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Biometals (2015) 28:605–614 DOI 10.1007/s10534-015-9857-5

Biometals (2015) 28:605–614 DOI 10.1007/s10534-015-9857-5
Biometals (2015) 28:605–614 DOI 10.1007/s10534-015-9857-5

Selenium as an antidote in the treatment of mercury intoxication

Geir Bjørklund

in the treatment of mercury intoxication Geir Bjørklund Received: 12 January 2015 / Accepted: 23 April

Received: 12 January 2015 / Accepted: 23 April 2015 / Published online: 7 May 2015 Springer Science+Business Media New York 2015

Abstract Selenium (Se) is an essential trace element for humans. It is found in the enzyme glutathione peroxidase. This enzyme protects the organism against certain types of damage. Some data suggest that Se plays a role in the body’s metabolism of mercury (Hg). Selenium has in some studies been found to reduce the toxicity of Hg salts. Selenium and Hg bind in the body to each other. It is not totally clear what impact the amount of Se has in the human body on the metabolism and toxicity of prolonged Hg exposure.

Keywords

Selenium Mercury Interaction Metal

toxicology

Introduction

Interactions between metals and selenium (Se) have been known for more than 60 years (Parˇ´ızek and Osˇt ˇ a´dalova´ 1967). The research was intensified after Ganther et al. (1972) had shown that Se can protect against the toxic effects of methylmercury (MeHg). Most studies have been conducted in experimental animals where high single doses of Hg and Se or only a few doses have been used. In the human situation,

G. Bjørklund ( & ) Council for Nutritional and Environmental Medicine (CONEM), Toften 24, 8610 Mo i Rana, Norway e-mail: bjorklund@conem.org

however, is the exposure characterized by low Hg doses for a long time. Supplementation of Se is continuously present through the diet. Selenium has in most animal studies been supplemented as inorganic salts (most often selenite), while the Se humans get via food is mainly organically bound. Multiple animal experiments have shown a very good effect of Se at high dosage level as antidote against a large range of toxic metals, but with some few exceptions, notably in the case of Pb. The selectivity of Se as an antidote for toxic rather than nutritionally essential metals is probably far better than for any of the chelators now used for treatment of heavy metal poisoning. When the dietary Se intake is less than optimal, Se- antagonistic toxic metals, such as Hg, cadmium (Cd) and silver (Ag), will bind Se in a biologically inert form as heavily soluble selenides. The toxic metals concerned cannot do any harm after they have been precipitated as selenides inside the cells, but they will reduce the amount of selenide ions available for synthesis of selenophosphate and selenocysteyl- tRNA, as well as for incorporation in the iron-sulphur groups of enzymes in the mitochondrial respiratory chain (Christophersen et al. 2012). In agreement with this theoretical expectation, it has been found that workers in an Hg mine had significantly lower (p \ 0.05) average blood plasma Se concentration (71.4 l g/L) than in the controls (77.3 lg/L) (Kobal et al. 2004). However, the miners

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had significantly more (p \ 0.05) Se in their urine (16.5 l g/g creatinine) than the controls (14.0 l g/g creatinine) (Kobal et al. 2004), which is puzzling, but perhaps might reflect enhancement of the diurnal creatinine excretion because of Hg-induced kidney damage (Tchounwou et al. 2003; Kern et al. 2012) rather than enhancement of the diurnal Se excretion.

