mercury - selenium interactions and health implications

8/9/2019 Mercury - Selenium Interactions and Health Implications

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Reviews of specific issues relevant to child development

SMDJ Seychelles Medical and Dental Journal, Special Issue, Vol 7, No 1, November 200472

Mercury: selenium interactions and health implications

Laura J Raymond, PhD; Nicholas VC Ralston, PhD.University of North Dakota, Grand Forks, North Dakota, USA.

Correspondence to Nicholas Ralston, Energy & Environmental Research Center, University of North Dakota, PO Box 9018,Grand Forks, ND 58202-9018, USA. Email [email protected]

Abstract

Measuring the amount of mercury present in the environment or food sources may provide an inadequate reflection of the potential for health risks if the protective effects of selenium are not alsoconsidered. Selenium's involvement is apparent throughout themercury cycle, influencing its transport, biogeochemical exposure,bioavailability, toxicological consequences, and remediation.Likewise, numerous studies indicate that selenium, present in many foods (including fish), protects against mercury exposure. Studieshave also shown mercury exposure reduces the activity of seleniumdependent enzymes. While seemingly distinct, these concepts mayactually be complementary perspectives of the mercury-selenium

binding interaction. Owing to the extremely high affinity betweenmercury and selenium, selenium sequesters mercury and reduces itsbiological availability. It is obvious that the converse is also true; asa result of the high affinity complexes formed, mercury sequestersselenium. This is important because selenium is required for normalactivity of numerous selenium dependent enzymes. Throughdiversion of selenium into formation of insoluble mercury-selenides,mercury may inhibit the formation of selenium dependent enzymeswhile supplemental selenium supports their continued synthesis.Further research into mercury-selenium interactions will help usunderstand the consequences of mercury exposure and identifypopulations which may be protected or at greater risk to mercurystoxic effects.

Key words mercury, selenium, mercury-selenide,selenocysteine, selenoenzymes, bioavailability,pathophysiology, mercury toxicity, selenium deficiency

Exposure to mercury

Mercury is a heavy metal of increasing concern as a globalpollutant. The primary human exposure to methyl mercury isdietary from fish consumption. The toxic effects of MeHg canmake it a potential health problem, and it is listed by theInternational Program of Chemical Safety as one of the mostdangerous chemicals in the environment (1). In June of 2003,48 scientists from 17 countries participated in the 61stmeeting of the Joint Expert Committee for Food Additives

and Contaminants (JECFA). Established by the Food andAgriculture Organization and the World HealthOrganization, JECFA recommended to the CodexAlimentarius Commission that the provisional tolerableweekly intake of methyl mercury be reduced from 3.3 to

1.6 g per kg of body weight per week (2:ftp://ftp.fao.org/es/esn/jecfa/jecfa61sc.pdf).

Although adults can experience neurological effects whenexposed to high concentrations of methyl mercury, advisorieshave mainly arisen because of the increasing concernsregarding methyl mercurys effects in the developing nervoussystems of unborn and growing children. Alarmingly, whilethe placental barrier can stop many toxic elements, methyl

mercury is an exception in that it not only crosses theplacenta, it accumulates at higher concentrations on the fetalside than on the maternal (3). Worsening the situation for thedeveloping fetus, mercury also crosses the blood-brain barrier

and exhibits long-term retention once it gets across (4). Thesefactors exacerbate mercurys neurotoxicity and conspire tointensify the pathological effects in this most important andmost vulnerable of the bodys tissues. Destruction of an earlygeneration of brain cells will naturally preclude developmentof further generations of cells, constraining development ofbrain and nerve tissues. While these are the expectedconsequences from high doses of mercury exposure, theeffects of chronic low exposure are undetermined.

