Hostname: page-component-77c89778f8-7drxs Total loading time: 0 Render date: 2024-07-20T01:41:54.982Z Has data issue: false hasContentIssue false

Emerging evidence on selenoneine and its public health relevance in coastal populations: a review and case study of dietary Se among Inuit populations in the Canadian Arctic

Published online by Cambridge University Press:  08 February 2024

Matthew Little*
Affiliation:
School of Public Health and Social Policy, University of Victoria, Victoria, BC V8P 5C2, Canada
Adel Achouba
Affiliation:
Axe santé des populations et pratiques optimales en Santé, Centre de Recherche du CHU de Québec, Hôpital du Saint-Sacrement, 1050, chemin Sainte-Foy, Québec, G1S 4L8, Canada
Pierre Ayotte
Affiliation:
Axe santé des populations et pratiques optimales en Santé, Centre de Recherche du CHU de Québec, Hôpital du Saint-Sacrement, 1050, chemin Sainte-Foy, Québec, G1S 4L8, Canada Département de Médecine Sociale et Préventive, Université Laval, Pavillon Ferdinand-Vandry, Québec, G1V 0A6, Canada Centre de Toxicologie du Québec, Institut national de santé publique du Québec (INSPQ), 945 Avenue Wolfe, Quebec, G1V 5B3, Canada
Mélanie Lemire
Affiliation:
Axe santé des populations et pratiques optimales en Santé, Centre de Recherche du CHU de Québec, Hôpital du Saint-Sacrement, 1050, chemin Sainte-Foy, Québec, G1S 4L8, Canada Département de Médecine Sociale et Préventive, Université Laval, Pavillon Ferdinand-Vandry, Québec, G1V 0A6, Canada
*
*Corresponding author: Matthew Little, email: matthewlittle@uvic.ca
Rights & Permissions [Opens in a new window]

Abstract

Selenium is an essential mineral yet both deficiency and excess are associated with adverse health effects. Dietary intake of Se in humans varies greatly between populations due to food availability, dietary preferences, and local geological and ecosystem processes impacting Se accumulation into agricultural products and animal populations. We argue there is a need to evaluate and reconsider the relevance of public health recommendations on Se given recent evidence, including the metabolic pathways and health implications of Se. This argument is particularly pertinent for Inuit populations in Northern Canada, who often exceed dietary tolerable upper intake levels and exhibit very high whole blood Se concentrations due to their dependence on local country foods high in the newly discovered Se compound, selenoneine. Since selenoneine appears to have lower toxicity compared to other Se species and does not contribute to the circulating pools of Se for selenoprotein synthesis, we argue that total dietary Se or total Se in plasma or whole blood are poor indicators of Se adequacy for human health in these populations. Overall, this review provides an overview of the current evidence of Se speciation, deficiency, adequacy, and excess and implications for human health and dietary recommendations, with particular reference to Inuit populations in the Canadian Arctic and other coastal populations consuming marine foods.

Type
Review Article
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2024. Published by Cambridge University Press on behalf of The Nutrition Society

Introduction

Selenium (Se) is a chalcogen trace element that is essential for human health(Reference Reich and Hondal1). Over the last three decades, there has been considerable advancement in our understanding of the sources and biological functions of Se. An important outcome of this research is the understanding that the health effects of Se depend upon the species of Se ingested and their metabolism(Reference Dumont, Vanhaecke and Cornelis2Reference Rayman4). This insight corresponds with the current trend in toxicological and public health research of determining the diverse health effects of various forms or species of several other elements found in the natural environment (for example, mercury and arsenic)(Reference Muñoz-Olivas and Cámara5,Reference Zahir, Rizwi and Haq6) . In Inuit Nunangat (the Inuit homelands of the Canadian Arctic comprised of Inuvialuit Settlement Region, Nunavut, Nunavik, and Nunatsiavut), the traditional diet of Inuit populations (comprised of ‘country foods’, as they are called locally) is exceptionally high in Se, largely due to the presence of selenoneine (SeN) – an organoselenium compound and Se isologue of ergothioneine – in marine foods, and particularly beluga skin, that serve important roles in food security, nutrition, and cultural integrity(Reference Lemire, Kwan and Laouan-Sidi7,Reference Achouba, Dumas and Ouellet8) . As a result, Inuit populations across Inuit Nunangat exhibit considerably higher blood Se concentrations than other reference populations in North America and Europe(Reference Achouba, Dumas and Ouellet9,Reference Little, Achouba and Dumas10) . There is a need for both individuals, who may wish to take responsibility for their own health, and government agencies, which often establish public nutrition programming and nutrition guidelines, to be attentive to SeN as it relates to Se dietary sufficiency, metabolism, and health implications. The objective of this article is to review the current evidence on Se as it pertains to Inuit populations in the Canadian Arctic and make recommendations for cohesive, evidence-based research priorities, risk assessment, and public health decision-making that considers the presence of SeN as a major selenium species in several key marine foods.

Human selenoproteins

The biological actions and proposed nutritional essentiality of Se occur largely through selenoproteins. Selenium metabolism of major forms of dietary Se and selenoprotein synthesis are well-documented(Reference Rayman3,Reference Combs11Reference Ha, Alfulaij and Berry14) . Organic forms of selenium, including selenomethionine (SeMet) and selenocysteine (Sec), are the most abundant forms of dietary Se, while inorganic compounds (selenite and selenate) represent a minor proportion of dietary intake(Reference Rayman15). Following absorption, Se compounds are mostly transported to the liver, which is the principal site of Se metabolism(Reference Ha, Alfulaij and Berry14). Dietary SeMet can be trans-selenated to Sec but is primarily non-specifically incorporated into body proteins (such as blood albumin) or converted to methylselenol (CH3SeH) (Fig. 1), although the importance of the latter process in humans is not known(Reference Okuno, Kubota and Kuroda16). Surplus Se may accumulate as SeMet in blood albumin or may be converted to methylated metabolites for excretion in the breath or (more commonly) urine(Reference Rayman3). In the liver, most Se compounds are metabolised to hydrogen selenide (H2Se). Subsequently, Sec is phosphorylated, leading to the formation of monoselenophosphate, which is used for the production of unique transfer RNA, Sec tRNA[Ser]Sec, that provides Sec for selenoprotein synthesis. In the presence of a Sec insertion sequence (SECIS), the UGA codon (which is normally a stop codon) is recoded to specify the insertion of Sec(Reference Labunskyy, Hatfield and Gladyshev17). A SECIS-binding protein recruits Sec tRNA[Ser]Sec for ribosomal translation and incorporation of Sec into nascent polypeptides(Reference Labunskyy, Hatfield and Gladyshev17).

Fig. 1. Metabolism of Se food species, adapted from Combs (2001)(Reference Combs11), Kayrouz et al., (2022)(Reference Kayrouz, Huang and Hauser71), Rayman et al. (2008)(Reference Rayman3), Rayman (2012)(Reference Rayman15), and Yamashita et al. (2010)(Reference Yamashita and Yamashita65). ETT, ergothioneine transporter; SCLY, selenocysteine β-lyase; SeMet, selenomethionine; Sec, selenocysteine; H2Se, hydrogen selenide; CH3SeCys, Se-methyl-selenocysteine; SeN, selenoneine; CH3SeH, methyl selenol; TSP, transsulfuration pathway.

Approximately 25 selenoproteins have been identified thus far that play a functional role in a variety of physiological processes, including cell maintenance, oxidative homeostasis, thyroid hormone metabolism, brain activity, and immune response(Reference Labunskyy, Hatfield and Gladyshev17). For a summary of selenoproteins and their nomenclature and functions, please refer to Pitts and Hoffman (2018)(Reference Pitts and Hoffmann18). Optimum blood plasma Se levels are between 60 and 150 μg/L to maximize selenoprotein synthesis and activity(Reference Smith, Garg, Garg and Smith19,Reference Bleys, Navas-Acien and Guallar20) . It is commonly accepted that when Se intake is sufficient, plasma selenoprotein concentrations and activities plateau. Several researchers have therefore argued that plateau concentrations of plasma selenoproteins reflect functional Se sufficiency(Reference Duffield, Thomson and Hill21Reference Yang, Zhu and Liu23). Consequently, total plasma Se concentrations and plasma selenoprotein (e.g., glutathione peroxidase 3 (GPX3) and selenoprotein P (SELENOP)) concentrations and activity levels are the most commonly used biomarkers for determining Se adequacy(Reference Thomson24).

