Skip to main content
SpringerLink
Log in

Methylmercury-Induced Neurotoxicity: Focus on Pro-oxidative Events and Related Consequences

  • Chapter
  • First Online:
Neurotoxicity of Metals

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 18))

Abstract

Methylmercury (MeHg) is a highly neurotoxic environmental pollutant. Even though molecular mechanisms mediating MeHg toxicity are not completely understood, several lines of evidence indicate that the neurotoxic effects resultant from MeHg exposure represent a consequence of its pro-oxidative properties. In this regard, MeHg is a soft electrophile that preferentially interacts with (and oxidize) nucleophilic groups (mainly thiols and selenols) from biomolecules, including proteins and low-molecular-weight molecules. Such interaction contributes to the occurrence of oxidative stress and impaired function of several molecules [proteins (receptors, transporters, enzymes, structural proteins), lipids (i.e., membrane constituents and intracellular messengers), and nucleic acids (i.e., DNA)], culminating in neurotoxicity.

In this chapter, an initial background on the general aspects regarding the neurotoxicology of MeHg, with a particular focus on its pro-oxidative properties and its interaction with nucleophilic thiol- and selenol-containing molecules, is provided. Even though experimental evidence indicates that symptoms (i.e., motor impairment) resultant from MeHg exposure are linked to its pro-oxidative properties, as well as to their molecular consequences (lipid peroxidation, disruption of glutamate and/or calcium homeostasis, etc.), data concerning the relationship between molecular parameters and behavioral impairment others that those related to the motor function (i.e., visual impairment, cognitive skills, etc.) are scarce. Thus, even though scientific research has provided a significant amount of knowledge concerning the mechanisms mediating MeHg-induced neurotoxicity in the last decades, the whole scenario is far from being completely understood, and further research in this area is well warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

GSH:

Glutathione (reduced form)

H2O2 :

Hydrogen peroxide

MeHg:

Methylmercury = CH3Hg+

-SeH:

Selenol = selenohydryl

-Se− (deprotonated form of selenol):

Selenolate

-SH:

Thiol = sulfhydryl

-S− (deprotonated form of thiol):

Thiolate

References

  • Adedara IA, Rosemberg DB, Souza DO, Farombi EO, Aschner M, Rocha JB. Neuroprotection of luteolin against methylmercury-induced toxicity in lobster cockroach Nauphoeta cinerea. Environ Toxicol Pharmacol. 2016;42:243–51. doi:10.1016/j.etap.2016.02.001.

    Article  CAS  PubMed  Google Scholar 

  • Allen JW, Mutkus LA, Aschner M. Methylmercury-mediated inhibition of 3H-D-aspartate transport in cultured astrocytes is reversed by the antioxidant catalase. Brain Res. 2001;902(1):92–100.

    Article  CAS  PubMed  Google Scholar 

  • Andersen HR, Andersen O. Effects of dietary alpha-tocopherol and beta-carotene on lipid peroxidation induced by methyl mercuric chloride in mice. Pharmacol Toxicol. 1993;73(4):192–201.

    Article  CAS  PubMed  Google Scholar 

  • Araie H, Shiraiwa Y. Selenium utilization strategy by microalgae. Molecules. 2009;14(12):4880–91. doi:10.3390/molecules14124880.

    Article  CAS  PubMed  Google Scholar 

  • Aschner M, Clarkson TW. Uptake of methylmercury in the rat brain: effects of amino acids. Brain Res. 1988;462(1):31–9.

    Article  CAS  PubMed  Google Scholar 

  • Aschner M, Yao CP, Allen JW, Tan KH. Methylmercury alters glutamate transport in astrocytes. Neurochem Int. 2000;37(2–3):199–206.

    Article  CAS  PubMed  Google Scholar 

  • Aschner M, Syversen T, Souza DO, Rocha JB, Farina M. Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity. Braz J Med Biol Res. 2007;40(3):285–91.