Several episodes of fetal MeHg poisoning have beenreported and confirm that the developing fetal brain isespecially susceptible (5-8). However, only in Minamata (9)and Niigata (10), Japan was the poisoning because of fish

consumption. Minamata disease, or methyl mercurypoisoning, was first recognized in 1956, around MinamataBay and occurred again in 1965 in the Agano River basin inNiigata, Japan. It has been estimated that 27 tons of mercurycompounds were dumped into the Minamata Bay from 1932to 1968. Minamata disease was caused by the consumption ofmercury contaminated fish and shellfish obtained from thesewaters. Typically, marine fish contain less than 0.5 ppmMeHg, with some high predator fish frequently having levelsover 1 ppm. Certain Canadian waters polluted with MeHghave fish levels exceeding 10 ppm. However, fish fromMinamata Bay were reported to contain up to 40 ppm MeHg.Over 3000 victims were recognized as having Minamata

disease. Children showed severe neurodevelopmentalimpairment even though the mothers experienced minimal orno clinical symptoms (3). No other children with symptomsof fetal poisoning from fish consumption have been describedsince the Minamata and Niigata episodes. This has causedmuch controversy over fish consumption and the risks ofmethyl mercury ingestion. However, recent research isbeginning to provide insight regarding possible mechanismsinvolved in methyl mercury poisoning and why thediscrepancies may occur among observations from variousstudies.

It is well recognized that mercury and sulphur bindtogether to form complexes. This binding property is the basis

of chelating therapy used as a treatment in cases of acutemercury poisoning. The complexes between mercury andselenium are less generally known but of much higheraffinity. Physiologically, sulphur is far more abundant thanselenium, yet because of seleniums higher affinity, mercuryselectively binds with selenium to form insoluble mercuryselenides (11-12). This interaction has been assumed to be aprotective effect whereby supplemental selenium complexesthe mercury and prevents negative effects in animals fedotherwise toxic amounts of mercury (13-14). The first reporton the protective effect of selenite against mercury toxicityappeared in 1967 (15). Since then, numerous studies haveshown selenium supplementation counteracts the negativeimpacts of exposure to mercury, particularly in regard toneurotoxicity, fetotoxicity, and developmental toxicity. Theability of selenium compounds to decrease the toxic action ofmercury has been established in all investigated species ofmammals, birds, and fish (16-17).


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SMDJ Seychelles Medical and Dental Journal, Special Issue, Vol 7, No 1, November 2004 73

Selenium as a nutrient

Ironically, until approximately 40 years ago, selenium wasknown only as a poison. It is now known that selenium isessential for the normal function of many of the systems ofthe body and selenium deficiency can have adverseconsequences on these systems. Selenium can act as a growthfactor; has powerful antioxidant and anticancer properties;and supports normal thyroid hormone homeostasis,immunity, and fertility (see table). Although still omittedfrom many biochemistry textbooks, two of the 22 primaryamino acids are distinguished by their possession ofselenium: selenomethionine and selenocysteine.Selenomethionine is biochemically equivalent to methionineand is chiefly regarded as an unregulated storagecompartment for selenium. In contrast, selenocysteine istightly regulated and specifically incorporated into numerousproteins that perform essential biological functions.

Table Mammalian selenoprotein / selenoenzymes

Mass Selenoprotein name: information

65kDa Selenoprotein P: primary Se transporter in plasma (10selenocysteines/molecule)

58kDaSelenoprotein N: enriched in pancreas, ovary, prostate and spleen;function unknown

57kDaThioredoxin reductase: active in DNA synthesis; hasimmunoregulatory influences (3 forms)

50kDaSelenophosphate synthetase: present in all tissues; required forselenoprotein synthesis

48kDaSelenoprotein Z: enriched in kidney, liver, testis, prostate, and thymus;function unknown (2 forms)

27kDa Phospholipid glutathione peroxidase: detoxifies lipid peroxides

23kDaCytosolic glutathione peroxidase: detoxifies peroxides in aqueouscompartment of cytosol

23kDaPlasma glutathione peroxidase: primarily synthesized in kidney; activein Se transport

23kDa

Sperm glutathione peroxidase: required for normal sperm activity;

function unknown23kDa Gastrointestinal glutathione peroxidase: tissue specific

18.8kDa Selenoprotein T: function unknown

18-kDaUnknown: found to be one of the most preferentially selenium-suppliedproteins; function unknown

16kDaSelenoprotein X: present in liver, leukocytes, lung, placenta and brain;function unknown

15kDa15kDa selenoprotein: discovered in leukocytes, but broadly distributed;function unknown

14kDaThyroid hormone 5deiodinase: present in tissues that convert T4T3 (thyroxine)

12.6kDa Selenoprotein R: function unknown

10kDaSelenoprotein W: first found in muscle, but widely distributed; functionunknown

