Selenium and Mercury in Fish
written by a distinguished college at LPI

     My reading of a few weeks ago included studies of diet vs mortality. Diets including plenty of vegetables, fruit, and fish excelled. One concern is the presence of mercury (Hg) in fish. However, numerous studies have shown that fish consumption correlates with lower overall mortality. Given that Hg is toxic, the positive effects of fish consumption apparently outweigh any negative effects of Hg in fish most commonly consumed. Or it might be more interesting than that. Another concern is that advisories to limit or avoid fish consumption may decrease the consumption of a healthy food. Advisories for during pregnancy may deny children known benefits of fish.

A recent article in the journal Fisheries co-authored by a neighbor prompted a further look. My neighbor, a retired aquatic toxicologist, basically said, “We’ve known for years that when there’s adequate selenium, the levels of mercury found in fish aren’t an issue.”

(Selenium (Se) is an essential nutrient and all animals with a nervous system have selenoenzymes.)

His recent article, “Fish Tissue Mercury in Lakes and the Moderating Effects of Selenium,” Hughes et al. Fisheries, 30 April 2024, states: “Fish mercury concentrations result in fish consumption advisories. However, selenium : mercury molar ratios >1 are protective to wildlife and humans.” From their sampling of over 12,000 lakes, they concluded: “However, the Se : Hg molar ratio was >1 in an estimated 90–97% of fish tested from NE and ID lakes. Therefore, we concluded that Se levels in these systems are usually sufficient to limit disruption of selenoprotein activities by Hg, and that fish consumption advisories based on Hg alone are unnecessarily restrictive.” A 2009 paper of theirs (Peterson et al. Environmental Science and Technology 43: 3919–3925) “reported that 97.5% of 468 stream fish tested from 137 sites from 12 western USA states had whole fish Se:Hg ratios >1. 4.”

Conclusions:  From this paper and several others I read, selenium (Se) ameliorates the toxic effects of mercury (Hg). Plausible molecular mechanisms for this effect have been published. The following papers describe how Se protects against Hg. Passages that I found most pertinent are underlined. A key quote is from Ref #1: “Methyl mercury bound to cysteine is the main form found in fish. It resembles the amino acid methionine and can cross the blood-brain barrier. However, because selenium’s binding affinity with mercury is approximately a million times greater than sulfur’s (Dyrssen and Wedborg, 1991) thermodynamics promote formation of HgSe adducts.”

     I celebrated tonight with tuna salad for dinner.

As an aside, and speaking of mercury, some Internet sources insist that ethyl mercury from the vaccine preservative thimerosal is far more toxic than methyl mercury found in fish. (Hg is absent from mRNA Covid vaccines, childhood vaccines, and all single-dose flu vaccines.)

A headline in Natural News states, “Mercury in vaccines may be up to 50 TIMES more toxic to the brain than mercury in fish.” References #7 and #8 on this list show that is nonsense and actually backwards. Of course, Mike Adams, leader of Natural News, also states on the same webpage that “Bill Gates is planning a new pandemic” and “Bill Gates launches new Netflix series that lays out mass suicide plan for global human depopulation.” Those “news” articles are alongside his ads for supplements and cancer quackery.

References:

The Wiki page for selenium states, “Increased dietary selenium reduces the effects of mercury toxicity, although it is effective only at low to modest doses of mercury.” But what is a modest dose? Here are four papers cited by that page, followed by others from a Google Scholar search.

–1. Dietary and tissue selenium in relation to methylmercury toxicity. Ralston et al. Neurotoxicology, Vol 29(5) September 2008, Pages 802-811.

–“Selenium (Se) supplementation in the nutritionally relevant range counteracts methylmercury (MeHg)

 toxicity.” Their study “compared MeHg toxicity in relation to MeHg exposurevs vs. Hg:Se molar ratios in diets and tissues.”

–“No Se-dependent differences in growth were noted among rats fed low-MeHg diets, but growth impairments among rats fed high-MeHg were inversely related to dietary Se. After 3 weeks on the diet, growth impairments were evident among rats fed high-MeHg with low- or adequate-Se and after 10 weeks, rats fed low-Se, high-MeHg diets started to lose weight and displayed hind limb crossing. No weight loss or hind limb crossing was noted among animals fed high-MeHg, rich-Se diets. Methylmercury toxicity was not predictable by tissue Hg, but was inversely related to tissue Se (P<0.001) and directly related to Hg:Se ratios (P < 0.001).”