    Article  CAS  PubMed  Google Scholar 

  • Aust AE, Eveleigh JF. Mechanisms of DNA oxidation. Proc Soc Exp Biol Med. 1999;222(3):246–52.

    Article  CAS  PubMed  Google Scholar 

  • Bakir F, Damluji SF, Amin-Zaki L, Murtadha M, Khalidi A, al-Rawi NY, Tikriti S, Dahahir HI, Clarkson TW, Smith JC, Doherty RA. Methylmercury poisoning in Iraq. Science. 1973;181(4096):230–41.

    Article  CAS  PubMed  Google Scholar 

  • Basu N, Scheuhammer AM, Rouvinen-Watt K, Evans RD, Trudeau VL, Chan LH. In vitro and whole animal evidence that methylmercury disrupts GABAergic systems in discrete brain regions in captive mink. Comp Biochem Physiol C Toxicol Pharmacol. 2010;151(3):379–85. doi:10.1016/j.cbpc.2010.01.001.

    Article  PubMed  Google Scholar 

  • Belletti S, Orlandini G, Vettori MV, Mutti A, Uggeri J, Scandroglio R, Alinovi R, Gatti R. Time course assessment of methylmercury effects on C6 glioma cells: submicromolar concentrations induce oxidative DNA damage and apoptosis. J Neurosci Res. 2002;70(5):703–11. doi:10.1002/jnr.10419.

    Article  CAS  PubMed  Google Scholar 

  • Branco V, Canário J, Holmgren A, Carvalho C. Inhibition of the thioredoxin system in the brain and liver of zebraseabreams exposed to waterborne methylmercury. Toxicol Appl Pharmacol. 2011;251(2):95–103. doi:10.1016/j.taap.2010.12.005.

    Article  CAS  PubMed  Google Scholar 

  • Branco V, Canário J, Lu J, Holmgren A, Carvalho C. Mercury and selenium interaction in vivo: effects on thioredoxin reductase and glutathione peroxidase. Free Radic Biol Med. 2012;52(4):781–93. doi:10.1016/j.freeradbiomed.2011.12.002.

    Article  CAS  PubMed  Google Scholar 

  • Bridges K, Venables B, Roberts A. Effects of dietary methylmercury on the dopaminergic system of adult fathead minnows and their offspring. Environ Toxicol Chem. 2016; doi:10.1002/etc.3630.

  • Brigelius-Flohe R. Glutathione peroxidases and redox-regulated transcription factors. Biol Chem. 2006;387(10–11):1329–35. doi:10.1515/BC.2006.166.

    CAS  PubMed  Google Scholar 

  • Brookes N, Kristt DA. Inhibition of amino acid transport and protein synthesis by HgCl2 and methylmercury in astrocytes: selectivity and reversibility. J Neurochem. 1989;53(4):1228–37.

    Article  CAS  PubMed  Google Scholar 

  • Carvalho MC, Franco JL, Ghizoni H, Kobus K, Nazari EM, Rocha JB, Nogueira CW, Dafre AL, Muller YM, Farina M. Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on methylmercury-induced locomotor deficits and cerebellar toxicity in mice. Toxicology. 2007;239(3):195–203. doi:10.1016/j.tox.2007.07.009.

    Article  CAS  PubMed  Google Scholar 

  • Carvalho CM, Matos AI, Mateus ML, Santos AP, Batoreu MC. High-fish consumption and risk prevention: assessment of exposure to methylmercury in Portugal. J Toxicol Environ Health A. 2008;71(18):1279–88. doi:10.1080/15287390801989036.

    Article  CAS  PubMed  Google Scholar 

  • Clarkson TW. The three modern faces of mercury. Environ Health Perspect. 2002;110(Suppl 1):11–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clarkson TW, Magos L, Myers GJ. The toxicology of mercury--current exposures and clinical manifestations. N Engl J Med. 2003;349(18):1731–7. doi:10.1056/NEJMra022471.