8kDa 8kDa selenoprotein: tissue-dependent occurrence and distributions;

function unknown7kDa 7kDa selenoprotein: tissue-dependent occurrence and distributions;

function unknown

5kDa 5kDa selenoprotein: tissue-dependent occurrence and distributions;function unknown


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perinatally, the thyroid hormone economy of the fetus isdisturbed (32). Thyroid hormones are essential for normalneurological development. Should disruption of thyroidhormone regulation occur at vulnerable periods ofdevelopment, irreversible neurological damage can result.Iodothyronine deiodinases are selenoproteins which regulatethe tissue levels of thyroid hormones. Therefore, severeselenium deficiency may be detrimental to the developing

brain. Considering mercurys extremely high binding affinityfor selenium and its ability to cross the blood-brain barrier, itis reasonable to suspect the mercury-selenium interactionmay have a role in developmental pathophysiology.

Through intense laboratory research and epidemiologicalstudies, Dr. Clarkson and his colleagues from the Universityof Rochester, New York, have been addressing the healtheffects from methyl mercury exposure for nearly half acentury. (For a review of their work, see Myers et al 2000(33).) Their research confirmed the neurological deficitsreported from MeHg poisoning incidents in Japan. However,they found no adverse associations from consuming fishcontaining typical mercury levels. Additionally, their studiesof both prenatal and postnatal measures of MeHg exposurefrom fish consumption in Seychellois children have beenassociated with beneficial effects. Their results, however,contrast with those found in studies being carried out in theFaroe Islands (34-35), which reported adverse associationsfrom prenatal MeHg exposure. There are several differencesbetween these studies and the populations in general.However, the most intriguing distinction may be the sourceof MeHg exposure.

The diet consumed by Faroe Islanders includes whalewhereas the Seychelles Islanders diet does not. Whale isknown to contain PCBs (36-38) as well as possibly othertoxins not typically found in fish. Additionally, the amount ofMeHg in some types of whale meat analysed has been

reported to be exceedingly high. The concentration ofmercury present in whale rises continually with age and canexceed the selenium content (39). This is seen in high-endpredator whales such as pilot whales rather than filter feederssuch as bowhead whales. Mercury concentrations in samplesof pilot whale have been 5000 times greater than the Japanesegovernments limit for mercury contamination of 0.4 ppm(40). In contrast to whales, methyl mercury concentrations infish rise with age, but as their mercury contents increase, sodo their selenium concentrations (41). To our knowledge,there are no reports of mercury exceeding seleniumconcentrations in any ocean fish.

Friedman et al. studied the protective effect of freeze-dried swordfish on methyl mercury toxicity in rats. The ratsthat were experimentally administered methyl mercury andfed a swordfish diet showed no signs of neurotoxic effectscharacteristic of mercury poisoning, while rats not fedswordfish did. Analysis of the swordfish showed seleniumconcentrations were at least twice as high as the mercurylevels. The authors suggested that the excess selenium

protected the rats from the effects of the administered methylmercury (42).

Although several population studies have suggested anassociation between high fish intake and reduced coronaryheart disease (CHD), men in eastern Finland who consumelarge amounts of freshwater fish have an exceptionally highCHD mortality. Salonen et al studied the relationshipbetween mercury intake from fish and CHD in Finland (43).The authors hypothesized that the high mercury levels fromfish contributed to increased incidence of CHD. Before soilsupplementation, Finland had the lowest selenium levelsthroughout Europe.

The authors suggested that mercury might contribute toCHD risk by complexing to selenium and reducing itsbioavailability for glutathione peroxidase, thus promotinglipid peroxidation. They further suggest that the lack of asimilar correlation between CHD and fish consumption inother population studies was owing to high intakes ofselenium.

Furthermore, because of the binding interaction betweenthese two elements, selenium appears also have an effect onthe bioavailability of mercury, both biologically andenvironmentally. Several studies suggest an important role ofselenium in the bioaccumulation of mercury in fish (44-46).Paulsson and Lindbergh reported selenium supplementationto lake waters in Sweden resulted in a 75%-85% reduction inmercury levels of fish when measured over a three-year

period (47). Southworth et al (48-49) reported that theelimination of selenium-rich discharges of fly ash to RogersQuarry in Tennessee in 1989 caused a steady increase inmercury concentrations. The aqueous selenium

concentrations decreased from 25 to < 2 g /L. The meanselenium concentrations in bass declined from 3 to 1 mg/kgover the first 5 years and remained at 11.5 mg/kg for the lastthree years of the study. During this time, the mean mercuryconcentrations in bass rose from 0.02 to 0.61 mg/kg. Studiessuch as these confirm the importance of seleniumconsideration in providing mercury exposure management.