Dietary reference values and safe upper limits

Although Se deficiency is rare, it is linked with reduced tissue concentrations and activity levels of selenoproteins and can contribute to Keshan disease (congestive cardiomyopathy caused by depletion of selenoprotein glutathione peroxidase, GPX), Kashin-Beck disease (atrophy and necrosis in cartilage tissue, possibly due to oxidative stress), hypothyroidism (due depletion of iodothyronine deodinases)(25), as well as increased risk of miscarriage and other reproductive and obstetric complications(Reference Al-Kunani, Knight and Haswell26Reference Rayman, Wijnen and Vader29). Conversely, Se toxicity (selenosis) can occur with acute or chronic ingestion of excess Se. The most common adverse health impacts of selenosis are alopecia and nail brittleness and loss(Reference Yang, Wang and Zhou30), as well as gastrointestinal disturbances, skin rash, garlic breath odor, fatigue, irritability, and eventually nervous system abnormalities and paresthesia(Reference D’Oria, Apicella and De Luca31,Reference Yang, Yin and Zhou32) . Mechanisms of Se toxicity remain unconfirmed but selenosis likely occurs as a result of oxidative stress generation and consequent disruptions of cellular and mitochondrial function(Reference Mézes and Balogh33,Reference Spallholz34) . Biomonitoring equivalents associated with protection against selenium toxicity range from 400–480 μg/L in whole blood and 180–230 μg/L in plasma(Reference Hays, Macey and Nong35).

Over the past three decades, authoritative bodies have established dietary reference intakes (DRIs) for Se. In their 2001 assessment, the Institute of Medicine established the recommended dietary allowance (RDA) and tolerable upper intake limit (UL) at 55 μg Se/day and 400 μg Se/day respectively for individuals above 14 years of age(25). These values were subsequently adopted by several national regulatory authorities, including Health Canada(36) and the United States Department of Health and Human Services(37). This UL was reaffirmed in separate risk assessments conducted by the National Health and Medical Research Council of Australia and New Zealand(38) and the World Health Organization in coordination the Food and Agriculture Organization of the United Nations(39). Meanwhile, the Scientific Committee on Food (which provided the European Commission on scientific advice on food safety prior to the establishment of the European Food Safety Authority (EFSA)) established a UL of 300 μg Se/day(40) and the UK Expert Group on Vitamins and Minerals established a UL of 450 μg Se/day(41). While the methodology for these risk assessments varied slightly, all were based on a limited number of observational and experimental studies conducted in China(Reference Yang, Yin and Zhou32,Reference Yang and Zhou42,Reference Yang, Zhou and Yin43) , the US(Reference Longnecker, Taylor and Levander44), and New Zealand(Reference Duffield, Thomson and Hill21). Recently, following a request from the European Commission, the EFSA Panel of Nutrition, Novel Foods, and Food Allergens (NDA) undertook a systematic review to establish a scientific opinion on the UL for Se. Grounded primarily in data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), this panel recommended a UL of 255 μg Se/day based on a lowest-observed-adverse-effect-level of 330 μg Se/day and an uncertainty factor of 1·3(Reference Turck and Bohn13).

Case study: Selenoneine and Se status among Nunavimmiut

Inuit living in the Arctic have blood concentrations of Se that are among the highest in the world due to consumption of traditional country foods that are exceptionally replete in Se. (Table 1). Indeed, Inuit from Nunavik(Reference Achouba, Dumas and Ouellet9), Nunavut(Reference Laird, Goncharov and Chan45), and Greenland(Reference Hansen, Deutch and Pedersen46) have considerably higher whole blood Se concentrations than First Nations populations in southern Canada(47) and general populations in Canada(48), USA(Reference Jain and Choi49), and Europe.

Table 1. Whole blood Se concentrations in Inuit compared to other global populations

NR=not reported.

* Geometric mean.

Median.

Arithmetic mean.

Research involving Nunavimmiut (Inuit living in Nunavik, Québec) suggests a large portion of dietary Se is consumed as SeN, which is a major Se compound in RBCs in this population. Analyses on 881 blood samples collected during the Qanuippitaa? 2004 Nunavik Inuit Health Survey showed that SeN accounted for up to 92% of Se in red blood cells (geometric mean: 26%)(Reference Achouba, Dumas and Ouellet8). Findings from this study also suggest Se intake is approximately 214 µg/day (range: 10–1973 µg/day) in a representative sample of Nunavimmiut based on food frequency questionnaire data(Reference Rochette and Blanchet50) and using food Se concentrations derived from Navarro-Alarcon 2008(Reference Navarro-Alarcon and Cabrera-Vique51) and Lemire et al. 2015(Reference Lemire, Kwan and Laouan-Sidi7). Of all consumed foods, mattaaq (skin and underlying fat) derived from beluga whales, which is considered a delicacy by Inuit, is the richest source of total Se for Nunavimmiut(Reference Little, Achouba and Dumas10). Specifically, SeN accumulates in the skin layer and comprises the majority (median 54% in five samples) of Se found in beluga mattaaq (Reference Achouba, Dumas and Ouellet8). Consumption of beluga mattaaq is strongly correlated with RBC SeN concentrations among Nunavimmiut(Reference Little, Achouba and Dumas10). Lesser amounts of Se (including SeN) are also found in other traditional marine foods, including walrus(Reference Tremblay and Lemire52). This dietary Se profile differs from reference populations in southern Canada(Reference Thompson, Erdody and Smith53,Reference Hu and Chan54) , United States(Reference Engberg and Sylvester55Reference Egan, Tao and Pennington57), Europe(Reference Mutanen58,Reference Waegeneers, Thiry and De Temmerman59) , New Zealand(Reference Thomson, Vannoort and Haslemore60), and Australia(61), who obtain Se almost exclusively through purchased meats, eggs, and cereals and other crops grown in Se-containing soil. Due to the accumulation of SeN in RBCs, Inuit exhibit a non-linear relationship between plasma and whole blood Se, in which plasma Se levels plateau around approximately 200 μg/L(Reference Achouba, Dumas and Ouellet9,Reference Hansen, Deutch and Pedersen46) . This contrasts with inland populations in Amazonian Brazil(Reference Lemire, Philibert and Fillion62), Malawi(Reference Stefanowicz, Talwar and O’Reilly63), and the United Kingdom(Reference Stranges, Laclaustra and Ji64), which exhibit a linear association between whole blood Se and plasma Se. Further, despite high whole blood Se, plasma Se and selenoproteins concentration among Inuit are in the normal ranges as reported elsewhere(Reference Achouba, Dumas and Ouellet9). Such findings therefore underscore that Se speciation in food plays a role in the Se species present, as well as their distribution in blood fractions, in consumers.