    Article  CAS  PubMed  Google Scholar 

  • Compeau GC, Bartha R. Sulfate-reducing bacteria: principal methylators of mercury in anoxic estuarine sediment. Appl Environ Microbiol. 1985;50(2):498–502.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dare E, Fetissov S, Hokfelt T, Hall H, Ogren SO, Ceccatelli S. Effects of prenatal exposure to methylmercury on dopamine-mediated locomotor activity and dopamine D2 receptor binding. Naunyn Schmiedeberg’s Arch Pharmacol. 2003;367(5):500–8. doi:10.1007/s00210-003-0716-5.

    Article  CAS  Google Scholar 

  • Darley-Usmar VM, Hogg N, O’Leary VJ, Wilson MT, Moncada S. The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein. Free Radic Res Commun. 1992;17(1):9–20.

    Article  CAS  PubMed  Google Scholar 

  • Davis LE, Kornfeld M, Mooney HS, Fiedler KJ, Haaland KY, Orrison WW, Cernichiari E, Clarkson TW. Methylmercury poisoning: long-term clinical, radiological, toxicological, and pathological studies of an affected family. Ann Neurol. 1994;35(6):680–8. doi:10.1002/ana.410350608.

    Article  CAS  PubMed  Google Scholar 

  • Dietrich MO, Mantese CE, Anjos GD, Souza DO, Farina M. Motor impairment induced by oral exposure to methylmercury in adult mice. Environ Toxicol Pharmacol. 2005;19(1):169–75. doi:10.1016/j.etap.2004.07.004.

    Article  CAS  PubMed  Google Scholar 

  • Dorea JG. The neurological effects of prenatal and postnatal exposure to mercury need to include ethylmercury. Chemosphere. 2015;139:667–8. doi:10.1016/j.chemosphere.2014.06.045.

    Article  CAS  PubMed  Google Scholar 

  • Dringen R. Oxidative and antioxidative potential of brain microglial cells. Antioxid Redox Signal. 2005;7(9–10):1223–33. doi:10.1089/ars.2005.7.1223.

    Article  CAS  PubMed  Google Scholar 

  • Dutczak WJ, Ballatori N. Transport of the glutathione-methylmercury complex across liver canalicular membranes on reduced glutathione carriers. J Biol Chem. 1994;269(13):9746–51.

    CAS  PubMed  Google Scholar 

  • Ekino S, Susa M, Ninomiya T, Imamura K, Kitamura T. Minamata disease revisited: an update on the acute and chronic manifestations of methyl mercury poisoning. J Neurol Sci. 2007;262(1–2):131–44. doi:10.1016/j.jns.2007.06.036.

    Article  CAS  PubMed  Google Scholar 

  • Eto K, Takeuchi T. Pathological changes of human sural nerves in Minamata disease (methylmercury poisoning). Light and electron microscopic studies. Virchows Arch B Cell Pathol. 1977;23(2):109–28.

    CAS  PubMed  Google Scholar 

  • Farina M, Dahm KC, Schwalm FD, Brusque AM, Frizzo ME, Zeni G, Souza DO, Rocha JB. Methylmercury increases glutamate release from brain synaptosomes and glutamate uptake by cortical slices from suckling rat pups: modulatory effect of ebselen. Toxicol Sci. 2003a;73(1):135–40. doi:10.1093/toxsci/kfg058.

    Article  CAS  PubMed  Google Scholar 

  • Farina M, Frizzo ME, Soares FA, Schwalm FD, Dietrich MO, Zeni G, Rocha JB, Souza DO. Ebselen protects against methylmercury-induced inhibition of glutamate uptake by cortical slices from adult mice. Toxicol Lett. 2003b;144(3):351–7.