Selenium

Selenium is an essential trace element for many animal species, including humans. It is an integral part of the enzyme glutathione peroxidase (GPx). This enzyme protects the organism against oxidative dam- age by reducing lipid peroxides and hydrogen perox- ide in the presence of glutathione. Selenium is found in the enzyme as the amino acid selenocysteine. GPx is composed of four identical parts with a Se atom in each. In experimental animals, it has been shown that Se is also included in a structural protein in sperm and heme metabolism, which appears to be independent of the GPx activity. Mammals have also a Se indepen- dent GPx (GSH-transferase B) that only converts lipid peroxides and not hydrogen peroxide. Most water-soluble Se compounds are rapidly absorbed from the gastrointestinal tract in animals regardless of dose. It can be assumed that the protein- bound Se in food are as Se-containing amino acids. Both organic and inorganic Se compounds appear in the organism converted to selenide to be incorporated in selenocysteine and further in the protein. Selenide can in high doses be methylated and excreted as dimetylselenid via lungs or trimethylselenium via urine. Selenide, together with a range of metals produce very stable metal complexes. In contrast thiol groups are selenol groups, when present in proteins, largely dissociated at physiological pH. This make that selenol groups easier complexbinds metal salts. The Se intake varies tremendously in different parts of the world. There are also reports from a Se deficient area of China, known as Keshan Province, that children with low Se values are affected by cardiomyopathy (Keshan disease) and Se alleviate or prevent this disease. If supplemented for a long time can selenite at doses of 0.5–1 mg/day cause toxic effects. Impaired intracellular antioxidative defense will, moreover, enhance the liability of cell populations to undergo mitochondrially induced apoptosis, which

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might be especially important as an important part of the pathogenetic mechanism of oligospermia in men—being now the most serious public health problem in Europe because of the disastrous decline in average sperm density for the entire male popula- tion that has occurred probably in all of Europe over the last 70 years. The intake of Se is less than optimal for much of the world population for a variety of reasons, including high dietary intake of Se-free foods such as refined sugar and dietary fats and oils, reduced food con- sumption because of sedentary lifestyles, topsoil erosion, anthropogenic fires (e.g. on savannas in Africa), and massive application of commercial fer- tilizers with low Se/phosphorus (P) ratio causing inhibition of Se uptake into plant roots (Haug et al. 2007; Christophersen et al. 2010, 2012). While Se deficiency in the soil is very widespread in poor countries, inhibition of Se uptake in plant roots by Se- poor fertilizers is probably the most important cause of low Se intake in Europe—which cannot be explained only as a consequence of low Se concentrations in the soil or natural binding of selenite ions to soil minerals (Christophersen et al. 2012). The Se intake is most likely much less than what is needed for optimal detoxification of Hg and other toxic metals (such as Cd) for most of the population in Europe (with the average dietary Se intake being especially low in Sweden, as well as in some of the countries on the Balkan Peninsula). The average Se intake in most parts of Europe is now far below the optimum for health, as illustrated i.a. by epidemiological data from the United States regarding the relationship between individual Se status and survival of AIDS patients. It will therefore be a synergistic interaction, unless the patient is taking Se as a dietary supplement at an adequate dosage level, between low Se intake and intoxication by strongly Se- antagonistic toxic metals such as Hg, Cd and Ag. The most probable main reason for the low Se intake in most of Europe is very large consumption of Se-poor commercial fertilizers. The fertilizers inhibit the uptake of Se in plant roots by a combination of mechanisms, including (a) competitive interactions between selenate and sulphate and between selenite and phosphate for the same membrane transport proteins in the plant roots (and presumably in mycorrhiza as well, although this has not so far been studied experimentally, as far as I know), and (b) coprecipitation of selenite with

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phosphate when new phosphate minerals are formed in the soil following commercial fertilizer application. The average Se intake must be considerably higher in North America than in Europe, if differences in average blood Se concentrations can be taken as representative of the geographic variations in Se intake (Shamberger et al. 1979; Christophersen 1983; Chakar et al. 1993; Wang et al. 1995; Bates et al. 2002; Berthold et al. 2012; Gac´ et al. 2012). But studies of toxic effects of Hg suggest that dietary Se intakes sometimes may be less than what is needed for optimal antidote protection against Hg in North America as well. This question, however, has probably never been well enough studied either epi- demiologically (e.g. by comparing the prevalence of Hg-related problems in the most Se-rich and the most Se-poor parts of the United States) or through clinical intervention trials (to establish the Se supplementation dose needed for optimal antidote protection against Hg or other toxic metals).

