Protection of Selenium Against Methylmercury in the Human Body: A Comprehensive Review of Biomolecular Interactions ^†

Abstract

Methylmercury (MeHg) contamination in seafood poses significant health risks to human populations worldwide, particularly neurotoxicity. Selenium protects against the toxicity of metals, such as mercury and inorganic arsenic, but at the same time, the loss of bioavailability of Se caused by these pollutants must also be taken into account. Several studies have performed a risk–benefit ratio evaluation. New criteria have been proposed to assess the risks of Hg exposure, the Se Health Benefit Value (HBVSe) and the Benefit–Risk Value (BRV), which allow the simultaneous evaluation of Hg exposures and dietary Se intakes. Additionally, changes in mercury bioaccessibility have been attributed to the cooking of fish that changes the conformation of native proteins. Various studies have shown that the benefits of consuming seafood outweigh the risks, especially when the protective effects of selenium are considered. This comprehensive review examines the biomolecular interactions underlying the protective effects of selenium against MeHg in the human body. We will discuss how selenium modulates MeHg toxicity, including its role in mitigating oxidative stress, preventing MeHg bioaccumulation, and facilitating detoxification pathways. Nevertheless, further research in the area is necessary to study the synergistic effects between the different variables to improve the understanding of the repercussions on health regarding fish and shellfish intake. Overall, this communication contributes to our understanding of the complex interplay between selenium and methylmercury in the human body and underscores the potential of selenium as a therapeutic agent for mitigating MeHg-related health risks.

1. Introduction

All seafood contains mercury, mainly in the form of methylmercury [1]. Methylmercury, in a sufficient dose, can cause neurodevelopmental, cardiovascular, and immunological health problems. Mercury concentrations in fish can vary widely even within the same species, as the mercury these species ingest comes from the water they live in. Karimi et al. [1] reported that mean mercury concentrations spanned from 0.3 to 2.4 orders of magnitude for the same seafood item. The presence of mercury is considered the highest risk when consuming seafood.

Mercury primarily targets the nervous system, disrupting cellular processes such as glutathione homeostasis, enzyme inhibition, and mitochondrial function. This can lead to severe neurological conditions such as ataxia, tremors, and cognitive deficits. Selenium, on the other hand, forms stable complexes with mercury, reducing its affinity for cellular targets and enhancing mercury excretion through biological processes. Selenium (Se), a common co-constituent in seafood, has emerged as a mitigating factor against mercury toxicity.

2. Methodology

A literature review on the interactions between selenium and methylmercury was conducted by searching for relevant papers using the Scopus and PubMed databases. Keywords such as “Selenium and Methylmercury Interaction,” “Mercury Toxicity,” and “Selenium Protection” were used in the search. Recent studies published in English, focusing on peer-reviewed articles, reviews, clinical trials, and meta-analyses that discussed selenium’s protective mechanisms against methylmercury toxicity, were included. Titles and abstracts were screened for relevance, followed by a full-text review and data extraction. The findings were then synthesized qualitatively and quantitatively.

3. Biochemical Interactions between Selenium and Mercury

The dynamic interplay between selenium (Se) and mercury (Hg) in biological systems is a complex phenomenon with significant environmental and human health implications. Despite mercury’s well-documented toxicity, selenium has been shown to exhibit protective effects against mercury toxicity through various biochemical pathways [2].

Mercury exerts a toxic effect by interacting with various key enzymes mainly involved in antioxidant regulation, including selenoenzymes like thioredoxin reductase (TrxR) and glutathione peroxidase (GPx). In vitro studies have shown that selenium supplementation can reactivate the mercury-inhibited TrxR, successfully recovering cell viability [3]. When zebrafish were exposed to mercury, those also treated with selenium selenite accumulated only half the amount of organic mercury. However, it was observed that selenium selenite had limited effectiveness in preventing mercury accumulation in the kidneys and brain [3]. Another in vivo study in rats compared animals that received organic or inorganic mercury accompanied with selenium supplementation. The study showed that even though selenium supplementation decreased mercury content in the kidneys, it increased it in the blood and liver. However, selenium had a counteraction effect against the decreased glutathione (GSH) and superoxide dismutase (SOD) in most tissues caused by mercury toxicity, suggesting that interactions of Se and Hg affect their accumulation, and Se may antagonize Hg-induced inhibition on organic activities [4].

Selenium has protective effects against mercury because of its high chemical affinity. Selenium and mercury form stable compounds due to their compatible electron configuration. As a chalcogen, selenium gains or shares electrons to achieve a stable electronic state, while mercury, a transition metal, tends to lose or share electrons. Compounds like mercury selenide (HgSe) have a bond where selenium donates a pair of electrons to mercury. Hg-Se complexes are generally less toxic than mercury alone, reducing mercury’s bioavailability to biological organisms. Figure 1 illustrates and summarizes the interactions between mercury and molecules present in the human body and the protective effects of selenium.