    Article  CAS  PubMed  Google Scholar 

  • Farina M, Franco JL, Ribas CM, Meotti FC, Missau FC, Pizzolatti MG, Dafre AL, Santos AR. Protective effects of Polygala paniculata extract against methylmercury-induced neurotoxicity in mice. J Pharm Pharmacol. 2005;57(11):1503–8. doi:10.1211/jpp.57.11.0017.

    Article  CAS  PubMed  Google Scholar 

  • Farina M, Campos F, Vendrell I, Berenguer J, Barzi M, Pons S, Sunol C. Probucol increases glutathione peroxidase-1 activity and displays long-lasting protection against methylmercury toxicity in cerebellar granule cells. Toxicol Sci. 2009;112(2):416–26. doi:10.1093/toxsci/kfp219.

    Article  CAS  PubMed  Google Scholar 

  • Farina M, Aschner M, Rocha JB. Oxidative stress in MeHg-induced neurotoxicity. Toxicol Appl Pharmacol. 2011a;256(3):405–17. doi:10.1016/j.taap.2011.05.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farina M, Rocha JB, Aschner M. Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies. Life Sci. 2011b;89(15–16):555–63. doi:10.1016/j.lfs.2011.05.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng S, Xu Z, Wang F, Yang T, Liu W, Deng Y, Xu B. Sulforaphane prevents methylmercury-induced oxidative damage and Excitotoxicity through activation of the Nrf2-ARE pathway. Mol Neurobiol. 2016; doi:10.1007/s12035-015-9643-y.

  • Fonnum F. Glutamate: a neurotransmitter in mammalian brain. J Neurochem. 1984;42(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  • Franco JL, Teixeira A, Meotti FC, Ribas CM, Stringari J, Garcia Pomblum SC, Moro AM, Bohrer D, Bairros AV, Dafre AL, Santos AR, Farina M. Cerebellar thiol status and motor deficit after lactational exposure to methylmercury. Environ Res. 2006;102(1):22–8. doi:10.1016/j.envres.2006.02.003.

    Article  CAS  PubMed  Google Scholar 

  • Franco JL, Braga HC, Stringari J, Missau FC, Posser T, Mendes BG, Leal RB, Santos AR, Dafre AL, Pizzolatti MG, Farina M. Mercurial-induced hydrogen peroxide generation in mouse brain mitochondria: protective effects of quercetin. Chem Res Toxicol. 2007;20(12):1919–26. doi:10.1021/tx7002323.

    Article  CAS  PubMed  Google Scholar 

  • Franco JL, Posser T, Dunkley PR, Dickson PW, Mattos JJ, Martins R, Bainy AC, Marques MR, Dafre AL, Farina M. Methylmercury neurotoxicity is associated with inhibition of the antioxidant enzyme glutathione peroxidase. Free Radic Biol Med. 2009;47(4):449–57. doi:10.1016/j.freeradbiomed.2009.05.013.

    Article  CAS  PubMed  Google Scholar 

  • Freitas AJ, Rocha JB, Wolosker H, Souza DO. Effects of Hg2+ and CH3Hg+ on Ca2+ fluxes in rat brain microsomes. Brain Res. 1996;738(2):257–64.

    Article  CAS  PubMed  Google Scholar 

  • Glaser V, Leipnitz G, Straliotto MR, Oliveira J, dos Santos VV, Wannmacher CM, de Bem AF, Rocha JB, Farina M, Latini A. Oxidative stress-mediated inhibition of brain creatine kinase activity by methylmercury. Neurotoxicology. 2010a;31(5):454–60. doi:10.1016/j.neuro.2010.05.012.

    Article  CAS  PubMed  Google Scholar 

  • Glaser V, Nazari EM, Muller YM, Feksa L, Wannmacher CM, Rocha JB, de Bem AF, Farina M, Latini A. Effects of inorganic selenium administration in methylmercury-induced neurotoxicity in mouse cerebral cortex. Int J Dev Neurosci. 2010b;28(7):631–7. doi:10.1016/j.ijdevneu.2010.07.225.

