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Mercury’s Neurotoxic Effects on Brain Selenoenzymes

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Handbook of Neurotoxicity

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Abstract

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. Mercury toxicity’s biochemical mechanisms, Se-dependent protective effects, variability in dose effects, prolonged latency, tissue specificity, and enhanced fetal vulnerability to high exposures are becoming increasingly well understood.

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Abbreviations

AP-1:

Activator protein 1

ApoER2:

Apolipoprotein E receptor 2

CH3Hg:

Methylmercury

CH3HgCH3:

Dimethylmercury

Cys:

Cysteine

DIO:

Deiodinase

DIO1:

Iodothyronine deiodinase 1

GPx:

Glutathione peroxidase

GSH:

Glutathione

GSSH:

Glutathione (oxidized form)

H2O2:

Hydrogen peroxide

Hg+:

Oxidized mercury

Hg+, Hg2+:

Inorganic mercury

Hg0:

Elemental mercury

HSe−:

Selenide

LAT1:

Large neutral amino acid transporter

Met:

Methionine

MsrB:

Methionine sulfoxide reductase B

NF-κB:

Nuclear factor kappa light-chain enhancer of activated B cells

OOH:

Hydroperoxo species

Prx:

Peroxyredoxins

RNR:

Ribonucleotide reductase

ROO.:

Peroxyl radical

RSe−:

Selenoate

RSH:

Sulfhydryl

Sec:

Selenocysteine

SeMet:

Selenomethionine

SeO3:

Selenium trioxide

SeO32−:

Selenite

SeO42−:

Selenate

Ser:

Serine

TGR:

Thioredoxin-glutathione reductase

Trx-(SH)2:

Thioredoxin

TRx1:

Thioredoxin reductase 1

TRx2:

Thioredoxin reductase 2

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Authors and Affiliations

  1. Earth System Science and Policy, University of North Dakota, Grand Forks, ND, USA

    Nicholas V. C. Ralston

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Correspondence to Nicholas V. C. Ralston .

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  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Ralston, N.V.C. (2021). Mercury’s Neurotoxic Effects on Brain Selenoenzymes. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_236-1

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  • DOI: https://doi.org/10.1007/978-3-030-71519-9_236-1

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