Selenides

Selenide is needed as a precursor to make seleno- cysteyl-tRNA, which is in turned needed for incorpo- ration of selenocysteyl groups into Se-dependent enzymes during translation, using UGA as codon in the mRNA molecule, while TGA is used as codon in the DNA molecule (Christophersen et al. 2012). Selenocysteyl-tRNA is produced by reaction between a specific form of phosphoseryl-tRNA and the energy- rich compound selenophosphate, with selenophos- phate being formed by an enzyme-catalyzed reaction between ATP and selenide ions (Xu et al. 2007; Turanov et al. 2011; Christophersen et al. 2012). The selenides of all the metals concerned have much lower solubility products, as found by Buketov et al. (1964), compared with the solubility products of the corresponding sulphides as found in ordinary chemical textbooks. The natural geochemical abun- dance of Se, on a molar basis, is four orders of magnitude less than for sulphur (S), being close to the Se/S elemental abundance ratio in the solar system as a whole. This is also close to the natural Se/S abundance ratio in the human body. However the heavy metal selenides are commonly from seven to 14 orders of magnitude less soluble than the corresponding sulphides. If the concentration ratio

of selenide to sulphide ions in the cell reflects the total Se/S abundance ratio in the human body, the selenides of various toxic metals will therefore precipitate long before the intracellular fluids will become saturated with respect to the corresponding sulphides. It is apparently a consequence of these evolutionary adaptations that there is strong antagonistic interaction between Se and several toxic metals that are not essential, but little antagonistic interaction between Se and nutritionally essential metals, although it is possible that copper (Cu) and perhaps more impor- tantly chromium (Cr) may be partial exceptions to this. However, use of Se as an antidote for heavy metal intoxication is not free of potential hazards of its own as there are anecdotal reports especially from Sweden about paradoxical intolerance to Se supplementation among patients suffering from Hg intoxication. It is possible (Alloway 2012) that this may be explained by an autoinhibition mechanism when selenite ions react with selenol groups of Se-dependent enzymes, form- ing –Se–Se– covalent bonds leading to inhibition of the enzyme, which is perhaps irreversible. The procedure should therefore be to start very cautiously with very low daily doses of a Se supple- ment and enhance the daily doses gradually over a long period of time, thus making it possible for the cells to make new selenoprotein molecules before the daily Se dose is increased. If symptoms of Se intolerance arise, one must stop for a while enhancing the daily doses. Animal experiments have been disappointing, regarding the use of Se as an antidote for lead (Pb) poisoning (Christophersen et al. 2012). It is proposed that PbSe in spite of heaving a low solubility product, compared for instance to CdSe, is easily oxidized because of simultaneous oxidation both of the selenide and Pb ?? ions (Christophersen et al. 2012). In CdSe, on the other hand, it is only the selenide ions that can be further oxidized. CdSe microcrystals are therefore from a kinetic point of view far more resistant to oxidation than PbSe microcrystals, and HgSe micro- crystals are also kinetically very resistant to oxidation (Christophersen et al. 2012). Mercuric selenide (HgSe) has a solubility product of about 10 - 64 (Buketov et al. 1964). This is so low that if one tries to calculate how much water is needed for dilution, if the solution shall be at equilibrium with solid HgSe with just 1 Se ion and 1 Hg ?? ion in the solution, one needs cubic kilometres of water for

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dilution. In practice this means that HgSe is totally insoluble in living organisms—and it is apparently also totally biologically inert. This explains why Se has been found to be a very good antidote against Hg poisoning in animal ex- periments (Underwood 1977; Christophersen et al. 2012), and it explains why marine animals such as tuna and sea eagles are well protected against the toxic effects of Hg, being present at high natural levels in marine food-chains (with Hg enrichment taking place upwards in the chain). Selenium supplementation should always be used as part of the treatment for heavy metal intoxication, even in the case of Pb poisoning in spite of the lack of efficacy of Se as an antidote against Pb. However, Pb has a strong in vivo prooxidant effect, and it is important also in the case of Pb poisoning to optimize the intracellular antioxidant defence (Christophersen et al. 2012).