–“…methylmercury covalently binds selenium in the active sites of selenium-dependent enzymes (selenoenzymes), thereby inhibiting their activity (Seppanen et al., 2004). Supplemental dietary

selenium apparently replaces the selenium lost to intracellular mercury binding, thereby maintaining normal selenoenzyme activities.”

—Methyl mercury bound to cysteine is the main form found in fish. It resembles the amino acid methionine and can cross the blood-brain barrier.” “However, because selenium’s binding

 affinity with mercury is approximately a million times greater than sulfur’s (Dyrssen and Wedborg, 1991) thermodynamics promote formation of HgSe adducts.”

–” Diets were prepared using low-Se torula yeast basal diets supplemented with Na2SeO4 to contain 0.1, 1.0, or 10.0 μmol Se/kg (∼0.01, 0.08, or 0.8 ppm Se), reflecting low-, adequate-, or rich-Se intakes, respectively. Diets contained either low or high (0.5 μmol or 50 μmol MeHg/kg) (∼0.10 or 10 ppm Hg).”

According to NIH, the USA recommended dietary intake for adult human males and females is 55 ug.

calculations:

1. According to an NIH website, adult rats consume about 15 g chow/da. Adequate Se intake for an adult rat is 150 ug/da. https://www.ncbi.nlm.nih.gov/books/NBK231925/table/ttt00002/?report=objectonly

Allometric scaling aims to normalize to surface area from rats to people. For drug dosing, the recommended scaling is as follows:  To convert animal dose in mg/kg to human equivalent dose in mg/kg, multiply animal dose by 0.162.

Therefore, rat chow at 0.1, 1, and 10 umol Se/kg chow, at 15 g/da chow intake, equals:

0.118, 1.185, and 11.846 ug Se/rat/da

1. Assume for example about 100 g body wt for adolescent rat. Therefore, the adequate Se intake would be 1.185 (1000/100) = 11.85 ug Se/kg. body weight.

Multiply the animal dose times 0.162 to yield 1.92 ug/kg human equivalent.

Multiply by 70 kg adult human weight to yield 134 ug Selenium equivalent human daily intake scaled    from the values used in rats by Ralston et al.

This is about double the US RDA of 55 ug Se/da. However, according to NIH, the average intake for an adult human male from food and beverage is 132 mcg. This all appears reasonable.

Note: These calcs are not exact because rat weights weren’t specified, but it appears reasonable.

https://ods.od.nih.gov/factsheets/Selenium-HealthProfessional/#h5

1. The rat chow contained methyl mercury at levels of 0.1 and 10 ppm Hg.

From the Wiki page “Mercury in Fish,” albacore tuna, halibut, skipjack tuna, cod, and salmon contain Hg at 0.36, 0.24, 0.14, 0.11 and 0.02 ppm Hg. This calculates to 1.8, 1.2, 0.7, 0.55, and 0.1 umol Hg/kg fish.

This study (Ralston et al) had Se at 0.01, 0.08 and 0.8 ppm, and Hg at 0.1 and 10 ppm in the diet.

The atomic weights of Se and Hg are 79 and 200.6.

This calculates to 0.13, 1.01, and 10.1 umol Se/kg diet, and 0.5 and 50 umol Hg/kg diet.

Thus, at the highest doses for both Se and Hg, the ratio of Se to Hg is only 0.2. Toxic symptoms of the highest Hg dosing (50 umol Hg/kg chow) were ameliorated by Se at 10 umol/kg chow.

Notice that the 50 umol Hg/kg chow is 29, 42, 72, 91, and 502-fold higher than found in the five fish species listed above.  All in all, quite reasonable numbers in this study. Plenty of safety margin.

–2. Protective Effect of Selenite Against Methylmercury Toxicity: Observations Concerning Time, Dose and Route Factors in the Development of Selenium Attenuation. Ohi et al. Industrial Health, 1975 Volume 13 Issue 3 Pages 93-99.

“Abstract: Protective effect of selenite against methylmercury toxicity was observed in experimentally induced acute and subacute methylmercury poisoning of rats. The protection becomes more evident as the acuteness of methylmercury poisoning decreases in terms of the total methylmercury dosage administered and the number of survival days after the last dosing, and there appears to be present an optimal dose relationship between the two substances. Protective effect of selenium is likewise clear in subacute methylmercury poisoning in regard to growth rate, incidence of neurological signs and mortality. We did not observe any differences in the protection when administration route was changed.”

–3. Post-transcriptional Defects of Antioxidant Selenoenzymes Cause Oxidative Stress under Methylmercury Exposure, Usuki et al. J Biol Chem. 2010 Nov 24;286(8):6641–6649.

