1.Selenium Overview

1.1 Bioavailability and Efficiency

Selenium (Se) is a primordial non-metal that occurs naturally in metal sulphide ores found in the Earth’s crust. Soils above granite bedrock are naturally low in Se; soils associated with coal seams and mining waste, black shale and peat deposits have a higher Se content.  Most bioavailable Se enters the food chain from the soil, air and water via uptake by plants  and animals through food or feed. Se content within plant species can vary considerably  depending on the soil where it is grown. For example, a regional comparison of wheat  samples suggests that USA and Canada attain the highest concentration of Se content  between approximately 206-707μg/kg and average UK Se content of wheat is approximately  25-33μg/kg. The efficiency of Se uptake and storage also varies between species and tissues within a plant or animal food source (Lamire et al, 2015; Radawiec et al, 2021). 

1.2 Nutritional Requirements for Selenium 

Approximate Se level required for optimal Se-enzymes activity has been stated as: a blood Se level ≈90μg/L and plasma Se level ≈70μg/L (Yang and Xia, cited in Lemire et al, 2015).  In the year 1991 in the UK, the Reference Nutrient Intake (RNI) for Selenium was stated as 1.0μg/kg body weight (COMA, 1991). The Expert Group on Vitamins and Minerals (2003) stated that the maximum intake achievable from diet for UK adults was approximately 100μg/d and safe supplementation is below 300μg/d for most people. Blood Se≈90μg/L and plasma Se≈70μg/L are also suggested targets for optimal levels of function.

1.3 Recommended Daily Intake of Selenium 

Table 1: Dietary recommendations for Selenium for people living in the UK  (Department of Health, 1991)



1.4 Food Sources of Selenium

According to a review by Ferreira et al (2021) the best food sources of Se are brazil nuts,  cereals, meat, fish and other seafood, milk and nuts. However, it should be noted that the interaction between Se and mercury (and other heavy metals) in contaminated seafood may reduce Se bioavailability.  Wheat is generally a good source of dietary Se (Rybicka et al, 2015) especially for vegetarians and vegans. Agaricus bisporus (White button mushroom) (Rzymski  et al, 2016), Urtica dioica L. (nettle) (Krystofova et al, 2010) and Spinacia oleracea L. (spinach)  (Zhu et al, 2004) are capable of bioaccumulation of significant amounts of Se, but may also  reach toxic levels of inorganic Se from contaminated soil. Foraging or gathering of herbs from disused industrial or mined sites, with potential for soil contamination, should therefore be avoided.  

50% of organic dietary Se molecules are in the form of selenomethionine (SeMet) (Lazard et  al, 2017); the rest is predominantly selenocysteine (SeCys or Sec) (the 21^st amino acid) and  methylselenocysteine (MSeC).  These forms follow the usual mechanisms of amino acid uptake from the digestive system. SeMet is transported to the liver bound as Se-albumin. SeMet requires enzymes, including S-adenosylmethionine (SAM) on the trans-selenation pathway, via SeHCys to SeCys and conversion to HSe^–. The  catabolism of Se-proteins also releases SeCys, which is cyclically reconverted into HSe^– (Roman et al, 2014). SeMet is found in plant and animal-derived foods and some  food supplements. SeCys is found predominantly in animal-derived foods but also cereals and bread. MSeC is a natural monomethylated organic Se found in vegetables such as garlic, onion, broccoli and leeks. MSeC may be used to artificially enrich broccoli, garlic and onions, with a higher Se content. SeMet, SeCys and their methylated derivatives are sulphur (S) amino analogs (reviewed by; Hu et al, 2021; Ferreira et al, 2021). In the future, plants that are capable of significant Se bioaccumulation may be used to enhance dietary availability. However, caution is necessary when artificially introducing Se species into food. This is because of the assumptions required about the Se intake and absorption of a population.  