Selenoproteins

The cells have probably much larger capacity to make selenide ions than sulphide ions, compared to total abundance of the two elements in the cells, causing the selenide/sulphide concentration rate in the cells to be much higher than the concentration ratios between total Se and total S. An important reason for this is probably that the cells need selenide ions to make selenophosphate by an enzyme-catalyzed reaction with ATP, and selenophosphate is needed to make selenocysteyl-tRNA prior to synthesis of selenopro- teins such as GPx and thioredoxin reductase. Among the selenoproteins, there are at least two that can form chelates, where the toxic metal is simultane- ously coordinated to a Se and an S atom, viz. thiore- doxin reductase and selenoprotein P. Selenoprotein P is important for antiatherogenic production, while inhi- bition of thioredoxin reductase will have multiple consequences in a wide range of different disease because of the important role of thioredoxin both in antioxidant defense (as cofactor for 2-Cys peroxire- doxins and methionine reductases, as well as par- ticipating in the repair of oxidatively damaged proteins by reduction of abnormal intramolecular disulphide bonds in the protein concerned) and in DNA synthesis and repair because it is one of the two reducing cofactors for thioredoxin reductase.

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The inhibition of the enzyme thioredoxin reductase by Hg ?? ions happens with an inhibition constant K i (for 50 % inhibition of the enzyme, and at a relevant concentration of the substrate thioredoxin) of 7.2 nM, while for inhibition of thioredoxin reductase by MeHg, K i is 19.7 nM (Carvalho et al. 2008). By contrast, the reduced glutathione (GSH) concentration in human erythrocytes has been reported to be in the range 1-3.2 mM (Hempe and Ory-Ascani 2014), which means 5 orders of magnitude higher concen- tration of GSH thiol groups, compared with the Hg ?? concentration needed for 50 % inhibition of thiore- doxin reductase. Thioredoxin reductase has been shown to be extremely vulnerable to inhibition by Hg ?? , as well as by gold (Au) and platinum (Pt) compounds that are or have been used therapeutically either for treatment of rheumatoid arthritis (in the case of Au) or cancer (in the case of Pt). But it is for obscure reasons not sensitive to inhibition by Pb ?? . It might be speculated, very hypothetically, that this is because Pb ?? is instead bound to thioredoxin as a tetrathiolate com- plex. There are two different dithiol configurations in thioredoxin, one at the active site and another in another part of the molecule, but it has not yet been experimentally verified that all the four thiol groups can be simultaneously coordinated to the same metal atom. Impaired scavenging of H 2 O 2 , peroxynitrite and organic hydroperoxides will lead to enhancement of the mutation rates in mitochondrial and nuclear DNA, with enhancement of the mutation rate in mitochon- drial DNA leading to patological enhancement of the rate of aging processes (which can lead to premature development of age-related degenerative diseases in several different organs, including the brain), and also impaired semen quality in men, while enhancement of the mutation rate in nuclear DNA will enhance the risk of cancer as well as of genetic diseases in the offspring of the patient concerned, if the patient is not beyond the age of reproduction. Potential consequences of enhanced mutation burden in human germ cells are truly disastrous (Christophersen 2012a). However, inhibition of thioredoxin reductase be- cause of low Se intake or toxic metals may also be expected to contribute to impairment of DNA synthe- sis and repair, especially if the patient is also GSH- deficient, because of the role of thioredoxin as one of the two alternative reducing cofactors for

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ribonucleotide reductase. The other reducing cofactor for ribonucleotide reductase is glutaredoxin (also called thioltransferase when functioning as a protein repair enzyme in its own right), which in turn depends on GSH as a reducing cofactor. Impaired intracellular antioxidative defense will, however, also affect the function of multiple redox- regulated intracellular signal cascades, including NF- kappaB, AP-1 and Sp1. This affects the regulation of cell growth and apoptosis, which is especially impor- tant in cancer patients, and the expression of a large number of proinflammatory proteins, which is impor- tant in all non-infectious inflammatory diseases, including the allergic diseases and rheumatoid arthritis.