    Article  CAS  PubMed  Google Scholar 

  • Glaser V, Martins Rde P, Vieira AJ, Oliveira Ede M, Straliotto MR, Mukdsi JH, Torres AI, de Bem AF, Farina M, da Rocha JB, De Paul AL, Latini A. Diphenyl diselenide administration enhances cortical mitochondrial number and activity by increasing hemeoxygenase type 1 content in a methylmercury-induced neurotoxicity mouse model. Mol Cell Biochem. 2014;390(1–2):1–8. doi:10.1007/s11010-013-1870-9.

    Article  CAS  PubMed  Google Scholar 

  • Grandjean P, Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014;13(3):330–8. doi:10.1016/S1474-4422(13)70278-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grandjean P, Weihe P, White RF, Debes F, Araki S, Yokoyama K, Murata K, Sorensen N, Dahl R, Jorgensen PJ. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol. 1997;19(6):417–28.

    Article  CAS  PubMed  Google Scholar 

  • Hintelmann H. Organomercurials. Their formation and pathways in the environment. Met Ions Life Sci. 2010;7:365–401. doi:10.1039/BK9781847551771-00365.

    Article  CAS  PubMed  Google Scholar 

  • Hirayama K, Inouye M, Fujisaki T. Alteration of putative amino acid levels and morphological findings in neural tissues of methylmercury-intoxicated mice. Arch Toxicol. 1985;57(1):35–40.

    Article  CAS  PubMed  Google Scholar 

  • Ho T-L. Hard and soft acids and bases principle in organic chemistry. 1st edn. Academic. 1977. eBook ISBN: 9780323140966. Published Date: 28th January 1977.

    Google Scholar 

  • Hoffman DJ, Newland MC. A microstructural analysis distinguishes motor and motivational influences over voluntary running in animals chronically exposed to methylmercury and nimodipine. Neurotoxicology. 2016;54:127–39. doi:10.1016/j.neuro.2016.04.009.

    Article  CAS  PubMed  Google Scholar 

  • Kajiwara Y, Yasutake A, Adachi T, Hirayama K. Methylmercury transport across the placenta via neutral amino acid carrier. Arch Toxicol. 1996;70(5):310–4.

    Article  CAS  PubMed  Google Scholar 

  • Kaur P, Schulz K, Aschner M, Syversen T. Role of docosahexaenoic acid in modulating methylmercury-induced neurotoxicity. Toxicol Sci. 2007;100(2):423–32. doi:10.1093/toxsci/kfm224.

    Article  CAS  PubMed  Google Scholar 

  • Kaur P, Heggland I, Aschner M, Syversen T. Docosahexaenoic acid may act as a neuroprotector for methylmercury-induced neurotoxicity in primary neural cell cultures. Neurotoxicology. 2008;29(6):978–87. doi:10.1016/j.neuro.2008.06.004.

    Article  CAS  PubMed  Google Scholar 

  • Kaur P, Aschner M, Syversen T. Biochemical factors modulating cellular neurotoxicity of methylmercury. J Toxicol. 2011;2011:721987. doi:10.1155/2011/721987.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kessler R. The Minamata convention on mercury: a first step toward protecting future generations. Environ Health Perspect. 2013;121(10):A304–9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Khan JY, Black SM. Developmental changes in murine brain antioxidant enzymes. Pediatr Res. 2003;54(1):77–82. doi:10.1203/01.PDR.0000065736.69214.20.

    Article  CAS  PubMed  Google Scholar 

  • Kim JY, Park HS, Kang SI, Choi EJ, Kim IY. Redox regulation of cytosolic glycerol-3-phosphate dehydrogenase: Cys(102) is the target of the redox control and essential for the catalytic activity. Biochim Biophys Acta. 2002;1569(1–3):67–74.