A closer look at selenoneine: A unique Se species from the marine environment

Selenoneine (2-selenyl-Nα,Nα,Nα-trimethyl-L-histidine or 3-(2-hydroseleno-1H-imidazol-5-yl)-2-(trimethylammonio) propanoate) is a selenoamino acid and Se-isologue to the sulfur-containing compound ergothioneine(Reference Yamashita and Yamashita65). SeN was identified in 2010 in the blood of bluefin tuna at concentrations in the range of 5–40 μg Se/g. Despite this, following more than a decade of subsequent research, SeN has also been reported in different biological matrices of marine animal origin, including beluga whale mattaaq (Reference Achouba, Dumas and Ouellet8), dolphins(Reference Pedrero Zayas, Ouerdane and Mounicou66), sea turtles(Reference Anan, Ishiwata and Suzuki67), various fishes (e.g., swordfish, Pacific mackerel, sardines, and tilapia)(Reference Yamashita, Yabu and Yamashita68), and seabirds(Reference El Hanafi, Pedrero and Ouerdane69), indicating trophic transfer through marine food webs. When found in animals, SeN is likely derived from the diet as only some fungi and bacteria synthesize ergothioneine and SeN(Reference Yamashita and Yamashita65,Reference Yamashita, Yamashita and Ando70,Reference Kayrouz, Huang and Hauser71) . Once consumed, SeN is transported across cell membranes by the ergothioneine transporter (ETT; formerly known as OCTN1), which is present in various tissues and organs(Reference Yamashita, Yabu and Yamashita68). In the bone marrow, uptake of SeN by maturing erythroid cells leads to SeN concentrating in red blood cells(Reference Gründemann, Hartmann and Flögel72).

Selenoneine and human health

Researchers have raised questions about potential health implications of SeN in animals, including humans(Reference Little, Achouba and Dumas10,Reference Yamashita, Yamashita and Suzuki73) . Such questions are particularly relevant to coastal populations that consume high amounts of marine foods, including Inuit living in northern Canada. As yet, however, relatively little is known about the chemistry and physiological functions of SeN.

SeN is one of several dietary Se species. The nutritional chemistry of Se is complex, and dietary Se compounds and their metabolites exhibit their own reactivity and biological activity. The metabolic pathways of the different forms of dietary Se and the relative abundance of Se metabolites are important to determine the overall health impacts of Se consumption (Fig. 1). Notably, as described above, hydrogen selenide (H2Se) plays a central role in Se metabolism; most dietary Se is transformed to H2Se before conversion to selenophosphate and incorporation into selenoproteins as Sec(Reference Berry, Banu and Chen74). However, SeN does not follow the H2Se metabolic pathway. Instead, SeN is distributed to organs and tissues via the ETT. In bone marrow, where the ETT is highly expressed, SeN is taken up by red blood cell precursors and incorporated into mature erythrocytes(Reference Yamashita, Yabu and Yamashita68,Reference Gründemann, Hartmann and Flögel72) . The physiological functions of SeN remain poorly elucidated. SeN has strong radical scavenging and antioxidant activity, and most researchers agree that this may be its primary function(Reference Alhasan, Nasim and Jacob12,Reference Yamashita, Yabu and Yamashita68,Reference Rohn, Kroepfl and Aschner75,Reference Tohfuku, Ando and Morishita76) . Indeed, it was shown to be more resistant to irreversible oxidative degradation compared to ergothioneine and engages in reversible oxidation and reduction reaction under conditions that irreversibly degrade ergothioneine(Reference Lim, Gründemann and Seebeck77). SeN has furthermore been shown to bind to myoglobin and hemoglobin to prevent auto-oxidation of iron(Reference Yamashita, Yabu and Yamashita68). SeN crosses the blood-brain barrier(Reference Drobyshev, Raschke and Glabonjat78) and a recent study showed that the SeN can accumulate in the brains of giant petrels(Reference El Hanafi, Pedrero and Ouerdane69). Authors suggest that SeN may play a role in the protection and function of the central nervous system. Additional implications on mammalian health have been noted; for example, animal model and in vitro studies have shown that SeN inhibits tyrosinase in melanoma cells and melanocytes (potentially by chelating copper at the active site of the enzyme)(Reference Seko, Imamura and Ishihara79), is protective against colorectal cancer in mice(Reference Masuda, Umemura and Yokozawa80), may attenuate hepatocellular injury and hepatic steatosis(Reference Miyata, Matsushita and Shindo81), and has ACE-inhibiting activity(Reference Seko, Imamura and Ishihara79).

Several metals, including lead, arsenic, cadmium, and Hg, form insoluble metal-selenide complexes in yeast, a reaction that may protect cells from both metal toxicity(Reference Kaur, Ponomarenko and Zhou82,Reference Ikemoto, Kunito and Tanaka83) and sodium selenide toxicity(Reference Dauplais, Lazard and Blanquet84). It is well recognized that Se can selectively bind with Hg and protect against MeHg toxicity, which is found in high concentrations at upper trophic levels of marine ecosystems(Reference Ikemoto, Kunito and Tanaka83). Recent experimental and epidemiological research provides evidence for the potential of Se to mitigate the cardiovascular and neurotoxic effects of MeHg exposure in humans(Reference Ayotte, Carrier and Ouellet85Reference Branco, Canário and Lu91). Following the discovery of SeN, several researchers have suggested that it may play a role in the detoxification of MeHg, possibly through demethylation of MeHg leading to the formation of stable inorganic mercury selenide (Hg-Se) complexes(Reference Achouba, Dumas and Ouellet8,Reference Yamashita, Yamashita and Suzuki73,Reference Palmer and Parkin92) . Palmer and colleagues (2015) speculate that SeN promotes MeHg-induced proteolytic cleavage of Hg-C bonds, thereby demethylating MeHg prior to Hg-Se precipitation(Reference Palmer and Parkin92). Stable inorganic mercury selenide (Hg-Se) complexes are found to accumulate over time in the livers of marine birds and marine mammals, as well as in the brains of humans exposed to high levels of MeHg(Reference Ikemoto, Kunito and Tanaka83,Reference Korbas, O’Donoghue and Watson93,Reference Lailson-Brito, Cruz and Dorneles94) , indicating that demethylation mediated by SeN or other forms of Se occurs in vivo and may simultaneously reduce metal toxicity and functional availability of Se. Indeed, studies on zebrafish embryos showed reduced MeHg accumulation and toxicity in the presence of SeN(Reference Yamashita, Yamashita and Suzuki73). It is likely that such mechanisms have bearing on human health. Among Nunavummiut (Inuit living in Nunavut) and Nunavimmiut, high whole blood Se status (a large portion of which was likely SeN) exhibited a protective effect against the adverse cardiovascular health effects of high MeHg exposure(Reference Ayotte, Carrier and Ouellet85,Reference Hu, Eccles and Chan95) , suggesting that Se-mediated detoxification of MeHg may occur in humans. This is particularly relevant due to the elevated exposure of Inuit populations to MeHg through their traditional dietary staples, including marine mammals and predatory fish species(Reference Lemire, Kwan and Laouan-Sidi7).

Overall, current research paints an incomplete picture of the physiological functions and health implications of SeN. Despite growing interest in recent years, further biological assessment of SeN has been hampered by the absence of a commercial source(Reference Alhasan, Nasim and Jacob12). However, as mentioned, an important observation of the research to date is that SeN does not appear to contribute to the pool of H2Se for selenoprotein synthesis. Incubating cells with SeN causes no effect on GPX or SELENOP despite cells rapidly taking up the compound(Reference Drobyshev and Schwerdtle96). By contrast, incubation with reference selenium compounds selenite and selenomethionine induce increased activity of selenoproteins(Reference Allan, Lacourciere and Stadtman97). We can therefore conclude that SeN metabolism, biological function, nutritional essentiality, and toxicity differ from those of SeMet, Sec, and other better-understood Se species that are metabolized through the H2Se cycle. Furthermore, current evidence suggests that SeN is less toxic than other forms of Se(Reference Yamashita, Yamashita and Ando70). Drobyshev and colleagues (2023) demonstrated that SeN causes no toxic effects up to 100 µM concentration in hepatocytes and capillary endothelial cells(Reference Drobyshev and Schwerdtle96). Such findings add evidence to the suspicions of previous authors, including Yamashita et al., (2010), who posited that SeN has limited toxicity in their paper describing the discovery of SeN(Reference Little, Achouba and Dumas10,Reference Yamashita and Yamashita65) . Thus, individuals consuming a high percentage of Se as SeN may not experience the same detrimental health effects as populations consuming high amounts of SeMet, Sec, selenite, and selenate, despite high total Se intake and high whole blood total Se. Conversely, populations consuming the majority of their dietary Se as SeN may need to ensure they have other dietary sources of Se to ensure adequate selenoprotein synthesis and activity.