Chalcophile and siderophile toxic metals

All chalcophile and siderophile toxic metals (Gold- schmidt’s classification), i.e. those found in sulphide minerals in common rocks or being so noble that they prefer going into an iron-rich melt rather than in a coexisting silicate melt, form heavily soluble se- lenides, and bind strongly to selenol groups in selenoproteins. They are therefore Se antagonists, and there will be a synergistic interaction between suboptimal Se intake and the toxic metals concerned as causes of depletion of Se-dependent enzymes. Depletion of the selenoproteins concerned causes impairment of antioxidant defense at a cellular level because of impaired scavenging of H 2 O 2 , organic hydroperoxides and peroxynitrite and impaired re- paired of oxidatively damaged proteins by thioredoxin and methione sulfoxide reductases. All the methionine sulfoxide reductases use thioredoxin as one of their reducing cofactors and one of them is itself a selenoprotein also called selenoprotein R, which is vulnerable to Se depletion because of suboptimal intake. All the toxic chalcophile and siderophile metals lead to enhancement of in vivo oxidant stress by a combination of mechanisms that includes ‘‘scaven- ing’’ of selenide ions because of precipitation of heavily soluble metal selenides, direct inhibition of Se-dependent enzymes, and pro-oxidant catalytic effects of metals that can occur in more than one oxidation number in vivo, such as Pb, vanadium (V), Cr, Cu (when present at a toxic concentration level in

the cells) and probably tin (Sn). Treatment with a good antioxidant cocktail should therefore be part of the standard therapy. A combination both of hydrophile and lipophile natural antioxidants should be used, and probably also melatonin because of the double func- tion of melatonin both as a good antioxidant in its own right, and, more importantly, as a hormone enhancing the expression of several antioxidant enzymes, as well as ancillary enzymes that participate in chains of electron transport leading to the actual antioxidant enzymes (with glutathione reductase as a good exam- ple). This antioxidant cocktail therapy should also be used for treatment of all acute intoxications with organic substances that exert a prooxidant effect, including alcohol and the fungal poison orellanine (Christophersen 2012b). Chalcophile metals that are essential nutrients, such as Cu, zinc (Zn) and nickel (Ni) form also selenides that have much lower solubility products of than the corresponding sulphides. But there must apparently have been evolutionary adaptations hindering too strong antagonistic interaction between Se and nutri- tionally essential metals, probably mainly because of strong binding of the essential metals concerned to those proteins, where they function as essential enzyme cofactors. CuSe has a solubiity product far lower than for CdSe, but Cu forms also very stable complexes with ordinary amino acids and proteins.

Selenides compared with sulphides

It has often been thought that the toxicity of Hg is mainly a consequence of Hg having high affinity for the thiols of cysteyl groups in proteins and GSH (Clarkson 2002; Lorscheider et al. 1995). It is well- known that thiol (–SH) groups are often found at the active site or other functionally important sites in protein molecules. Thus, it has been thought that the Hg 2 ? ion may bind to thiol groups of enzymes, proteins, ion channels, membranes, etc., alter their normal function and, in many instances, render them essentially nonfunctional. These ideas at best represent a gross oversimplifi- cation. It is possible that binding of Hg to thiol groups may help to explain some of the effects of Hg in the control of gene expression (for apometallothionein, various CYPs and heme oxygenase), and it is certainly correct that strong binding will occur, when the same

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toxic metallic ion can bind to two different thiol groups or more simultaneously. But the traditional idea referred to above cannot be entirely true, if we think about thiol groups in general, because Hg can exert toxic effects at tissue concentrations, where there is a vast suberabundance of thiol groups, compared with the number of Hg atoms, and because Hg ? and Hg ?? ions bind much more strongly to selenide ions (Se ) and selenol groups (R-SeH or R-Se ) than to sulphide ions (S - ) and thiol groups (R-SH) (Christo- phersen et al. 2012). Sulphide is formed from methionine S by two different enzymes simultaneously as methionine is degraded to form cysteine (Christophersen et al. 2012), for which reason the concentration ratio sulphide/selenide in the cells is probably determined mainly by the ratio of methionine to total Se in the diet (Christophersen et al. 2012). A comparison of the solubility products for sul- phides and selenides of the same metals (Buketov et al. 1964; Christophersen 1983) gives a measure of the difference in binding strength for the same metallic cations to sulphide and selenide ions. Thus measured, the difference in binding strength (comparing the same metal atoms binding to S and Se atoms), exceeds the S/Se abundance ratio in living cells by a large factor both for Hg ? , Hg ?? , and the cationic forms of several other toxic metals, including Ag, Au and Pt (Christo- phersen 1983; Christophersen et al. 2012). The Se/S atomic abundance ratio is about 10 4 both in the igneous rocks of the Earth’s crust (Krauskopf 1982) and in the solar system as a whole (Suess 1987), thus demonstrating little Se/S fractionation when the Earth and its core were formed (Christophersen et al. 2012). But it is considerably higher in average shale and many natural topsoils, which can partly be explained by Se coming from volcanoes and partly by biological transport processes (Christophersen et al. 2012). The Se/S concentration ratio is low in seawater (much lower than in the Earth’s crust) because of Se removal from seawater by biological processes, but high in most marine animals because of active uptake of Se (in form of selenite ions) in plankton organisms from seawater, while there is no similar bio-enrichment of S in marine organisms because of the very high sulphate concentration in seawater (Krauskopf 1982). All heavy metal selenides have much lower solubility products (Buketov et al. 1964) than the