Figure The normal cycle of selenoprotein synthesis is depicted on the left. Putative disruption of this cycle by mercury is depicted on the right. Selenidefreed during selenoprotein breakdown becomes available to bind with mercury. Formation of insoluble mercury selenides may reduce the bioavailability ofselenium for protein synthesis


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Consequently, it is possible that the health risks of methylmercury exposure may vary in response to individual andregional differences in selenium intake. The geologicaldistribution of selenium can be highly variable: abundant insoils of one area and deficient in regions only miles away.These variances will influence the amounts of selenium infoods, predisposing for or protecting against consequences ofmercury exposure. Furthermore, variations in relative

quantities and quality of food choices can result in individualdifferences in selenium status. Conceivably, a transientselenium deficiency may briefly occur after ingesting a high-mercury-containing food, such as certain whale meat. Thistransient deficiency could then be recovered fromconsuming adequate amounts of selenium to compensate forthe loss. However, if a deficiency such as this were to happenduring pregnancy, the fetus might be affected dependingupon the severity of the deficiency and the time ofdevelopment. This would only appear likely in populationswith a compromised selenium status along with exposure tofoods containing unusually high levels of mercury.

Recommended selenium intakeThe standard of recommended intake levels of selenium isunder debate. (For a full review, see Rayman (50).) The UK

reference nutrient intake (RNI) of 75 g per day for men and

60 g per day for women has been determined as the intakebelieved to be necessary to maximize the activity of theantioxidant selenoenzyme GPx in plasma (51). The American

recommended dietary allowance (RDA), set at 55 g per dayfor both men and women, is based on the investigations ofthe selenium intake required to achieve plateauconcentrations of plasma GPx (52). The WHO/FAO/IAEA

expert group recommended an intake level of only 40 g per

day for men and 30 g per day for women, assuming only

two-thirds of the full expression of GPx activity is required(53). However, as Rayman (50) points out, if levels of GPxactivity saturation are determined using platelets rather thanplasma, then the intake levels needed should be

approximately 80-100 g per day. Additionally, intake levelswhich saturate plasma GPx activity are insufficient tooptimise the immune response, and reduce cancer risk. Thisinsufficiency is amplified at intake levels suggested by theWHO/FAO/IAEA which only accommodate two thirds ofplasma GPx activity. Currently, the UK and other Europeancountries have intake levels of approximately half the RNI,

and areas of China have intakes of less than 19 g per day for

men and less than 13 g per day for women. Likewise, low-

selenium soils are prevalent in many areas of the worldincluding New Zealand, Russia, and Africa, thuscompromising the selenium status of these populations.

It should be noted that selenium toxicity has also been aconcern. Although selenium toxicities have been reported,human toxicity is rare. Consumption of selenium-toxic foodwas reported in Enshi County, China (54). Chronicallyintoxicated individuals ingested an average of 4.99 mgselenium/day, with some individuals consuming as much as38 mg selenium/day. Signs of selenosis included loss of hairand nails, skin lesions, tooth decay, and abnormalities of thenervous system. Selenium poisoning was also reported in 13persons in the United States who consumed a health food

supplement that contained ~182 times more selenium thanstated on the label (55-56). The total amount of seleniumingested by the victims was calculated to be 272387 mg. Themost common symptoms were nausea, vomiting, hair loss,nail changes, irritability, fatigue, and peripheral neuropathy.

Since the biochemical basis of selenosis is not understood, theupper limit of the estimated safe and adequate dietary intake

is currently set at 200 g per day (57).