The flaws of current Se recommendations for Inuit populations living in Canada

Dietary Se guidelines and information sheets often refer to dietary reference intakes established by the Institute of Medicine, with the goal of preventing overt signs of deficiency and excess(36). Under Health Canada’s Chemicals Management Plan, which aims to assess and manage chemicals to “protect the health of Canadians and the environment”, the Government of Canada has published an assessment of Se and its compounds(98). As a part of this assessment, Health Canada prepared and distributed an overview of information on Se focused on North and Northern communities, which notes that “Se can be harmful to human health at levels above what the body needs to function” and “blood levels of selenium above the international guidance level (i.e. 480 microgram/L) have been measured in up to 28% of Inuit” (Health Canada, Information on Selenium in the North, 2018, personal communication). Notably, however, these assessments and communication contain no reference to SeN, which comprises one of the primary species of dietary Se among Nunavimmiut and likely all Inuit living in northern Canada.

The continued failure to disaggregate Se species in research, dietary guidelines, and communications about Se is problematic and may lead to unnecessary concern about selenosis among Inuit populations. This trend is reflected in the fact that RDAs and ULs apply to total Se intake, thereby overlooking dietary Se speciation and disregarding the varied functions of dietary Se compounds and metabolites(Reference Rayman3). The RDAs developed by the IOM are based on only two experimental studies – one conducted by Yang and colleagues (1987) in China(Reference Yang, Zhu and Liu23), and one conducted by Duffield and colleagues (1999) in New Zealand(Reference Duffield, Thomson and Hill21). These foundational studies have limited external validity due to their small sample sizes, interventions that comprised only one Se species (SeMet) or unquantified Se species, and a limited number of female, youth, and elderly participants. Such limitations minimize the generalizability of findings to other global populations, including Inuit in northern Canada, for whom SeMet is not the primary form of dietary Se. Further, studies that informed the development of RDAs used GPX activity as an indicator of Se sufficiency(Reference Duffield, Thomson and Hill21,Reference Yang, Zhu and Liu23) . A major limitation of this approach is that, despite their contributions to total dietary Se intake, SeN accumulates in RBCs and has little bearing on plasma Se or selenoprotein synthesis or activity, as stated earlier. Indeed, evidence suggests that Inuit populations exhibit normal levels of selenoproteins despite very high total Se intake and RBC Se status(Reference Achouba, Dumas and Ouellet9).

Similarly, ULs promoted by the IOM are based on two observational studies – one conducted by Yang and colleagues (1994) in Enshi, China(Reference Yang and Zhou42), and another conducted in western United States(Reference Longnecker, Taylor and Levander44). These studies were once again limited in their external validity due to small sample sizes and unspecified Se species and exposure routes, thereby limiting their relevance in determining ULs for Inuit populations. The recent systematic review and scientific opinion published by the EFSA NDA recommended lowering the UL from 300 to 255 μg Se/day. While this review recognized the existence of SeN in marine foods, their risk assessment failed to consider dietary Se speciation in establishing ULs.

Despite very high dietary intake of Se (often exceeding ULs promoted by the IOM and EFSA NDA) and whole blood Se concentration, Inuit populations in Nunavut(Reference Hu, Eccles and Chan95), Nunavik(Reference Achouba, Dumas and Ouellet9), and Greenland(Reference Hansen, Deutch and Pedersen46) exhibit little evidence of selenosis. Since marine food consumption has declined rapidly following colonial policies enforced by the Government of Canada (e.g., forced settlement and introduction of retail foods)(Reference Little, Hagar and Zivot99), it is reasonable to assume that SeN intake was considerably higher prior to colonial contact. Although data do not exist prior to 1992, there is no historical record of selenosis (or symptoms thereof) among Inuit. It is likely that dietary Se speciation accounts for variations in perceived tolerances of total Se intake between populations. For example, it has been shown that selenite ingestion leads to excess at much lower doses compared to SeMet(25), while SeN appears to be a non-toxic form of Se, as previously mentioned(Reference Yamashita, Yabu and Yamashita68). Overall, this research suggests that current DRIs and recommendations on Se are not relevant for Inuit populations, and future risk assessments and communications regarding Se exposure in northern Canada need to be cognizant of dietary intake of SeN in combination with other Se species.

Future directions for research and risk assessment incorporating evidence on SeN

There remain several gaps in our understanding of SeN. First, little is known regarding the natural synthesis and origins of SeN in the marine food chain. Ergothioneine, the sulfur analogue of SeN, is synthesized by bacteria and fungi but not plants or animals(Reference Jones, Doyle and Fitzpatrick100), and researchers have speculated that the same is true of SeN(Reference Kayrouz, Huang and Hauser71). Recently, Kayrouz et al. (2022) used a genome-mining strategy to identify a three-gene cluster that encodes a dedicated enzymatic pathway for producing selenoneine in bacteria, disproving prior theories that selenoneine is synthesized due to non-specific incorporation of Se during ergothioneine production(Reference Kayrouz, Huang and Hauser71). Since animals do not synthesize SeN, marine species exhibiting high concentrations of SeN (e.g., beluga whales and tuna) likely obtain SeN through dietary sources or through their microbiome(Reference Achouba, Dumas and Ouellet8), however additional research is necessary to identify and confirm natural sources of SeN. Furthermore, given the emerging nature of evidence on SeN, there is a need for research on SeN kinetics, metabolic pathways, biological functions, and health implications to appropriately assess the benefits and potential risks of SeN consumption. Such research must consider Se and SeN bioavailability and metabolism vis-à-vis consumption of metallic elements, including MeHg. It is also imperative that researchers, health practitioners, and public health agencies work together to identify and appropriately deploy relevant and appropriate biomarkers of Se status. In particular, whole blood Se concentration may be a poor measure of Se adequacy for selenoprotein function, considering SeN accumulates in red blood cells but does not serve as a Se reservoir for selenoprotein synthesis. Researchers should instead measure plasma Se and selenoproteins (e.g., SELENOP concentration and GPX activity) as biomarkers of Se functional sufficiency. Meanwhile, there is a need for more widespread measurement of SeN levels among humans to determine the concentrations and distribution of this compound across global populations. Recent advances in SeN analytical methods published by Achouba and colleagues (2023) should make this process more accessible, sensitive, specific, precise, and cost effective(Reference Achouba, Dumas and Ayotte101).

It is important to recognize the value of traditional country foods of marine origin, which are often high in Se, to the cultural integrity and food basket of Inuit populations. This recognition must permeate all research and public health messaging that occur with Inuit populations in northern Canada. Above all, country foods play an integral role in Inuit life by providing a spiritual connection to the land(Reference McGrath-Hanna, Greene and Tavernier102) and improving nutritional status(Reference Kuhnlein and Receveur103,Reference Johnson-Down and Egeland104) , food security(Reference Chan, Fediuk and Hamilton105), and mental health(Reference McGrath-Hanna, Greene and Tavernier102,Reference Lucas, Dewailly and Blanchet106) . Thus, it is important to recognize the dangers of endorsing and disseminating existing ULs for Se, as such actions may exacerbate current fears surrounding the consumption of country foods that have arisen due to zoonotic diseases (e.g., Giardia spp., Trichinella spp., Toxoplasma gondii, etc.) and environmental contaminants (e.g., MeHg and persistent organic pollutants, among others)(Reference Pufall, Jones and McEwen107,Reference Donaldson, Van Oostdam and Tikhonov108) . Given the significance of country foods to Inuit populations, we must be careful to not discourage country food consumption due to its importance for food security and nutrition(Reference Lemire, Kwan and Laouan-Sidi7). It is therefore crucial to provide the best evidence on Se and SeN to local public health practitioners and clinicians (including physicians and midwives) to help them promote country foods while minimizing the risk of exposure to harmful contaminants when designing and implementing public health education and clinical recommendations on environmental contaminants, Se, and other country food nutrients among Inuit populations.