4. Impact of Cooking and Food Processing

Cooking and food processing techniques can significantly alter the bioavailability of mercury in fish. Methods such as frying and boiling can remove a substantial portion of mercury, reducing its potential harm when consumed.

Food chemically and physically transforms while being cooked or processed as it is exposed to high temperatures, contact with water or oil, and even mechanical transformations. It has been suggested that these transformations can diminish the heavy metal content of food or reduce its bioavailability. The addition of plants that contain organic acids and phytochelates also has the power to sequestrate these heavy metals [5]. Adding black coffee and green or black tea to a meal reduced mercury bioavailability by 50–60% [6]. Milea et al. [7] tested the co-ingestion of garlic and broccoli and concluded that it positively decreased the bioavailability of mercury.

In terms of cooking processes, it appears that frying is the cooking process that removes the most bioavailable mercury (>80%) when compared to boiling (60%) or raw fish [6]. Milea Ș, Lazăr [7] concluded that the reduction in the bioavailability of mercury increased with the severity of the heat treatment, showing a higher reduction with frying and baking. Moreover, the pre-cooking, soaking, and washing processes only released about 0.2% and 0.3% of the total mercury. However, steaming and marinated fish samples showed a higher concentration on the cooked sample than on the raw sample, increasing almost 20%. This was suggested to be due to water loss in the sample. Maulvault [8] observed a similar increase, where cooked black scabbard showed a significant increase in mercury availability after grilling. Mirroring this, Houlbrèque et al. [9] observed increased cadmium in mussels after cooking, but its bioavailability decreased considerably. In the case of heavy metal arsenic, boiling caused a significant reduction in both total and inorganic arsenic but an increase in the bioavailability of the inorganic arsenic [10]. In the case of algae, soaking seems to be a very effective method for removing arsenic, with the removal of 88.7–91.5% of arsenic in the brown sea algae Hijikia fusiforme [11]. Soaking rice in water and washing until the water is clear before cooking also showed a reduction of up to 57% of arsenic; however, it depends on how much water is used in the cooking process and how much is discarded after [12].

It is equally important to assess the influence of different cooking methods on selenium bioavailability since the presence of selenium reduces mercury bioavailability. Mirroring what happens with mercury, processing foods through cooking usually reduces the presence of selenium. For example, Dong et al. [13] showed that boiling selenium-fortified potatoes reduced their content in selenium by 43.3%. Additionally, boiling also affects the speciation of selenium compounds with losses of specific selenium compounds, like selenocysteine, in cereals [14]. Frying also results in selenium loss, with frying selenium-fortified potatoes resulting in a loss of 31.7% of selenium content [13]. This loss is reported to come from the volatilization of selenium. Steaming is considered the cooking method that results in the least loss of selenium in bio-fortified cereals, with a minimal loss of 13.5% [14]. The same authors reported that milking selenium-fortified soybeans results in the loss of 49.1% of total selenium, with most of it being retained in the residuals. Boiling seafood also causes some of the selenium to leech onto the cooking water, with the boiling process of tuna and cod resulting in a maximum 30% reduction in total selenium, with frying causing a similar reduction [15]. However, Martins et al. studied various methods of cooking six marine species, including sardine, horse mackerel, gilthead seabream, silver scabbardfish, hake, and octopus, and concluded that no statistical difference was found in the selenium content of raw and cooked fish (including boiled, grilled, and fried fish) [16]. A study on the impact of cooking methods on selenium distribution in swordfish concluded that oven baking increased the presence of selenomethylselenocysteine [17].

Traditional cooking and processing methods can significantly diminish the burden of heavy metals in some foods, like algae. However, their effectiveness is limited, so other more reliable ways to remove the metals should be explored. Similarly, the choice of cooking method has a significant impact on selenium bioavailability in foods. This should be considered when consuming selenium-rich foods to counteract the effects of mercury.

5. Epidemiological Evidence and Health Assessments

Numerous statements in the medical literature have been made recommending pregnant women limit their intake of seafood to avoid exposure to mercury in the unborn child. Exposure to mercury during pregnancy has been linked to pregnancy complications and developmental problems in infants [18]. It is well known that methylmercury can pass through the placental barrier and accumulate in the fetal organ, which poses a significant threat to the fetus’s health [19].

A study on 200 births in the Caribbean, where fish is the main source of protein, correlated with low mercury exposure to a lower birth weight [20]. In the Faroe Islands, where episodic consumption of marine animals exists, more than 1000 children were observed during the first 14 years of their lives, during which a series of physiological endpoints based on a detailed neurobehavioral examination were assessed. At age 7, decrements in attention, language, motor speed, and visual–spatial function were associated with maternal methylmercury exposure. At age 14, these children still indicated the prevalence of deficits in motor, attention, and verbal decrements, delayed brainstem auditory-evoked potentials, and alterations of cardiac autonomic activity [21].