2. Selenium in Brain Health

2.1  Transport of Selenium to the Brain

The main transport of Se around the body occurs in the blood in the form of selenoprotein P  (SELENOP). Selenium also binds to α and β globulins, low density lipoprotein (LDL) and very  low density lipoprotein (VLDL). A small amount of Se in plasma is also bound to glutathione  peroxidase. Se homeostasis is achieved by reserves of SeMet stored in organs, primarily the  kidney and liver and the stored Se is used when food intake is too low to maintain  selenoprotein synthesis (Medhi et al, 2013). At the bloodbrain barrier (BBB), most Se enters the brain via SELENOP binding to cell surface receptor apolipoprotein E receptor-2 (apoER2,  also known as LRP8) (Solovyev et al, 2018; Kurokawa et al, 2014). However, the exact mechanism of SELENOP transport from the liver to BBB and from BBB to brain cells is not clear.  

Delivery of Se to the brain is important for maintaining antioxidant activity of selenium enzymes GPx. GPx plays a pivotal role in maintaining cellular redox homeostasis where H₂O₂ is  reduced to water with 2H⁺ donated from glutathione (GSH). Oxidised glutathione (GSSG) then needs to be reduced back for the sequence to start again. Glutathione reductase, the enzyme that reduces GSSG back to active GSH, is a flavin dependent enzyme, which utilises vitamin B₂ (Bender, 2014). GSH synthesis relies on reusing  endogenous cysteine, so it follows that a low intake of dietary methionine and cysteine, as well as B2, would be expected to have an unfavourable influence on GSH status and synthesis (The  Nutrition Society, 2009). As reviewed by Minich and Brown (2019), there is also some evidence that supply of sulphur-rich compounds, such as sulforaphane, from consumption of cruciferous vegetables may increase GSH and glutathione-related enzymes. Moreover, impairment of the glutaredoxin system leads to proliferation of intracellular reactive oxygen species and lipid peroxidation (Spiller, 2017). This pathway has implications for brain inflammation.

2.2 Forms of Selenium in the Brain

Although SELENOP is the main selenoprotein and is important for transporting Se around the  human body, it is not the only consideration. Transcriptomic analysis by Fagerberg et al, cited in Zhang and Song (2021), confirmed the expression of 25 selenoproteins in the human brain,  including the important classes of glutathione peroxidases (Gpx) and thioredoxin reductase (TrxR), the most highly expressed being SELENOW, GPX₄ and SELENOP. SELENOW protects neurons against oxidative stress injury during neuronal development (Chung et al, cited in  Zhang and Song, 2021). Mutations in SELENOI (also known as ethanolamine phosphotransferase1 or EPT1) leads to cerebellar and brain stem atrophy, confirmed by  human studies where EPT1 is indispensable in myelination, neurodevelopment and the maintenance of phospholipid homeostasis (Horibata et al cited in Zhang and Song, 2021).  Specific selenoproteins also participate in endoplasmic reticulum homeostasis in the brain and neural cells (Zhang and Song, 2021).  

2.3 Selenium and Brain Development

Neonate animal models have been used to  demonstrate that Se proteins are essential for brain development (Schweizer et al, cited in  Zhang and Song, 2021). Se sufficiency is also very important for maintaining brain health, as it may protect against mercury toxicity (Spiller, 2017).  Selenop^-/- mice neonates raised in a low Se environment exhibit severe hypoplasia and death  but SELENOP production by the liver will support Se supply to the brain (Hill et al cited in  Zhang and Song, 2021), assuming that the Se can cross the blood brain barrier (BBB). This  pathway is especially important if SELENOP expression localised in the brain is low compared to the demand (either by impairment or epigenetic means).  

A study by Dailey et al (2021) identified that there is a potential antisense  targeting of selenop and near abrogation of SELENOP expression in Zika virus infected cells. The perturbation of Se biochemistry and subsequent decrease in the supply of Se to the  central nervous system may partly explain the neuronal cell death, cerebral atrophy and  microcephaly in newborns, whose development has been affected by the virus. The  investigators suggest that a similar mechanism may explain the association of Se in the  pathogenesis of other RNA virus infections such as HIV-1, Ebola and SARS-CoV-2. 

2.4 Selenium and Alzheimer’s Disease (AD)

ApoE ε4 (the isoform linked to increased risk of AD) lacks cysteine at  terminal residues whereas isoform ApoE ε2 (Low risk of AD) contains 2 cysteine residues and  ApoE ε3 (medium risk of AD) contains 1 cysteine residue. A recent in vitro study, using a BBB model, investigated how SELENOP may interact with apoliprotein E (ApoE) at the BBB via dual  binding. The interaction may regulate the onward secretion of exosomal SELENOP into the  brain (Jin et al, 2020). This makes biological sense because the basic function of the exosome  is to protect the contents from premature cleavage before reaching the target cell.  The ease of the interaction of SeCys with ApoE at the BBB, in place of cysteine, may be an important consideration to the risk of AD.   