    Article  CAS  PubMed  Google Scholar 

  • Kung MP, Kostyniak P, Olson J, Malone M, Roth JA. Studies of the in vitro effect of methylmercury chloride on rat brain neurotransmitter enzymes. J Appl Toxicol. 1987;7(2):119–21.

    Article  CAS  PubMed  Google Scholar 

  • Lafon-Cazal M, Pietri S, Culcasi M, Bockaert J. NMDA-dependent superoxide production and neurotoxicity. Nature. 1993;364(6437):535–7. doi:10.1038/364535a0.

    Article  CAS  PubMed  Google Scholar 

  • Lobanov AV, Hatfield DL, Gladyshev VN. Eukaryotic selenoproteins and selenoproteomes. Biochim Biophys Acta. 2009;1790(11):1424–8. doi:10.1016/j.bbagen.2009.05.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lockman PR, Roder KE, Allen DD. Inhibition of the rat blood-brain barrier choline transporter by manganese chloride. J Neurochem. 2001;79(3):588–94.

    Article  CAS  PubMed  Google Scholar 

  • LoPachin RM, Barber DS. Synaptic cysteine sulfhydryl groups as targets of electrophilic neurotoxicants. Toxicol Sci. 2006;94(2):240–55. doi:10.1093/toxsci/kfl066.

    Article  CAS  PubMed  Google Scholar 

  • LoPachin RM, Gavin T. Reactions of electrophiles with nucleophilic thiolate sites: relevance to pathophysiological mechanisms and remediation. Free Radic Res. 2016;50(2):195–205. doi:10.3109/10715762.2015.1094184.

    Article  CAS  PubMed  Google Scholar 

  • Lu J, Holmgren A. Selenoproteins. J Biol Chem. 2009;284(2):723–7. doi:10.1074/jbc.R800045200.

    Article  CAS  PubMed  Google Scholar 

  • McCord JM, Fridovich I. The utility of superoxide dismutase in studying free radical reactions. I. Radicals generated by the interaction of sulfite, dimethyl sulfoxide, and oxygen. J Biol Chem. 1969;244(22):6056–63.

    CAS  PubMed  Google Scholar 

  • Mokrzan EM, Kerper LE, Ballatori N, Clarkson TW. Methylmercury-thiol uptake into cultured brain capillary endothelial cells on amino acid system L. J Pharmacol Exp Ther. 1995;272(3):1277–84.

    CAS  PubMed  Google Scholar 

  • Mori K, Yoshida K, Nakagawa Y, Hoshikawa S, Ozaki H, Ito S, Watanabe C. Methylmercury inhibition of type II 5′-deiodinase activity resulting in a decrease in growth hormone production in GH3 cells. Toxicology. 2007;237(1–3):203–9. doi:10.1016/j.tox.2007.05.012.

    Article  CAS  PubMed  Google Scholar 

  • Murata K, Weihe P, Budtz-Jorgensen E, Jorgensen PJ, Grandjean P. Delayed brainstem auditory evoked potential latencies in 14-year-old children exposed to methylmercury. J Pediatr. 2004;144(2):177–83. doi:10.1016/j.jpeds.2003.10.059.

    Article  CAS  PubMed  Google Scholar 

  • Ni M, Li X, Yin Z, Sidoryk-Wegrzynowicz M, Jiang H, Farina M, Rocha JB, Syversen T, Aschner M. Comparative study on the response of rat primary astrocytes and microglia to methylmercury toxicity. Glia. 2011;59(5):810–20. doi:10.1002/glia.21153.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ninomiya T, Imamura K, Kuwahata M, Kindaichi M, Susa M, Ekino S. Reappraisal of somatosensory disorders in methylmercury poisoning. Neurotoxicol Teratol. 2005;27(4):643–53. doi:10.1016/j.ntt.2005.03.008.