“Results indicated that the MeHg-induced relative selenium-deficient condition affects the major antioxidant selenoenzymes GPx1 and TrxR1 through a post-transcriptional effect, resulting in the disturbance of cellular redox systems and the incidence of oxidative stress. Treatment with ebselen, a seleno-organic compound, effectively suppressed oxidative stress and protected cells against MeHg-induced relative selenium deficiency and cytotoxicity.” Ebselen is a Se-containing aromatic compound with anti-inflammatory, anti-oxidant and cytoprotective properties (Wiki).

“MeHg has a post-transcriptional effect on the main antioxidant selenoenzymes GPx1 and TrxR1, most likely through MeHg-induced selenium deficiency, resulting in the disturbance of cellular redox systems and the incidence of oxidative stress. The mechanism shown in this study is most likely universal in MeHg toxicity, because the same phenomenon was recognized in soleus muscle in a usual MeHg-intoxicated rat model (Fig. 3) and a wild-type C2C12-DMPK5 cell line.”

–4. Selenium prevents downregulation of antioxidant selenoprotein genes by methylmercury. Penglase et al. Free Radical Biology and Medicine, Vol 75, Oct 2014, Pages 95-104.

Zebrafish embryos maternally exposed to Se and MeHg were analyzed. MeHg downregulated selenogenes mainly from antioxidant pathways. Elevated Se partially prevented MeHg-induced selenogene downregulation. The data suggest MeHg regulates selenogenes by disrupting Se availability.”

–5. Mercury’s Neurotoxic Effects on Brain Selenoenzymes. In Handbook of Neurotoxicity, 03 January 2023, pp 2391–2417.

— “Toxic mercury (Hg) exposures inhibit selenium (Se)-dependent enzymes (selenoenzymes) required in the brain. Selenocysteine (Sec), the 21st genetically encoded amino acid, is the most powerful intracellular nucleophile, making it vulnerable to electrophiles such as Hg. The human genome includes 25 genes which express selenoenzymes with essential functions that control cellular redox status, thyroid hormone and calcium-dependent processes, immune responses, and other vital processes. Methyl-Hg (CH₃Hg) binds to cysteine (Cys) to form the CH₃Hg-Cys adducts which predominate in tissues. Due to molecular similarities between methionine (Met) and CH₃Hg-Cys, cellular membrane transporters actively mobilize this species across membranes and into proteins. Because many selenoenzymes directly act upon or work in concert with thiomolecules, the CH₃Hg-Cys in these molecules function as a suicide substrate that brings Hg into direct contact with the selenoenzyme’s active site Sec. Since Hg’s affinity for Se is far higher than its affinity for sulfur, CH₃Hg exchanges partners to form CH₃Hg-Sec, irreversibly inhibiting the enzyme and subsequently forming insoluble HgSe. Exposures to CH₃Hg can impair Se availability in maternal, placental, and fetal tissues, but provided tissue reservoirs and intakes of Se are sufficient to ensure Sec synthesis proceeds without hindrance, the oxidative damage and other pathological consequences of high exposures are averted. Exposure to toxic amounts of Hg overcome the ability of these sources to offset Se losses…”

–Wiki page on Mercury Selenide: “Mercury selenide (HgSe; sometimes mercury(II) selenide) is a chemical compound of mercury and selenium. It is a grey-black crystalline solid semi-metal with a sphalerite structure… HgSe occurs naturally as the mineral Tiemannite, and is a component of the “intimate mixture” of HgSe and Se known as HgSe₂.”

HgSe is a grey-black solid with a melting point of 1000C, density of 8.3 and is insoluble in water.

–6. Rethinking mercury: the role of selenium in the pathophysiology of mercury toxicity.

Henry A. Spiller, Clinical Toxicology, Vol 56(5) 2018.

“There is increasing evidence that the pathophysiological target of mercury is in fact selenium, rather than the covalent binding of mercury to sulfur in the body’s ubiquitous sulfhydryl groups. The role of selenium in mercury poisoning is multifaceted, bidirectional, and central to understanding the target organ toxicity of mercury.”

“Mercury has a lower affinity for thiol groups and higher affinity for selenium containing groups by several orders of magnitude, allowing for binding in a multifaceted way.”

“Mercury impairs control of intracellular redox homeostasis with subsequent increased intracellular oxidative stress.”

“Recent work has provided convincing evidence that the primary cellular targets are the selenoproteins of the thioredoxin system (thioredoxin reductase 1 and thioredoxin reductase 2) and the glutathione-glutaredoxin system (glutathione peroxidase). Mercury binds to the selenium site on these proteins and permanently inhibits their function, disrupting the intracellular redox environment.”