Studies indicate that Plasma Se concentrations and erythrocyte GPx activity may be slightly  but significantly lower in AD patients compared to control participants (Vural et al, 2010;  Cardoso et al, 2009). Interestingly, a meta-analysis conducted by de Wilde et al (2017)  suggests that there is no difference to Se concentration in the AD brain compared to healthy  brain. However, this study did not discriminate between Se species or compartmentalisation  within the brain. The analysis concurs that AD patients may have lower levels of circulating Se  in the plasma.  

An RCT conducted by Cardoso et al (2019), in which sodium selenate or placebo was given to AD patients for 24 weeks, indicated that sodium selenate increased albumin Se and selenoP in serum, with some improvement also observed with regards to selenate and selenite  concentration, as measured in serum. An additional finding was that selenate and selenite were observed to be high in the cerebrospinal fluid (CSF). The investigators concluded that selenoP may be regarded as the main regulator of Se to the Central Nervous System (CNS).

Although evidence in this area is limited and warrants further investigation, studies so far appear to indicate that AD patients may have suboptimal circulating  SELENOP concentration, and that the interaction of SELENOP with the receptors at the BBB may be impaired. Whilst sodium selenate supplementation may increase SELENOP (which  indicates that protein expression of seleno may not be the problem, per se) it may lead to  raised concentrations of selenate and selenite in the CSF. There are no studies to confirm  that this is a desirable outcome. From the evidence we may further speculate that the contributing factors for the observed  differences of SELENOP serum concentration between AD patients and healthy controls may be:

 1) AD patients have lower concentrations of bioavailable selenium due to dietary  insufficiency.

2) Genetic, epigenetic or failure of the transcription machinery may affect SELENOP mRNA isoforms with differing amounts of SeCys residues that interact differently  with receptors at cell membranes (as per the biochemistry explained in a paper by Kurokawa  et al, 2014).

 3) A contributing infection by species such as E. coli transforms  bioavailable selenium to its elemental form and this may lead to excretion of selenium from  the gut or liver in faeces or urine. 

2.5 Selenium and Depression

A study by Ghimire et al (2019) concludes that inadequate dietary intake of Se may increase  the risk of depressive symptoms. However, the median concentration of serum Se in their  study was very high at 193.9 μg/l . The investigators concluded that there was no detected  benefit for reducing depressive symptoms by supplementing Se when dietary intake is adequate, or above the recommended daily amount (taken from the findings of the National  Health and Nutrition Examination Survey (NHANES) 2011-2014). 

Overall, it should be noted that research is ongoing to explore potential of Se in cognitive decline, diseases such as Parkinson’s, Huntington’s and conditions such as epilepsy (Pillai et al, 2014), depression, anxiety (Weeks et al, 2012) and the stress response (Torres, 2021). However, it should be noted that both over exposure and insufficiency of certain Se species may be linked to conditions of neurodegeneration in humans (Vinceti et al, 2014)

3. Selenium Deficiency and Consequences

3.1 Deficiency in General and Specific At-Risk Populations 

In the UK, 50.3% of females and 25.8% of males may have total intakes of Se that are below  the lower recommended nutrient intake (LRNI). Similarly, an investigation of nutrient intake from a four day food diary completed by 20 vegan, 16 vegetarian and 26 omnivorous UK women concludes that all groups recorded Se intake below the recommended nutrient intake (RNI), especially in the vegan group  (24.7⁺/_– 11.9 μg/day) and vegetarian group (38.7⁺/_– 19 μg/day) (Fallon and Dillon, 2020). Typically, low serum status may accompany alcoholism, congestive cardiomyopathy, acute myocardial infarction, coronary heart disease,  malignancies, liver cirrhosis and dialysis patients. Pregnant and breast-feeding women may also be at increased risk of low Se status (Mehdi et al., 2013).   