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corresponding sulphides (Christophersen 1983), with the quotient between the solubility products for corresponding sulphides and selenides increasing (when the solubility products of sulphides and se- lenides of different metals are compared) as the solubility of the sulphide decreases—reaching more than 10 orders of magnitude for those metals that are least soluble in form of sulphides and selenides (Christophersen 1983). This is much more than the atomic abundance ratio S/Se in the solar system and the Earth’s crust (4 orders of magnitude), while in living organisms, the S/Se ratio can often be even less than in common igneous rocks. The sulphide/selenide concentration ratio in living cells is less than the total S/Se ratio in the cells because of various biochemical pathways for selenide produc- tion that are specific to Se and don’t form sulphide ions simultaneously (Christophersen 1983; Christophersen et al. 2012). The ratio between the solubility products for corresponding toxic metal sulphides and selenides is therefore much higher than the sulphide/selenide concentration ratio in the cells, which means that if the concentration of a metallic cation is gradually in- creased from zero upwards, while sulphide and selenide concentrations are kept constant at their normal intracellular levels, saturation will be reached for the metal selenide concerned well before the solution becomes saturated with the corresponding sulphide. The intracellular fluids are therefore under- saturated with regard to all of the toxic metal sulphides as well as FeS (while iron-sulphur groups in enzymes are stabilized by the presence of thiol groups being part of the protein molecule), while they can be saturated or slightly oversaturated with regard to various toxic metal selenides, including CdSe, HgSe and Ag 2 Se. Precipitated PbSe, however, is most likely thermo- dynamically and kinetically unstable because of simul- taneous oxidation both of Pb ?? and Se - ions, following PbSe precipitation (Christophersen et al. 2012). The same is most likely also the case with stannous selenide (SnSe), since Sn ?? , similarly as Pb ?? , can easily be oxidized to higher oxidation numbers.

Vapor of metallic mercury: selenium

Mercury vapor (Hg 0 ) accumulates in the nervous system. There have been very few studies on the