“The roles selenium plays in this reduction of mercury toxicity partially depends on the form of mercury and may be multifaceted including: 1) facilitating demethylation of organic mercury to inorganic mercury; 2) redistribution of mercury to less sensitive target organs; 3) binding to inorganic mercury and forming an insoluble, stable and inert Hg:Se complex; 4) reduction of mercury absorption from the GI tract; 5) repletion of selenium stores (reverse selenium deficiency); and 6) restoration of target selenoprotein activity and restoring the intracellular redox environment. There is conflicting evidence as to whether selenium increases or hinders mercury elimination, but increased mercury elimination does not appear to be a major role of selenium. Selenium supplementation has been shown to restore selenoprotein function and reduce the toxicity of mercury, with several significant limitations including: the form of mercury (methylmercury toxicity is less responsive to amelioration) and mercury dose.”

(However, the previous listed references showed that Se was effective for methylmercury.)

–7. Rethinking treatment of mercury poisoning: the roles of selenium, acetylcysteine, and thiol chelators in the treatment of mercury poisoning: a narrative review, Henry A. Spiller et al. Toxicology Communications, Vol 5(1), 2021.

–“Acetylcysteine increases urinary clearance, reduces target organ mercury levels, including increased efflux from the brain, as well as shows improvement in organ function (brain, liver and kidney). The remediation of neurotoxicity is likely due, in part, to the protective increased glutathione production in the brain, a unique feature of acetylcysteine.”

“Ethylmercury has a shorter half-life and greater difficulty crossing the blood brain barrier than methylmercury.” The reference given is #8 shown next.

–8. Toxicity of ethylmercury (and Thimerosal): a comparison with methylmercury. Dórea et al.

Appl Toxicol. 2013 Aug;33(8):700-11.

“In vitro studies comparing etHg with meHg demonstrate equivalent measured outcomes for cardiovascular, neural and immune cells. However, under in vivo conditions, evidence indicates a distinct toxicokinetic profile between meHg and etHg, favoring a shorter blood half-life, attendant compartment distribution and the elimination of etHg compared with meHg.”

“more recent studies on the pathophysiology of mercury, suggest selenium supplementation may not only be protective, but also corrective of a mercury-induced selenium deficiency state.”

“…in a methylmercury rat model treated with methyl Hg and sodium selenite and/or acetylcysteine… Selenium alone was more effective than acetylcysteine alone, but selenium plus acetylcysteine together restored the rat (reduced brain lipid peroxidation, increased brain acetyl cholinesterase and increased brain, liver and kidney glutathione) to within 80% of control (no MeHg+) in 7 days, at the time of sacrifice. Additionally, selenium and acetylcysteine administered together reduced brain, kidney and liver mercury concentrations by 87%, 88% and 86%, respectively, in 7 days, at the time of sacrifice compared with MeHg+ poisoned rats receiving no treatment.”

“Additional in vitro evidence showed selenocysteine increased hepatic uptake of MeHg+ as a Se-MeHg complex, and reduced cytotoxicity of the MeHg.” (Ref cited is Ref #9 shown next.)

“In a chronic methylmercury rat model (MeHg+; 4 mg/Kg p.o. every other day for 28 days) the addition of selenium (Se 2.74 mg/kg p.o., equimolar dose 1:1 to MeHg) on day 29 for 90 days, showed restoration of gut flora, increased total mercury in feces and decreased the portion of MeHg+ in feces, supporting increased demethylation.”

–9. Selenocystine against methyl mercury cytotoxicity in HepG2 cells. Wang et al. Sci Rep 7, 147 (2017).

“The formation of MeHg and SeCys₂ aggregation promotes the uptake of MeHg; majority of MeHg transforms into small molecular complexes (MeHg-glutathione (GSH) and MeHg-cysteine (Cys)) in HepG2 cells; and MeHg-GSH is the elimination species which results in reducing the cytotoxicity of MeHg.”

“In summary, this study on SeCys₂ against MeHg cytotoxicity demonstrates a possible pathway for the incorporation and excretion of mercury species at molecular level, and reveals the mechanism of SeCys₂ against MeHg cytotoxicity in HepG2 cells: aggregation of MeHg and SeCys₂ is the main species to promote the uptake of MeHg, MeHg-GSH is the species for the elimination of MeHg from HepG2 cells, the transformation of MeHg into complexes species (MeHg-GSH and MeHg-Cys) in cytosol is the key point for the detoxication of SeCys2 to MeHg cytotoxicity in HepG2 cells.”