3.2 Bioavailability and Dietary Causes of Deficiency

Individuals following a gluten-free diet, where wheat is removed from the diet, may have a lower Se status and increased risk of Se deficiency (Rybicka et al., 2015). Some agricultural areas that have a naturally low soil selenium content may result in deficiencies for the local  population. For example, some areas of China have recorded intakes as low as 12μg/d Se and  may be associated with an increased incidence risk of Keshan disease (COMA, 1991). On the  other hand, Inuit people following a traditional diet have high Se status from consumption of  beluga, caribou and arctic char, but these foods also carry an exceptionally high methyl-mercury load, which may pose a risk to brain health, as well as overall health (Lemire et al., 2015). 

3.3 Consequences of Deficiency 

Additionally, a severe dietary deficiency of Se may lead to Keshan disease or Keshin-Beck disease (Expert  Group on Vitamins and Minerals, 2003). Furthermore, low serum concentration of the Se transport protein, SELENOP, is detected in people with a severe dietary insufficiency (Mehdi et al., 2013).   

3.4 Other Causes of Deficiency

The in vivo activity of selenium-containing molecules is affected by other elements  such as sulphur and heavy metals such methyl-mercury. Absorption of Se species may be reduced or increased by commensal and pathogenic  microbes in the human gut, and therefore ensuring the health of the gut microbiome is vital. Interestingly, microbes found in the human digestive tract, such as Escherichia coli (E. coli),  Lactobacillus planatarum and Sacchromyces cerevisiae, are capable of transforming SeO^2-4 and SeO^2-₃ to elemental Se (Se⁰)(Turner et al, 1998) and bioavailable SeMet (Nasim et al,  2021) and SeHCys. This suggests that Se species in the human body, given the correct  conditions, may be transformed to other Se species by microbes. Environmental studies show  that Se⁰(as well as SeO^2-₄ and SeO^2-₃) is reduced further to soluble Se^2- by microbes such as  E. coli, Salmonella enterica and Clostridium pasteurianum (Eswayah, 2016). This suggests that  there is a potential for pathogens to contribute to Se redox cycling that consumes  glutathione, and thus may lead to cellular damage as previously discussed.  

3.5 Measurements of Selenium Status

Human Se status is measured directly from plasma, serum, whole blood, milk or tissue, urine, hair and nails with differing levels of accuracy. The enzyme glutathione peroxidase (GPx) contains Se and so the concentration of this enzyme group in erythrocytes is used as an indirect measurement for Se status (by measuring the efficiency of hydrogen peroxide (H₂O₂)  metabolization) (Mehdi et al, 2013). The problems associated with using the available techniques to infer individual Se status are discussed in the SACN position statement on selenium and health (SACN, 2013). 

4. Selenium Toxicity

Although the natural Se content of agricultural soils around the World has declined, in some regions the risk of Se toxicity has increased, chiefly due to anthropogenic activity on Se rich  mineral deposits, as well as subsequent release of pollutants into soil and water sources. Toxicity from environmental pollutants containing hydrogen selenide and selenium dioxide may  cause irritation of the respiratory tract. Excessive Se exposure via ingestion or pollution is toxic and may cause death (Hadrup and Ravin-Haren, 2020; WHO, 2021). Individuals may be  exposed to selenium dioxide, selenite and sodium selenite via industrial applications from mined ores, copper refining and burning of coal (WHO, 2021). Additional sources of exposure include Se species derived  from agriculture, animal feed, photocells, photocopiers, glass production, pigments, pharmaceutical products, dietary supplements and anti-dandruff shampoo (Broadley et al., 2006, Mehdi et al., 2013; WHO, 2021). 

5. Summary

Key points raised in this review are as follows:

• Encourage a balanced diet that includes appropriate sources of Selenium
• Avoid foods grown or raised on contaminated soils or in contaminated water 
• Consider using a validated Se testing protocol to inform supplementation decisions
• Use the appropriate food database for the region of the population or individual  being assessed to determine risk of selenium deficiency and toxicity 
• Consider exposure to selenium toxicity from foraging or food culture 
• Be aware that there is a narrow beneficial range between dietary deficiency and  toxicity 
• This beneficial range may be reduced by lifestyle choices, health history,  environmental factors and supplementation

Researcher

Tracey Anne Hipkiss, MSc Personalised Nutrition (CNELM / Middlesex University).  BSc (Hons) Nat Sci (Open University) Biology

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