude was seen also in B10.S males compared with females. Differences in WBR and organ Hg accumulation are therefore regulated by non-H-2 genes and gender. Lymph nodes lacked the strain- and gender-dependent Hg accumulation profile of kidney, liver and spleen. After 15 days without Hg A.SW mice showed a 4-fold higher WBR and liver Hg concentration, but 11-fold higher renal Hg concentration, showing the key role for the kidneys in explaining the slower Hg elimination in A.SW mice. The trait causing higher mercury accumulation was not dominantly inherited in the F1 hybrids. F2 mice showed a large inter-individual variation in Hg accumulation, showing that multiple genetic factors influence the Hg toxicokinetics in the mouse. The genetically heterogeneous human population may therefore show a large variation in mercury toxicokinetics.     

The effect of selenium on the brain uptake of methylmercury

Twenty-four h after the subcutaneous administration of 0.5 moles selenite labelled with ⁷⁵Se to rats of 200 g body weight, the retention of selenium at the injection site was significantly increased by the presence of equimolar amounts of methylmercury in the injection solution. The retention of Me²⁰³HgCl was not affected by the presence of selenite. The most significant shift caused by interaction was a decrease in the blood content and an increase in the brain content of ²⁰³Hg. The brain content of ⁷⁵Se was also increased to a lesser extent. The shift in the distribution — which was the same whether the two metals were injected at the same site or separately — continuously decreased from 6–48 h. The same interaction pattern was observed when methylmercury and selenite were administered by gastric gavage and differences in distribution increased when the dose was increased from 1.25 moles/kg to 2.5 moles/kg. The increase in the brain content of mercury caused by selenite was not restricted to simultaneous administration and occurred when selenite was given 2–7 days after methylmercury.Supported partly by International Atomic Energy Agency Grant Number 1530/RB     

The influence of administered mass on the subcellular distribution and binding of mercury in rat liver and kidney

The influence of the administered mass on the tissue and sub-cellular distribution of mercury (Hg) was investigated in rats, using ²⁰³Hg. The fraction of the dose deposited in liver increased threefold over the dose range 0.17–1.65 mg Hg · kg^–1, while the retention in the kidney decreased by a factor of 2. The uptake in other organs, lung, spleen, brain, thymus, salivary glands showed no dose-dependent variation.Subcellular fractionation studies showed a dose-dependent increase in the Hg content of the liver cytosol, with corresponding decreases in the deposition in the lysosomal and nuclei-cell debris fractions. In contrast, no clear changes in the distribution of Hg amongst the subcellular organelles of the kidney were observed.The amount of Hg bound to metallothionein in the liver cytosol rose steeply with increasing dose. However, in the kidney cytosol the mass of Hg bound to metallothionein increased with dose up to 0.55 mg Hg · kg^–1, thereafter remaining approximately constant. These observations suggest that the Hg-binding metallothionein in the kidney was saturated by administered doses greater than 0.55 mg Hg · kg^–1, whereas in liver saturation levels of the metal were not reached even at the highest dose tested, 1.65 mg Hg · kg^–1.     

Combined Oral Treatment with racemic and meso-2,3-Dimercaptosuccinic Acid for Removal of Mercury in Rats

Abstract: Racemic dimercaptosuccinic acid (DMSA) was found more efficient than the meso-isoform in enhancing the removal of mercury in rats. However. racemic-DMSA has recently been found more toxic. The efficiency of combined oral treatment with the two isoforms of DMSA for removal of mercury has now been evaluated. Female albino rats were treated orally for four days with meso- (M) and/or racemic- (R) DMSA (1 mmol/kg each), five days after a single intraperitoneal administration of ²⁰³Hg with 0.5 mg HgCl₂/kg. The animals were divided into six groups according to the number of treatments with each isomer: control (untreated), 4M, 1R + 3M, 2R + 2M, 3R+1M, and 4R. Whole body, kidney, liver and brain mercury contents were measured nine days after ²⁰³Hg administration. In all treated groups retention in the whole body and kidneys was greatly reduced. The groups treated with racemic-DMSA, regardless of the number of doses, showed a greater removal of mercury than the group treated with meso-DMSA alone (4M). All treatments were less efficient in reducing liver retention, and the brain retention was not affected. It was concluded that even a single application of the more toxic racemic-DMSA during a four-day oral treatment regimen is sufficient to improve the removal by meso-DMSA of mercury from rats.