While this case study has focused primarily on the Inuit populations, our arguments likely have broader relevance. SeN is found in high concentrations in many marine animals that serve as staple food sources for populations globally. Marine foods are especially crucial to the food security, nutrition, and cultural traditions of coastal populations, including coastal Indigenous populations(Reference Cisneros-Montemayor, Pauly and Weatherdon109). For example, SeN has been also identified as a major Se compound found in the blood of human populations consuming large amounts of marine foods in northern Japan(Reference Little, Achouba and Dumas10,Reference Yamashita, Yamashita and Ando70) . Although population-level analyses of blood SeN concentrations are extremely limited, we posit that SeN may comprise a large fraction of whole blood Se in coastal populations around the globe. As such, the evidence reviewed in this manuscript, and the arguments emerging therefrom, may be broadly applicable to coastal populations globally. There is a need for additional research on Se status, Se adequacy, and SeN sources and whole blood concentrations in understudied coastal populations. Following this, there is a need to incorporate such evidence into our existing body of research, DRIs, and public health guidance regarding Se to reflect the presence of SeN in foods and human populations. As a further complication, SeN and MeHg often occur in high concentrations in the same marine foods (e.g., Lemire et al. 2015(Reference Lemire, Kwan and Laouan-Sidi7)) and are highly correlated in human populations (e.g., Achouba et al. 2019(Reference Achouba, Dumas and Ouellet8)). Such evidence must comprise an important component of any risk assessment and public health strategy on Se.

Conclusion

In recent years, there have been substantial advancements in the study of different chemical forms of Se in food sources and tissues. The recent discovery of SeN, a selenoamino acid and Se-isologue to the sulfur-containing compound ergothioneine that accumulates in red blood cells, underscores the importance of Se speciation in research, risk assessment, and dietary reference intakes. In this article, we have argued a case to evaluate and reconsider the relevance of public health recommendations on Se with a special focus on Inuit in northern Canada, who consume a large portion of their dietary Se as SeN. Our arguments may have relevance for other populations who consume marine diets high in SeN. Since SeN does not appear to be as toxic as other dietary Se species and does not contribute to synthesis of selenoproteins, it is important to consider nuanced dietary and public health guidelines for Se that are responsive to emerging evidence. While selenoneine has limited relevance to Se metabolism involving synthesis of selenoproteins, there is a need for further research on the health implications of this compound, including its potential to serve as a strong dietary antioxidant and detoxifying agent for methylmercury.

Acknowledgements

We are grateful to all participants of research studies conducted in Nunavik and elsewhere in Inuit Nunangat over the past decades, including the 2004 Qanuippitaa? Inuit Health Survey, the 2007-08 International Polar Year Inuit Health Survey, and the 2017 Qanulirppitaa? Inuit Health Survey. We also acknowledge the contributions of Cole Heasley, who provided comments on previous drafts of the manuscript.

Financial support

This research was funded by a post-doctoral fellowship through the Canadian Institutes of Health Research, ArcticNet grant no. P74, and Crown-Indigenous Relations and Northern Affairs Canada Northern Contaminants Program grant no. H-12. Matthew Little is a Michael Smith Health Research BC Scholar. Mélanie Lemire is a member of Quebec Océan and also received a salary grant from the Fonds de recherche du Québec – Santé (FRQS): Junior 1 and 2 (2015-2023) and Senior (2023-2027). She is the titular of the Littoral Research Chair – the Sentinel North Partnership Research Chair in Ecosystem Approaches to Health (2019-2024), which is mainly funded by Sentinel North and by the Northern Contaminants Program (NCP) of the Crown-Indigenous Relations and Northern Affairs Canada.

Competing interests

The authors declare none.

Authorship

Matthew Little: Conceptualization, Data curation, Funding acquisition, Formal analysis, Writing – original draft, Writing – review & editing Adel Achouba: Conceptualization, Writing – review & editing Mélanie Lemire: Conceptualization, Data curation, Formal analysis, Writing – review & editing Pierre Ayotte: Conceptualization, Data curation, Formal analysis, Writing – review & editing. All authors read and approved the final manuscript.