However, another study has shown that even small amounts of mercury can affect a child’s development. Since the target organ is the metabolically immature developing fetus brain, a study was conducted on the correlation between low mercury exposure of mothers and the size of the newborn’s cerebellum. Mothers with higher body levels of mercury (defined as >1 µg/g in hair) had fetuses with a lower median cerebellum length of 1.6 mm on average. It is expected that in newborns born to mothers with higher mercury hair levels, the cerebellum length will measure 18–20 mm, up to 30 mm less than those born to mothers with low mercury hair levels [22]. However, this decreased size of the cerebellum did not undergo testing on its possible correlation with decrements in child development, like neurological or behavior testing. The consumption of fish, and, therefore, EPA and DHA, could have denied the adverse effects of methylmercury exposure, as these fatty acids are heavily associated with brain development.

Perhaps a more relevant project would be the Seychelles Child Development Study, created in 1986 to monitor the effects of mercury exposure from fish consumption. No significant associations were found between mercury concentrations in maternal hair and adverse outcomes in children, regardless of age. The test performance of children with higher mercury exposure was even enhanced in some instances. This enhancement probably comes from the higher consumption of beneficial components of fish [23]. A similar but smaller study was conducted in New Zealand with mothers who consumed at least three seafood meals per week during pregnancy, with the main species consumed being sharks. The analysis did not find significant associations between mercury exposure and the children’s test scores [24].

During pregnancy, mothers need a higher nutrition quality and a higher import of nutrients. Fish is rich in such nutrients, but given mercury’s toxic effects, this consumption should be performed with precautions. Despite many studies pointing to the higher benefits of fish consumption than its risks, various agencies still recommend limitations, especially for species that knowingly have higher mercury concentrations. The British Food Standard Agency (FSA) recommends that pregnant women, women of childbearing age, and children under 16 should avoid consuming swordfish and tuna and that pregnant women and women of childbearing age should avoid consuming more than two tuna steaks per week. Even the US Department of Agriculture (USDA) recommends that the general public should not consume more than 227 g (8 ounces) of a variety of seafood per week. The different recommendations by different health authorities can be seen in

Table 1. Recommendations of fish consumption by the different authorities to different populations.

Recommendation	Fish Type	Organization	Reference
125 g per week for healthy adults	Oily fish	EFSA	[25]
50 g per week for children aged 3–12 (total of 120 g per month).
Up to four medium-sized cans or two tuna steaks per week for pregnant women and women intending to become pregnant.	Tuna	FSA	[26]
Children and other adults do not need to restrict their tuna amount.
No more than 85 g (3 ounces) per week for children.	Canned light or white (albacore) tuna, cod, perch, black sea bass	Dietary Guidelines for Americans	[27]
Up to 340 g (12 ounces) per week for pregnant or nursing women or women who might become pregnant, with a maximum of 170 g (6 ounces) of albacore tuna.	All fish	US EPA	[28]
Up to a total of 150 g per week for adults.	Tuna, shark, swordfish, escolar, marlin, and orange roughie	Bureau of Chemical Safety (Canada)	[29]
150 g per month for women who are or may become pregnant and breastfeeding mothers.
1 portion of 150 g per week for the general population.	Shark, swordfish, and marlin	Food standards Australia New Zealand	[30]
1 portion of 150 g per fortnight for women who are pregnant or planning pregnancy (and no other fish during that fortnight).
1 portion of 75 g per fortnight for children up to 6 years old (and no other fish during that fortnight).

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6. Health Criteria and Public Health Implications

Introducing health benefit values, such as the Selenium Health Benefit Value (HBV_Se) and the Benefit–Risk Value (BRV), provides a framework for evaluating the risks and benefits of seafood consumption. These criteria help in assessing the protective effects of selenium against mercury toxicity. The HBV_Se and the BRV are innovative criteria that help understand the balance of selenium and mercury in seafood, guiding safer consumption practices [31].

The benefit–risk assessment carried out by the EFSA provides answers based on scientific resources on the benefit of food in relation to exposure to the contaminant it may contain [32]. Fish is an excellent example of risk–benefit assessment [31]. In this regard, it is essential to speak about the role of mineral selenium, as it helps to achieve a balance between contaminants and nutrient interactions. It is well known that selenium acts as a protector against the toxicity of metals, such as Hg and inorganic As [33], but at the same time, it must be considered that to make a reasonable assessment of the adequate intake of Se, the loss of bioavailability of Se caused by these pollutants must also be taken into account [34].