Conclusion

In summary, studying the pathology of mercury toxicity mayrequire a more insightful question than simply, How muchmercury is consumed? The more appropriate question maybe, Is a sufficient amount of free selenium available in the cellto create the necessary selenoenzymes or is too muchselenium lost by binding to mercury? In this regard, thesensitivity to mercury-induced neurotoxicity may be due tothe balance of mercury and selenium. Selenium's involvementis apparent throughout the mercury cycle, influencing itstransport, biogeochemical exposure, bioavailability,toxicological consequences, and remediation. Therefore,measuring the amount of mercury present in the environmentor food sources may provide an inadequate reflection of thepotential for health risks if the protective effects of seleniumare not also considered. Further research in these areas willprovide valuable information that is needed to understand

the true impact of mercury exposure as well as identify areaswhich may be protected or at greater risk to mercurys toxiceffects.

Competing interests None declared.

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Nutrition and neurodevelopment: the search for candidate nutrients in theSeychelles Child Development Nutrition Study

JJ Strain1, PhD; Maxine P Bonham1, PhD; Emeir M Duffy1, PhD; Julie MW Wallace1, DPhil; Paula J Robson1, DPhil; Thomas WClarkson2, PhD; Conrad Shamlaye3,MD.Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Northern Ireland 1; University of Rochester Schoolof Medicine and Dentistry, Rochester, New York, USA2; Ministry of Health, Republic of Seychelles3.

Correspondence to Professor JJ Strain, Centre for Molecular Biosciences (CMB), School of Biomedical Sciences, Faculty of Lifeand Health Sciences, University of Ulster, Coleraine, BT52 1SA Northern Ireland. Email [email protected]

Abstract

This review examines the role of nutrients in child development andoutlines the key nutrients identified as potentially important toneurodevelopment among high fish consumers in the SeychellesChild Development Nutrition Study (SCDNS). It describes theclinical assessment of these nutrients in the blood and breast milksamples collected from the cohort of 300 pregnant women who wererecruited, at their first antenatal visit, on the SCDNS. These keynutrients include the long chain polyunsaturated fatty acids(LCPUFA), docosohexaenoic acid (DHA) and arachidonic acid(AA), both of which may affect neurodevelopment in the later stagesof fetal growth. Only DHA, however, is strongly associated with fish consumption, the predominant source of the neurotoxicantmethyl mercury (MeHg). Any benefits of increased selenium statuson neurodevelopment are likely to accrue via detoxification of MeHgduring fetal growth, while benefits of optimal iodine or thyroidstatus are likely to be directly related to neurodevelopment duringlate fetal growth. Unlike LCPUFA, Se, and I, the status of the Bvitamins, folate, vitamin B12, vitamin B6, and riboflavin areunlikely to be closely related to fish consumption but the status ofeach of these B vitamins is likely to impinge on overall status ofcholine, which is expected to have direct effects onneurodevelopment both prenatally and postnatally and may alsoimpact on MeHg toxicity. Choline status, together with the statusof two other candidate nutrients, zinc and copper, which are alsolikely to have effects on neurodevelopment prenatally and

postnatally, are expected to have some correlation with fishconsumption.

Key words long chain polyunsaturated fatty acids, iodine,selenium, choline, B-vitamins, iron, child development

Introduction

The Seychelles Child Development Study (SCDS) wasinitiated in 1987 to test for adverse effects of methyl mercuryexposure from fish consumption on child development.Contrary to expected findings, no adverse outcomes on childdevelopment have been associated with increasing mercuryexposure (1). As fish intake has been shown to correlate withhair mercury, researchers from the SCDS have sincehypothesised that various micronutrients in fish may beresponsible for the lack of adverse effects. It is hypothesisedthat these nutrients in fish may either be beneficial to child

development and/or protective against the neurotoxic effectsof methyl mercury. The Seychelles Child DevelopmentNutrition Study (SCDNS) was subsequently established toexamine this proposed interrelationship between nutritionand child development. A cohort of 300 pregnant women wasrecruited at first antenatal visit and blood samples taken atenrolment, 28 weeks gestation, and post-delivery. A total of24 were excluded subsequently because of miscarriage,neonatal death or deliveries overseas. Cord blood samplesand breast/formula milk samples were also collected. Anextensive battery of psychological tests have been carried outon the infants with more tests yet to be completed; theintention being to correlate neurodevelopmental outcome

with prenatal and postnatal nutrient exposure. The aim of thispaper is to examine the role of nutrients in child developmentand to outline the key nutrients identified as important in theSCDNS and to describe their clinical assessment in thecollected blood and milk samples.

mercury - selenium interactions and health implications

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