Mercury interactions with selenium and sulfur and the relevance of the Se:Hg molar ratio to fish consumption advice

Abstract

Eating fish is often recommended as part of a healthful diet. However, fish, particularly large predatory fish, can contain significant levels of the highly toxic methylmercury (MeHg). Ocean fish in general also contain high levels of selenium (Se), which is reported to confer protection against toxicity of various metals including mercury (Hg). Se and Hg have a high mutual binding affinity, and each can reduce the toxicity of the other. This is an evolving area of extensive research and controversy with variable results in the animal and epidemiologic literature. MeHg is toxic to many organ systems through high affinity for –SH (thiol) ligands on enzymes and microtubules. Hg toxicity also causes oxidative damage particularly to neurons in the brain. Hg is a potent and apparently irreversible inhibitor of the selenoenzymes, glutathione peroxidases (GPX), and thioredoxin reductases (TXNRD) that are important antioxidants, each with a selenocysteine (SeCys) at the active site. Hg binding to the SeCys inhibits these enzymes, accounting in part for the oxidative damage that is an important manifestation of Hg toxicity, particularly if there is not a pool of excess Se to synthesize new enzymes. A molar excess of Se reflected in an Se:Hg molar ratio > 1 is often invoked as evidence that the Hg content can be discounted. Some recent papers now suggest that if the Se:Hg molar ratio exceeds 1:1, the fish is safe and the mercury concentration can be ignored. Such papers suggested that the molar ratio rather than the Hg concentration should be emphasized in fish advisories. This paper examines some of the limitations of current understanding of the Se:Hg molar ratio in guiding fish consumption advice; Se is certainly an important part of the Hg toxicity story, but it is not the whole story. We examine how Hg toxicity relates also to thiol binding. We suggest that a 1:1 molar ratio cannot be relied on because not all of the Se in fish or in the fish eater is available to interact with Hg. Moreover, in some fish, Se levels are sufficiently high to warrant concern about Se toxicity.

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Data availability

Data sharing is not applicable to this paper because no data sets were generated or analyzed during the study. All references used are listed in the reference section. All are available through PUBMED or at the URLs provided (updated 10 December 2020).

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Acknowledgments

We thank our colleagues Michael Gallo, Jeffrey Laskin, Dan Morse, Ken Reuhl, and Helmut Zarbl who have shared their extensive knowledge of biochemistry and toxicology in general and mercury and selenium in particular. Nicholas Ralston provided valuable discussions, questioned our assumptions, and addressed our questions. We have benefitted from decades of discussions and collaborations on issues of fish consumption advice and advisories including Ned Groth, Philippe Grandjean, and Alan Stern. This paper benefitted greatly from two knowledgeable and thoughtful anonymous reviewers who encouraged us to re-examine and substantiate many of our assumptions. And thanks to our patients who came to our clinic with high mercury levels and symptoms of mercury poisoning from eating a lot of fish, usually for “health reasons.” Fortunately most of them have gotten better as their mercury levels declined. Our clinic colleagues Howard Kipen, Iris Udasin, Michael Pratt, Nancy Fiedler, and Rob Laumbach contributed with valuable discussions of differential diagnoses and management options. Christian Jeitner handled searches, manuscript preparation, formatting, and submission details in addition to preparing graphics for the oral presentations. Last but not least we thank Carlos Lodeiro Espiño and Jose Luis Capello for the invitation to participate in the 3rd PTIM conferences and present these ideas to an audience of diverse expertise.

Funding

This research was funded by the National Institute of Environmental Health Science Center for Environmental Exposure and Disease (NIH-NIEHS P30ES0050022), the USDA National Institute of Food and Agriculture (Hatch Multistate Project 1008906 through NJAES (Hatch NJ 12233, W4045), and the US DOE (DE-FC 01-06EW 07503 grant to the Consortium for Risk Evaluation with Stakeholder Participation (CRESP)). Travel support for J Burger was provided by the PTIM conference organization as a plenary speaker.

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Gochfeld and Burger both contributed to the conceptualization of the paper, literature reviews, and analysis of the concepts and data presented in the paper. All references are noted in the literature cited.

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Correspondence to Michael Gochfeld.

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Highlights

1. Fish have high nutritional value, but some also have high levels of methylmercury.

2. Mercury exerts toxic effects by binding to sulfhydryl (–SH) groups which are its most abundant ligand in the fish and in the human.

3. Mercury inhibits many enzymes by reacting with thiols and also selenols.

4. Mercury inhibits microtubule formation essential for cell structure, cellular transport, and cell division, by binding to –SH sites on the tubulin protein to prevent assembly.

5. Mercury has high affinity for selenium and causes oxidative damage by inhibiting selenoenzymes (e.g., GPX, TXNRD) that are major components of cells’ antioxidant defenses. Some believe that this is the major mechanism for Hg toxicity.

6. Exposure to methylmercury from fish poses a public health risk, although a great excess of Se may partially mitigate the risk by assuring an adequate supply of selenocysteine for selenoprotein replacement. However, the risk of Se toxicity should not be ignored.

7. The Se:Hg molar ratio provides information on the relative excess of Se, but people who eat fish frequently should avoid fish with high mercury content. Fish advisories should take into account the mercury concentration and not rely solely on the molar ratio.

Responsible Editor: Philippe Garrigues

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Gochfeld, M., Burger, J. Mercury interactions with selenium and sulfur and the relevance of the Se:Hg molar ratio to fish consumption advice. Environ Sci Pollut Res 28, 18407–18420 (2021). https://doi.org/10.1007/s11356-021-12361-7

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Keywords

  • Methylmercury
  • Selenium
  • Fish consumption
  • Tubulin
  • Microtubules
  • Selenocysteine
  • Oxidative stress
  • Enzyme inhibition
  • Selenoproteins
  • Thioredoxin reductase
  • Glutathione peroxidase
  • Se:Hg molar ratio