New criteria have been proposed to assess the risks of mercury exposure, mainly the Se Health Benefit Value (HBV_Se), which simultaneously evaluates mercury exposure and selenium dietary intake [35]. Another risk assessment proposed is the Benefit–Risk Value (BRV), which reflects the molar excess of mercury consumed relative to selenium intake. In the case of tuna, the molar ratio oscillates between 1.3 and 20 (Se: Hg), with the HBV_Se oscillating between 7.9 and 296. This shows that it is highly likely that the high amount of selenium produces a protective effect against mercury toxicity [35].

The HBV_Se is calculated based on the molar relative concentration of selenium and mercury in a given sample (Equation (1)) as follows:

$${HBV}_{Se}={\displaystyle \frac{\left[Se\right]}{\left[Hg\right]}}$$

(1)

In Equation (1), $\left[Se\right]$ and $\left[Hg\right]$ are the molar concentrations of selenium and mercury, respectively. If the ${HBV}_{Se}$ is higher than 1, then the amount of selenium exceeds the amount of mercury in the sample. Due to this excess, selenium will likely sufficiently bind with all the mercury present in the sample, potentially neutralizing its effects. If the ${HBV}_{Se}$ is less than 1, there is an excess of mercury compared to the amount of selenium. In these cases, there might not be enough selenium to counteract the toxicity effects of mercury. The ${HBV}_{Se}$ has a limitation in certain extreme cases. When Se intake is below the level required for a normal functioning organism, the safety requirement of ${HBV}_{Se}$ > 1 is still met. This also happens when the organism ingests an elevated level of selenium, which can cause selenium toxicity.

This equation has recently been modified by Raslton et al. [32] to reflect a more accurate risk. The modified selenium health benefit value ($Se-HBV$) follows Equation (2) as follows:

$$Se-HBV={\displaystyle \frac{\left[Se\right]-\left[Hg\right]}{\left[Se\right]}}\times (\left[Se\right]+\left[Hg\right])$$

(2)

This equation was refined to incorporate the relative and absolute amounts of mercury and selenium while eliminating the molar ratios that can result in disproportionately high values due to very low mercury amounts. Additionally, the equation indicates a net selenium surplus or deficit [32]. If the $Se-HBV$ result is positive ($Se-HBV$ > 0), the amount of selenium is in excess of mercury, possibly negating the toxicity of mercury. If the Se-HBV is negative ($Se-HBV$ < 0), then the amount of mercury is in excess of selenium; therefore, the amount of selenium is not enough to offer protection against mercury.

Another developed equation to assess the risk of mercury when in the presence of selenium is the $BRV$ (Benefit–Risk Value) (Equation (3)) and the ${PDI}_{Se}$ (Probable Daily Intake) (Equation (4)) developed by Zhang et al. [26] as follows:

$$BRV={PDI}_{Se}-{∆}_{Se}-{PDI}_{Hg}$$

(3)

$$PDI=\sum {(C}^i\times {IR}^i)/bw$$

(4)

where $C^i$ is the metal concentration in the exposed medium, ${IR}^i$ is the intake rate (rate of ingestion or inhalation), ${∆}_{Se}$ represents the lowest safest intake of Se for a human, 11 nmol/kg/day, and ${\nabla }_{Se}$ represents the threshold value for Se poisoning (170 nmol/kg/day), considering the protective effects from Hg exposure in this case.

If the BRV is between 0 and the threshold value for Se poisoning (0 < $BRV$ < ${\nabla }_{Se}$), the amount of selenium protects against the harmful effects of mercury exposure. Suppose the $BRV$ is negative ($BRV$ < 0) or if the $BRV$ is higher than the threshold value for Se poisoning ($BRV$ > ${\nabla }_{Se}$), the amount of Hg present in the sample is in excess.

With Equation (4), Zhang et al. [26] take into account the amount of dietary selenium needed for the normal function of selenoenzymes in the human body, as well as the threshold value for selenium poisoning, taking into account the protective effects of mercury exposure in this case. The BRV criterion shows a broad, simple, and concise application as a great model for estimating dietary mercury exposure, considering the protective effects of selenium exposure.

7. Conclusions

While mercury contamination poses significant health risks, selenium is a protective agent that mitigates these risks and supports safe seafood consumption. Selenium has the particular ability to bind to mercury, reducing its negative impact on human health. This is achieved via various biochemical pathways, including the formation of stable selenium-mercury compounds that decrease mercury’s bioavailability and facilitate its excretion from the body.

Different cooking methods have also been found to affect the bioavailability of both mercury and selenium in food. Most methods (boiling, frying, and steaming) effectively reduce the amount of both metals, as well as change their distribution, impacting the protective balance between selenium and mercury. New criteria like the Selenium Health Benefit Value (HBV_Se) and the Benefit–Risk Value (BRV) can help assess the balance between selenium intake and mercury exposure in seafood, providing a framework for safer consumption.

Further studies are necessary to better understand the protective interaction between selenium and mercury in the human body, informing public health policies and improving dietary recommendations.