References

Reich, HJ & Hondal, RJ (2016) Why nature chose selenium. ACS Chem Biol 11, 821841.CrossRefGoogle ScholarPubMed
Dumont, E, Vanhaecke, F & Cornelis, R (2006) Selenium speciation from food source to metabolites: a critical review. Anal Bioanal Chem 385, 13041323.CrossRefGoogle ScholarPubMed
Rayman, MP (2008) Food-chain selenium and human health: emphasis on intake. Br J Nutr 100, 254268.CrossRefGoogle Scholar
Rayman, MP (2020) Selenium intake, status, and health: a complex relationship. Hormones 19, 914.CrossRefGoogle Scholar
Muñoz-Olivas, R & Cámara, C (2001) Speciation related to human health. Trace Element Speciation Environ, Food and Health 331, 53.CrossRefGoogle Scholar
Zahir, F, Rizwi, SJ, Haq, SK, et al. (2005) Low dose mercury toxicity and human health. Environ Toxicol Pharmacol 20, 351360.CrossRefGoogle ScholarPubMed
Lemire, M, Kwan, M, Laouan-Sidi, AE, et al. (2015) Local country food sources of methylmercury, selenium and omega-3 fatty acids in Nunavik, Northern Quebec. Sci Total Environ 509, 248259.CrossRefGoogle ScholarPubMed
Achouba, A, Dumas, P, Ouellet, N, et al. (2019) Selenoneine is a major selenium species in beluga skin and red blood cells of Inuit from Nunavik. Chemosphere 229, 549558.CrossRefGoogle Scholar
Achouba, A, Dumas, P, Ouellet, N, et al. (2016) Plasma levels of selenium-containing proteins in Inuit adults from Nunavik. Environ Int 96, 815.CrossRefGoogle Scholar
Little, M, Achouba, A, Dumas, P, et al. (2019) Determinants of selenoneine concentration in red blood cells of Inuit from Nunavik (Northern Québec, Canada). Environ Int 127, 243252.CrossRefGoogle Scholar
Combs, GF (2001) Selenium in global food systems. Br J Nutr 85, 517547.CrossRefGoogle ScholarPubMed
Alhasan, R, Nasim, MJ, Jacob, C, et al. (2019) Selenoneine: a unique reactive selenium species from the blood of tuna with implications for human diseases. Curr Pharmacol Rep 5, 163173.CrossRefGoogle Scholar
EFSA Panel on Nutrition NF and FA (NDA), Turck, D, Bohn, T, et al. (2023) Scientific opinion on the tolerable upper intake level for selenium. EFSA J 21, e07704.Google ScholarPubMed
Ha, HY, Alfulaij, N, Berry, MJ, et al. (2019) From selenium absorption to selenoprotein degradation. Biol Trace Elem Res 192, 2637.CrossRefGoogle ScholarPubMed
Rayman, MP (2012) Selenium and human health. Lancet 379, 12561268.CrossRefGoogle ScholarPubMed
Okuno, T, Kubota, T, Kuroda, T, et al. (2001) Contribution of enzymic alpha, gamma-elimination reaction in detoxification pathway of selenomethionine in mouse liver. Toxicol Appl Pharmacol 176, 1823.CrossRefGoogle ScholarPubMed
Labunskyy, VM, Hatfield, DL & Gladyshev, VN (2014) Selenoproteins: molecular pathways and physiological roles. Physiol Rev 94, 739777.CrossRefGoogle ScholarPubMed
Pitts, MW & Hoffmann, PR (2018) Endoplasmic reticulum-resident selenoproteins as regulators of calcium signaling and homeostasis. Cell Calcium 70, 7686.CrossRefGoogle ScholarPubMed
Smith, LD & Garg, U (2017) Chapter 17 - Disorders of trace metals. In: Biomarkers in Inborn Errors of Metabolism (Internet), pp. 399426 [Garg, U & Smith, LD, editors]. San Diego: Elsevier. https://www.sciencedirect.com/science/article/pii/B9780128028964000158 Google Scholar
Bleys, J, Navas-Acien, A & Guallar, E (2008) Serum selenium levels and all-cause, cancer, and cardiovascular mortality among US adults. Arch Intern Med 168, 404410.CrossRefGoogle ScholarPubMed
Duffield, AJ, Thomson, CD, Hill, KE, et al. (1999) An estimation of selenium requirements for New Zealanders. Am J Clin Nutr 70, 896903.CrossRefGoogle Scholar
Levander, OA (1991) Scientific rationale for the 1989 recommended dietary allowance for selenium. J Am Dietetic Assoc 91, 15721576.CrossRefGoogle Scholar
Yang, G-Q, Zhu, LZ, Liu, SJ, et al. (1987) Human Selenium Requirements in China. Selenium in Biology and Medicine. New York: Van Nostrand Reinhold Co. pp. 589607.Google Scholar
Thomson, CD (2004) Assessment of requirements for selenium and adequacy of selenium status: a review. Eur J Clin Nutr 58, 391402.CrossRefGoogle Scholar
Institute of Medicine (2000) Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids: A Report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of Dietary Reference Intak. Washington, DC: Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds.Google Scholar
Al-Kunani, AS, Knight, R, Haswell, SJ, et al. (2001) The selenium status of women with a history of recurrent miscarriage. BJOG: Int J Obstet Gynaecol 108, 10941097.Google ScholarPubMed
Kumar, KSD, Kumar, A, Prakash, S, et al. (2002) Role of red cell selenium in recurrent pregnancy loss. J Obstet Gynaecol: J Institute Obstet Gynaecol 22, 181183.CrossRefGoogle ScholarPubMed
Mistry, HD, Broughton Pipkin, F, Redman, CWG, et al. (2012) Selenium in reproductive health. Am J Obstet Gynecol 206, 2130.CrossRefGoogle ScholarPubMed
Rayman, M, Wijnen, H, Vader, H, et al. (2011) Maternal selenium status during early gestation and risk for preterm birth. Can Med Assoc J 183, 549.CrossRefGoogle ScholarPubMed
Yang, GQ, Wang, SZ, Zhou, RH, et al. (1983) Endemic selenium intoxication of humans in China. Am J Clin Nutr 37, 872881.CrossRefGoogle Scholar
D’Oria, L, Apicella, M, De Luca, C, et al. (2018) Chronic exposure to high doses of selenium in the first trimester of pregnancy: case report and brief literature review. Birth Defects Res 110, 372375.CrossRefGoogle ScholarPubMed
Yang, G, Yin, S, Zhou, R, et al. (1989) Studies of safe maximal daily dietary Se-intake in a seleniferous area in China. Part II: relation between Se-intake and the manifestation of clinical signs and certain biochemical alterations in blood and urine. J Trace Elements Electrolytes Health Dis 3, 123130.Google Scholar
Mézes, M & Balogh, K (2009) Prooxidant mechanisms of selenium toxicity–a review. Acta Biologica Szegediensis 53, 1518.Google Scholar
Spallholz, JE (1994) On the nature of selenium toxicity and carcinostatic activity. Free Radical Biol Med 17, 4564.CrossRefGoogle ScholarPubMed
Hays, SM, Macey, K, Nong, A, et al. (2014) Biomonitoring equivalents for selenium. Regul Toxicol Pharm 70, 333339.CrossRefGoogle ScholarPubMed
Government of Canada (2017) Selenium and its Compounds - Information Sheet [Internet]. 2017 Dec. https://www.canada.ca/en/health-canada/services/chemical-substances/fact-sheets/chemicals-glance/selenium-compounds.html (accessed 16 December 2023).Google Scholar
US Department of Health and Human Services National Institutes of Health Office of Dietary Supplements (2021) Selenium: Fact Sheet for Health Professionals [Internet]. https://ods.od.nih.gov/factsheets/Selenium-HealthProfessional/ (accessed 15 December 2023).Google Scholar
National Health and Medical Research Council IRD (2005) Nutrient Reference Values for Australia and New Zealand [Internet]. Government of Australia and New Zealand; pp. 8. https://www.nrv.gov.au/nutrients/selenium (accessed 15 December 2023).Google Scholar
World Health Organization/Food and Agriculture Organization of the United Nations (2004) Vitamin and Mineral Requirements in Human Nutrition: Report of a Joint FAO/WHO Expert Consultation. Bangkok, Thailand: World Health Organization. pp. 17299.Google Scholar
SCF (Scientific Committee on Food) (2000) Guidelines of the Scientific Committee on Food for the Development of Tolerable Upper Intake Levels for Vitamins and Minerals [Internet]. https://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf (accessed 15 December 2023).Google Scholar
EVM (Expert Group on Vitamins and Minerals) (2003) Safe Upper Levels for Vitamins and Minerals. Food Standards Agency; pp. 360. https://cot.food.gov.uk/sites/default/files/vitmin2003.pdf (accessed 15 December 2023).Google Scholar
Yang, G & Zhou, R (1994) Further observations on the human maximum safe dietary selenium intake in a seleniferous area of China. J Trace Elements Electrolytes Health Dis 8, 159165.Google Scholar