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interaction between Se and Hg 0 . Some studies have been performed in rats and mice with short-term exposure to Hg 0 (from 1 hour to 1 day). These show that supplementation of Se (0.1 mg/kg for 5 days, 1 mg selenite per liter of drinking water, 10 l mol/kg) seems to lead to an increased retention of Hg, particularly in the lungs, kidneys, blood, and to varying degrees in the liver and the brains of mice. Retention seems to increase at high Se dosage or when Se poor animals are used. Retention in the liver has also been demonstrated in rats. The immediate organ distribution of Hg 0 in the organism does not appear to be significantly altered by Se (Nygaard and Hansen 1978; Hansen et al. 1981; Khayat and Dencker 1983). It may be possibilities for some protection in that Hg 0 is oxidized to divalent Hg intracellularly. Some of the protective effect of Se against HgCl 2 is probably intracellular interactions with divalent Hg (Magos and Webb 1980). Several studies have shown remarkably high Hg levels in the brain of individuals previously exposed to Hg even long time after exposure. In a study by Kosta et al. (1975) from a district with Hg mines showed one of the former miners brain levels of Hg up to 13,000 l g/kg. In different parts of the brain of the person with the highest Hg level was it found retention of Hg and Se in a molar ratio close to 1:1. It has also in skin biopsies from Hg exposed workers been found Hg and Se (Kennedy et al. 1977). There are at least two studies on interactions between Hg and Se in workers exposed to Hg 0 (Alexander et al. 1983; Suzuki et al. 1986). Alexander et al. (1983) found an increased excretion of Se in Hg exposed individuals (mean air-Hg 38 lg/m 3 , urinary Hg 6–260 lg/L) compared to an unexposed control group (urinary Hg 1–9 lg/L). How- ever, the study didn’t show a direct correlation between Hg levels in urine and corresponding Se levels in the exposed group. A possible explanation for increased Se excretion may be increased Se levels in the kidneys of Hg exposed individuals. Suzuki et al. (1986) found in a study of Japanese workers exposed to Hg 0 (urinary Hg for men 78 lg/L, urinary Hg for women 22 lg/L) that exposure to Hg 0 likely affected the endogenous metabolism of Se. Mercury and Se were in this study analyzed in plasma, erythrocytes and urine. The study showed that plasma Hg significantly correlated with Se in erythrocytes and plasma, but it was not found a direct relationship between urinary levels of Hg and Se (Suzuki et al. 1986).

The interaction between Hg 0 and Se is probably complex. This is because it can be both complex formation, accumulation of Hg and Se and effects on urine, plasma and blood levels of Se. However, the levels are both dependent on the current ongoing exposure and to what degree and for how long time prior exposure to Hg 0 has been going on. It is not reported whether exposure to Hg 0 can affect the enzyme GPx, or if different Se status is relevant to the toxicity of Hg 0 .

Inorganic mercury salts: selenium

The critical organ for mercury chloride (HgCl 2 ) exposure are the kidneys. The best protection against the toxic effects of HgCl 2 (Hg ?? ) can be seen in animal experiments with high doses of Hg and at the same time administration of Se (most often selenite) in equimolar doses (Parˇ´ızek and Osˇt ˇ a´dalova´ 1967; Magos and Webb 1980; Ho¨gberg and Alexander 2007). The most acute effects including acute tubular necrosis can under these conditions be counteracted. However, the protective effect of Se is poor in continuous HgCl 2 exposure. Usually, it is seen a greater retention of both Hg and Se in the organism. There are also changes in organ distribution with increased retention of Hg in the liver, spleen and blood. From animal experiments it has been reported both increased and reduced Hg levels in the kidneys after simultaneous Se exposure. A redistribution of Hg in the kidneys from low to higher molecular weight proteins, which also contain Se seems to take place. It is probably also created a Hg-selenid-complex with little biological activity. Mercury compounds usually reduces the toxicity of high doses of Se, but increases the toxicity of methylated Se compounds. Inorganic Hg salts inhibit glutathione metabolizing enzymes and GPx in the kidneys. This effect can be counteracted by supplementation of Se (Ridlington and Whanger 1981; Chung et al. 1982). The activity of GPx is inhibited to varying degrees in other organs (Chung et al. 1982). Inorganic Hg occur as elemental Hg (Hg 0 ) and Hg salts (Hg 2 ? ). The critical organ is defined as the organ where it first develops changes. The critical organ for Hg 0 is the CNS, whereas the critical organ for Hg 2 ? is the kidney. In the blood is Hg 0 after a few minutes oxidized to Hg 2 ? by the action of the enzyme catalase. Before the oxidation approximately 10 % of the Hg 0

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in the blood passes the blood–brain barrier and the placenta. In the brain is Hg 0 converted to Hg 2 ? and accumulated (Bjørklund 1991). When selenite is given shortly after mercuric Hg, it protects effectively against damage to the kidneys, acute tubular necrosis and death. However, selenite gives only partial protection for kidney damage caused by Hg if it repeatedly is co-administered with mercuric chloride (Chmielnicka et al. 1978). The protective effect of Se declines strongly with increased exposure time of Hg (Magos and Webb 1980; Watanabe 2002). The Co-administration of Hg and Se usually increases whole-body retention of both elements, and especially of Hg. Both fecal and renal excretion of Hg are reduced, and changes in the organ distribution are seen (Hansen et al. 1981; Kristensen and Hansen 1979; Magos and Webb 1980). Mercury and Se form a high- molecular-weight complex with selenoprotein P, when they are co-administered, which leads to a reduction of Hg in target organs such as the kidneys. High-molecular-weight complexes of Hg and Se are also common in other organs (Yoneda and Suzuki

1997).