Yang, G, Zhou, R, Yin, S, et al. (1989) Studies of safe maximal daily selenium intake in a seleniferous area in China: I. Selenium intake and tissue levels of the inhabitants. J Trace Elements Electrolytes Health Dis 3, 7787.Google Scholar
Longnecker, MP, Taylor, PR, Levander, OA, et al. (1991) Selenium in diet, blood, and toenails in relation to human health in a seleniferous area. Am J Clin Nutr 53, 12881294.CrossRefGoogle Scholar
Laird, BD, Goncharov, AB & Chan, HM (2013) Body burden of metals and persistent organic pollutants among Inuit in the Canadian arctic. Environ Int 59, 3340.CrossRefGoogle ScholarPubMed
Hansen, JC, Deutch, B & Pedersen, HS (2004) Selenium status in Greenland Inuit. Sci Total Environ 331, 207214.CrossRefGoogle Scholar
Assembly of First Nations (2013) First Nations Biomonitoring Initiative: National Results 2011. https://iportal.usask.ca/record/38767 (accessed 8 March 2022).Google Scholar
Jain, RB & Choi, YS (2015) Normal reference ranges for and variability in the levels of blood manganese and selenium by gender, age, and race/ethnicity for general U.S. population. J Trace Elements Med Biol 30, 142152.Google Scholar
Rochette, L & Blanchet, C (2004) Qanuippitaa? How are we? Methodological Report (Internet). http://www.ncbi.nlm.nih.gov/pubmed/20872596 (accessed 8 March 2022).Google Scholar
Navarro-Alarcon, M & Cabrera-Vique, C (2008) Selenium in food and the human body: a review. Sci Total Environ 400, 115141.CrossRefGoogle ScholarPubMed
Guillaume Cinq-Mars, Tremblay, JE, Lemire, M (2022) Les aliments de la mer au Nunavik: mieux comprendre les variations des concentrations d’éléments essentials et de méthylcercure chez les phoques anneleés, les bélugas et les morse [Internet]. Université Laval. https://corpus.ulaval.ca/entities/person/2b468f4e-6650-4dac-ac32-ecc9e4fa792f (accessed 3 November 2023).Google Scholar
Thompson, JN, Erdody, P & Smith, DC (1975) Selenium content of food consumed by Canadians. J Nutr 105, 274277.CrossRefGoogle ScholarPubMed
Hu, XF & Chan, HM (2018) Factors associated with the blood and urinary selenium concentrations in the Canadian population: results of the Canadian Health Measures Survey (2007–2011). Int J of Hygiene Environ Health 221, 10231031.CrossRefGoogle Scholar
Engberg, RA & Sylvester, MA (1993) Concentrations, distribution, and sources of selenium from irrigated lands in Western United States. J Irrigat Drain Eng Am Soc Civil Eng 119, 522536.Google Scholar
Pennington, JAT & Young, B (1990) Iron, zinc, copper, manganese, selenium, and iodine in foods from the United States total diet study. J Food Compos Anal 3, 166184.CrossRefGoogle Scholar
Egan, SK, Tao, SS-H, Pennington, JAT, et al. (2002) US Food and Drug Administration’s Total Diet Study: intake of nutritional and toxic elements, 1991–1996. Food Addit Contam 19, 103125.CrossRefGoogle Scholar
Mutanen, M (1984) Dietary intake and sources of selenium in young Finnish women. Hum Nutr Appl Nutr 38, 265269.Google ScholarPubMed
Waegeneers, N, Thiry, C, De Temmerman, L, et al. (2013) Predicted dietary intake of selenium by the general adult population in Belgium. Food Additives Contam: Part A 30, 278285.CrossRefGoogle ScholarPubMed
Thomson, BM, Vannoort, RW & Haslemore, RM (2008) Dietary exposure and trends of exposure to nutrient elements iodine, iron, selenium and sodium from the 2003–2004 New Zealand Total Diet Survey. Br J Nutr 99, 614625.CrossRefGoogle Scholar
Food Standards Australia New Zealand (2003) The 20th Australian Total Diet Survey–A Total Diet Survey of Pesticide Residues and Contaminants. https://www.foodstandards.gov.au/sites/default/files/2023-11/20th-ATDS.pdf (accessed 21 July 2023).Google Scholar
Lemire, M, Philibert, A, Fillion, M, et al. (2012) No evidence of selenosis from a selenium-rich diet in the Brazilian Amazon. Environ Int 40, 128136.CrossRefGoogle Scholar
Stefanowicz, FA, Talwar, D, O’Reilly, DSJ, et al. (2013) Erythrocyte selenium concentration as a marker of selenium status. Clin Nutr 32, 837842.CrossRefGoogle ScholarPubMed
Stranges, S, Laclaustra, M, Ji, C, et al. (2010) Higher selenium status is associated with adverse blood lipid profile in British adults. J Nutr 140, 8187.CrossRefGoogle ScholarPubMed
Yamashita, Y & Yamashita, M (2010) Identification of a novel selenium-containing compound, selenoneine, as the predominant chemical form of organic selenium in the blood of bluefin tuna. J Biol Chem 285, 1813418138.CrossRefGoogle ScholarPubMed
Pedrero Zayas, Z, Ouerdane, L, Mounicou, S, et al. (2014) Hemoglobin as a major binding protein for methylmercury in white-sided dolphin liver. Anal Bioanal Chem 406, 11211129.CrossRefGoogle Scholar
Anan, Y, Ishiwata, K, Suzuki, N, et al. (2011) Speciation and identification of low molecular weight selenium compounds in the liver of sea turtles. J Anal Spectrom 26, 8085.CrossRefGoogle Scholar
Yamashita, Y, Yabu, T & Yamashita, M (2010) Discovery of the strong antioxidant selenoneine in tuna and selenium redox metabolism. World J Biol Chem 1, 144150.CrossRefGoogle ScholarPubMed
El Hanafi, K, Pedrero, Z, Ouerdane, L, et al. (2022) First time identification of selenoneine in seabirds and its potential role in mercury detoxification. Environ Sci Technol 56, 32883298.CrossRefGoogle ScholarPubMed
Yamashita, M, Yamashita, Y, Ando, T, et al. (2013) Identification and determination of selenoneine, 2-selenyl-N α, N α, N α -trimethyl-L-histidine, as the major organic selenium in blood cells in a fish-eating population on remote Japanese Islands. Biol Trace Elem Res 156, 3644.CrossRefGoogle Scholar
Kayrouz, CM, Huang, J, Hauser, N, et al. (2022) Biosynthesis of selenium-containing small molecules in diverse microorganisms. Nature 610, 199204.CrossRefGoogle ScholarPubMed
Gründemann, D, Hartmann, L & Flögel, S (2022) The ergothioneine transporter (ETT): substrates and locations, an inventory. FEBS Lett 596, 12521269.CrossRefGoogle ScholarPubMed
Yamashita, M, Yamashita, Y, Suzuki, T, et al. (2013) Selenoneine, a novel selenium-containing compound, mediates detoxification mechanisms against methylmercury accumulation and toxicity in zebrafish embryo. Mar Biotechnol 15, 559570.CrossRefGoogle ScholarPubMed
Berry, MJ, Banu, L, Chen, YY, et al. (1991) Recognition of UGA as a selenocysteine codon in type I deiodinase requires sequences in the 3’ untranslated region. Nature 353, 273276.CrossRefGoogle ScholarPubMed
Rohn, I, Kroepfl, N, Aschner, M, et al. (2019) Selenoneine ameliorates peroxide-induced oxidative stress in C. elegans. J Trace Elem Med Biol 55, 7881.CrossRefGoogle ScholarPubMed
Tohfuku, T, Ando, H, Morishita, N, et al. (2021) Dietary intake of selenoneine enhances antioxidant activity in the muscles of the amberjack Seriola dumerili grown in aquaculture. Mar Biotechnol 23, 847853.CrossRefGoogle ScholarPubMed
Lim, D, Gründemann, D & Seebeck, FP (2019) Total synthesis and functional characterization of selenoneine. Angew Chem Int Ed 58, 1502615030.CrossRefGoogle ScholarPubMed
Drobyshev, E, Raschke, S, Glabonjat, RA, et al. (2021) Capabilities of selenoneine to cross the in vitro blood–brain barrier model. Metallomics 13, mfaa007.CrossRefGoogle ScholarPubMed
Seko, T, Imamura, S, Ishihara, K, et al. (2020) Selenoneine suppresses melanin synthesis by inhibiting tyrosinase in murine B16 melanoma cells and 3D-cultured human melanocytes. Fisheries Sci 86, 171179.CrossRefGoogle Scholar
Masuda, J, Umemura, C, Yokozawa, M, et al. (2018) Dietary supplementation of selenoneine-containing tuna dark muscle extract effectively reduces pathology of experimental colorectal cancers in mice. Nutrients 10, 1380.Google ScholarPubMed
Miyata, M, Matsushita, K, Shindo, R, et al. (2020) Selenoneine ameliorates hepatocellular injury and hepatic steatosis in a mouse model of NAFLD. Nutrients 12, 1898.CrossRefGoogle Scholar
Kaur, G, Ponomarenko, O, Zhou, JR, et al. (2020) Studies of selenium and arsenic mutual protection in human HepG2 cells. Chem Biol Interact 327, 109162.CrossRefGoogle ScholarPubMed
Ikemoto, T, Kunito, T, Tanaka, H, et al. (2004) Detoxification mechanism of heavy metals in marine mammals and seabirds: interaction of selenium with mercury, silver, copper, zinc, and cadmium in liver. Arch Environ Contam Toxicol 47, 402413.CrossRefGoogle ScholarPubMed
Dauplais, M, Lazard, M, Blanquet, S, et al. (2013) Neutralization by metal ions of the toxicity of sodium selenide. PLoS One 8, e54353.Google ScholarPubMed
Ayotte, P, Carrier, A, Ouellet, N, et al. (2011) Relation between methylmercury exposure and plasma paraoxonase activity in Inuit adults from Nunavik. Environ Health Perspect 119, 10771083.CrossRefGoogle ScholarPubMed
Hu, XF, Eccles, KM & Chan, HM (2017) High selenium exposure lowers the odds ratios for hypertension, stroke, and myocardial infarction associated with mercury exposure among Inuit in Canada. Environ Int 102, 200206.CrossRefGoogle ScholarPubMed
Lemire, M, Fillion, M, Frenette, B, et al. (2010) Selenium and mercury in the Brazilian Amazon: opposing influences on age-related cataracts. Environ Health Perspect 118, 15841589.CrossRefGoogle ScholarPubMed
Lemire, M, Fillion, M, Frenette, B, et al. (2011) Selenium from dietary sources and motor functions in the Brazilian Amazon. Neurotoxicol 32, 944953.CrossRefGoogle ScholarPubMed
Yang, D-Y, Chen, Y-W, Gunn, JM, et al. (2008) Selenium and mercury in organisms: interactions and mechanisms. Environ Rev 16, 7192.CrossRefGoogle Scholar
Houston, MC (2011) Role of mercury toxicity in hypertension, cardiovascular disease, and stroke. J Clin Hypertens 13, 621627.CrossRefGoogle Scholar
Branco, V, Canário, J, Lu, J, et al. (2012) Mercury and selenium interaction in vivo: effects on thioredoxin reductase and glutathione peroxidase. Free Radical Biol Med 52, 781793.CrossRefGoogle ScholarPubMed
Palmer, JH & Parkin, G (2015) Protolytic cleavage of Hg–C bonds induced by 1-Methyl-1,3-dihydro-2H-benzimidazole-2-selone: synthesis and structural characterization of mercury complexes. J Am Chem Soc 137, 45034516.CrossRefGoogle ScholarPubMed
Korbas, M, O’Donoghue, JL, Watson, GE, et al. (2010) The chemical nature of mercury in human brain following poisoning or environmental exposure. ACS Chem Neurosci 1, 810818.CrossRefGoogle ScholarPubMed
Lailson-Brito, J, Cruz, R, Dorneles, PR, et al. (2012) Mercury-selenium relationships in liver of Guiana dolphin: the possible role of Kupffer cells in the detoxification process by tiemannite formation. PLoS One 7, e42162.CrossRefGoogle ScholarPubMed
Hu, XF, Eccles, KM & Chan, HM (2017) High selenium exposure lowers the odds ratios for hypertension, stroke, and myocardial infarction associated with mercury exposure among Inuit in Canada. Environ Int 102, 200206.Google Scholar
Drobyshev, E & Schwerdtle, T (2023) Toxic or beneficial? What is the role of food-relevant selenium species selenoneine? Lebensmittelchemie 77, S2S146.CrossRefGoogle Scholar
Allan, CB, Lacourciere, GM & Stadtman, TC (1999) Responsiveness of selenoproteints to dietary selenium. Ann Rev Nutr 19, 116.CrossRefGoogle Scholar
Government of Canada (2013) Selenium-containing Substance Grouping (Internet). https://www.canada.ca/en/health-canada/services/chemical-substances/substance-groupings-initiative/selenium.html (accessed 9 October 2023).Google Scholar
Little, M, Hagar, H, Zivot, C, et al. (2021) Drivers and health implications of the dietary transition among Inuit in the Canadian Arctic: a scoping review. Public Health Nutr 24, 26502668.CrossRefGoogle ScholarPubMed
Jones, GW, Doyle, S & Fitzpatrick, DA (2014) The evolutionary history of the genes involved in the biosynthesis of the antioxidant ergothioneine. Gene 549, 161170.Google ScholarPubMed
Achouba, A, Dumas, P & Ayotte, P (2023) Simultaneous determination of ergothioneine, selenoneine, and their methylated metabolites in human blood using ID-LC–MS/MS. Anal Bioanal Chem (Internet) 415, 72597267. https://doi.org/10.1007/s00216-023-04994-z CrossRefGoogle Scholar
McGrath-Hanna, NK, Greene, DM, Tavernier, RJ, et al. (2003) Diet and mental health in the Arctic: is diet an important risk factor for mental health in circumpolar peoples? A review. Int J Circumpolar Health 62, 228241.CrossRefGoogle ScholarPubMed
Kuhnlein, HV & Receveur, O (2007) Local cultural animal food contributes high levels of nutrients for Arctic Canadian Indigenous adults and children. J Nutr 137, 11101114.CrossRefGoogle ScholarPubMed
Johnson-Down, L & Egeland, GM (2010) Adequate nutrient intakes are associated with traditional food consumption in nunavut inuit children aged 3–5 years. J Nutr 140, 13111316.CrossRefGoogle ScholarPubMed
Chan, HM, Fediuk, K, Hamilton, S, et al. (2006) Food security in Nunavut, Canada: barriers and recommendations. Int J Circumpolar Health 65, 416431.CrossRefGoogle ScholarPubMed
Lucas, M, Dewailly, E, Blanchet, C, et al. (2009) Plasma omega-3 and psychological distress among Nunavik Inuit (Canada). Psychiatry Res 167, 266278.CrossRefGoogle ScholarPubMed
Pufall, EL, Jones, AQ, McEwen, SA, et al. (2011) Perception of the importance of traditional country foods to the physical, mental, and spiritual health of Labrador Inuit. Arct 64, 242250.Google Scholar
Donaldson, SG, Van Oostdam, J, Tikhonov, C, et al. (2010) Environmental contaminants and human health in the Canadian Arctic. Sci Total Environ 408, 51655234.CrossRefGoogle ScholarPubMed
Cisneros-Montemayor, AM, Pauly, D, Weatherdon, LV, et al. (2016) A global estimate of seafood consumption by coastal Indigenous peoples. PLOS ONE 11, e0166681.CrossRefGoogle ScholarPubMed
Allaire, J, Johnson-Down, L, Little, M, et al. (2017) Country and Market Food Consumption and Nutritional Status. Quebec: Nunavik Regional Board of Health and Social Services.Google Scholar
Muckle, G, Ayotte, P, Dewailly, E, et al. (2001) Determinants of polychlorinated biphenyls and methylmercury exposure in Inuit women of childbearing age. Environ Health Perspect 109, 957963.CrossRefGoogle ScholarPubMed
Nielsen, ABS, Davidsen, M & Bjerregaard, P (2012) The association between blood pressure and whole blood methylmercury in a cross-sectional study among Inuit in Greenland. Environ Health: Global Access Sci Source 11, 44.CrossRefGoogle Scholar
Batáriová, A, Cerná, M, Sp&ebreve;vácková, V, et al. (2005) Whole blood selenium content in healthy adults in the Czech Republic. Sci Total Environ 338, 183188.Google ScholarPubMed
Gundacker, C, Komarnicki, G, Zödl, B, et al. (2006) Whole blood mercury and selenium concentrations in a selected Austrian population: does gender matter? Sci Total Environ 372, 7686.CrossRefGoogle Scholar
Bocca, B, Madeddu, R, Asara, Y, et al. (2011) Assessment of reference ranges for blood Cu, Mn, Se and Zn in a selected Italian population. J Trace Elem Med Biol 25, 1926.CrossRefGoogle Scholar
Heitland, P & Köster, HD (2006) Biomonitoring of 37 trace elements in blood samples from inhabitants of northern Germany by ICP–MS. J Trace Elem Med Biol 20, 253262.CrossRefGoogle ScholarPubMed
Lemire, M, Mergler, D, Fillion, M, et al. (2006) Elevated blood selenium levels in the Brazilian Amazon. Sci Total Environ 366, 101111.CrossRefGoogle ScholarPubMed
Valera, B Dewailly, E Poirier, P et al. (2011) Influence of mercury exposure on blood pressure, resting heart rate and heart rate variability in French Polynesians: a cross-sectional study. Environ Health: Global Access Sci Source 10, 99.CrossRefGoogle ScholarPubMed
Figure 0

Fig. 1. Metabolism of Se food species, adapted from Combs (2001)(11), Kayrouz et al., (2022)(71), Rayman et al. (2008)(3), Rayman (2012)(15), and Yamashita et al. (2010)(65). ETT, ergothioneine transporter; SCLY, selenocysteine β-lyase; SeMet, selenomethionine; Sec, selenocysteine; H2Se, hydrogen selenide; CH3SeCys, Se-methyl-selenocysteine; SeN, selenoneine; CH3SeH, methyl selenol; TSP, transsulfuration pathway.

Figure 1

Table 1. Whole blood Se concentrations in Inuit compared to other global populations