Kosta et al. (1975) investigated retired miners that previously were exposed to elemental Hg. They found that the co-accumulation of Hg and Se in a molar ratio was close to unity in the brain, the kidneys, the thyroid, and the pituitary. The Hg levels in the brain were remarkably high, up to 13 lg/g. Analysis of biopsy samples of skin pig- mentations from the Hg-exposed workers revealed deposits containing Hg and Se (Kennedy et al. 1977). Workers, who are exposed to elemental Hg 0 , excrete significantly more Se in urine than unex- posed controls (Alexander et al. 1983).

Organic mercury compounds: selenium

By giving selenite shortly before, at the same time or shortly after exposure to MeHg can selenite effective- ly increase survival and prevent neurological symp- toms and biochemical and pathological-anatomical changes. However, the protective effect of Se is more uncertain for long-term exposure to MeHg. The interaction mechanisms are probably very complex. The combined exposure to MeHg and selenite accom- plished a lipophilic Se-dimethyl-Hg complex which

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probably is not very biologically active. However, the complex penetrates the blood–brain barrier easily. Thereby bringing drawn both distribution and excre- tion of MeHg. Prolonged high MeHg exposure combined with a Se deficient diet decreases glu- tathione in the brain something in rats (Ganther 1980; Ridlington and Whanger 1981). Such inhibition of GPx has also been observed in the brain and muscles in cats following prolonged MeHg exposure and in the liver of mouse fetus when female mice are exposed. The level of glutathione can be maintained with Se supplementation. Methylmercury selectively damages the nervous system in man, resulting in dysarthria, ataxia, con- striction of the visual field, and paresthesias. Ganther et al. (1972) were the first who reported that Se had a protective effect against MeHg toxicity. The same effect was later found in quail, chick, mice, rat, and cat (Ganther 1980; Magos and Webb 1980; Skerfving 1978). When MeHg is given in a single dose or a limited number of doses, selenite prevents the onset of neurological disorders effectively. During long-term dosing with MeHg, selenite offers some protection or at least delays the onset of symptoms (Chang 1983; Magos and Webb 1980). Surprisingly small amounts of selenite are sufficient to provide a protective effect even in cell cultures (Alexander et al. 1979; Ganther

1980).

The protective effects of Se occur even if the co- administration leads to increased levels of Hg in the brain (Chen et al. 1975; Alexander and Norseth 1979; Ganther 1980; Magos and Webb 1980). However, decreased levels of Hg in the brain have also been reported (Komsta-Szumska and Miller 1984). The elimination of Hg after multiple doses of MeHg can be described by a one-compartment model (half-time, 23.6 days). Co-administration of multiple doses of selenite and MeHg revealed a two compartment model for elimination of Hg (halftime, 8.7 and 40.8 days) (Komsta-Szumska and Miller 1984). After exposure to MeHg are the levels of GPx decreased in several organs including the brain. These are restored when Se in small amounts are added (Ganther 1980). MeHg exposure can also affect other selenoproteins, such as the deiodinases (Watanabe 2002). A co-accumalation of Hg and Se in thalamus and in the occipital pole of the brain has been shown in macaques exposed to MeHg (Bjo¨rkman et al.

1995).

Biometals (2015) 28:605–614

613

Conclusions

Selenium play a role in the metabolism of Hg. Under defined conditions in animal studies may Se reduce the toxicity of Hg compounds. The mechanisms are complex and only partially understood, and require systematic dose effect/dose response studies. The retention of Hg and Se in previously Hg exposed individuals may possibly be a reflection of the formation of biologically active Hg-complexes.

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