    Article  CAS  PubMed  Google Scholar 

  • O’Kusky JR, McGeer EG. Methylmercury poisoning of the developing nervous system in the rat: decreased activity of glutamic acid decarboxylase in cerebral cortex and neostriatum. Brain Res. 1985;353(2):299–306.

    Article  PubMed  Google Scholar 

  • Osawa M, Magos L. The chemical form of the methylmercury complex in the bile of the rat. Biochem Pharmacol. 1974;23(13):1903–5.

    Article  CAS  PubMed  Google Scholar 

  • Penglase S, Hamre K, Ellingsen S. Selenium prevents downregulation of antioxidant selenoprotein genes by methylmercury. Free Radic Biol Med. 2014;75:95–104. doi:10.1016/j.freeradbiomed.2014.07.019.

    Article  CAS  PubMed  Google Scholar 

  • Powis G, Mustacich D, Coon A. The role of the redox protein thioredoxin in cell growth and cancer. Free Radic Biol Med. 2000;29(3-4):312–22.

    Article  CAS  PubMed  Google Scholar 

  • Rabenstein DL, Evans CA. The mobility of methylmercury in biological systems. Bioinorg Chem. 1978;8(2):107–101,104.

    Article  CAS  PubMed  Google Scholar 

  • Radi R, Beckman JS, Bush KM, Freeman BA. Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys. 1991;288(2):481–7.

    Article  CAS  PubMed  Google Scholar 

  • Rahola T, Hattula T, Korolainen A, Miettinen JK. Elimination of free and protein-bound ionic mercury (20Hg2+) in man. Ann Clin Res. 1973;5(4):214–9.

    CAS  PubMed  Google Scholar 

  • Reynolds JN, Racz WJ. Effects of methylmercury on the spontaneous and potassium-evoked release of endogenous amino acids from mouse cerebellar slices. Can J Physiol Pharmacol. 1987;65(5):791–8.

    Article  CAS  PubMed  Google Scholar 

  • Richardson RJ, Murphy SD. Effect of glutathione depletion on tissue deposition of methylmercury in rats. Toxicol Appl Pharmacol. 1975;31(3):505–19.

    Article  CAS  PubMed  Google Scholar 

  • Roda E, Coccini T, Acerbi D, Castoldi A, Bernocchi G, Manzo L. Cerebellum cholinergic muscarinic receptor (subtype-2 and -3) and cytoarchitecture after developmental exposure to methylmercury: an immunohistochemical study in rat. J Chem Neuroanat. 2008;35(3):285–94. doi:10.1016/j.jchemneu.2008.01.003.

    Article  CAS  PubMed  Google Scholar 

  • Roos DH, Puntel RL, Farina M, Aschner M, Bohrer D, Rocha JB, de Vargas Barbosa NB. Modulation of methylmercury uptake by methionine: prevention of mitochondrial dysfunction in rat liver slices by a mimicry mechanism. Toxicol Appl Pharmacol. 2011;252(1):28–35. doi:10.1016/j.taap.2011.01.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenblum ER, Gavaler JS, Van Thiel DH. Lipid peroxidation: a mechanism for alcohol-induced testicular injury. Free Radic Biol Med. 1989;7(5):569–77.

    Article  CAS  PubMed  Google Scholar 

  • Rush T, Liu X, Nowakowski AB, Petering DH, Lobner D. Glutathione-mediated neuroprotection against methylmercury neurotoxicity in cortical culture is dependent on MRP1. Neurotoxicology. 2012;33(3):476–81. doi:10.1016/j.neuro.2012.03.004.

    Article  CAS  PubMed  Google Scholar 

  • Sakamoto M, Ikegami N, Nakano A. Protective effects of Ca2+ channel blockers against methyl mercury toxicity. Pharmacol Toxicol. 1996;78(3):193–9.

    Article  CAS  PubMed  Google Scholar 

  • Seres T, Ravichandran V, Moriguchi T, Rokutan K, Thomas JA, Johnston RB Jr. Protein S-thiolation and dethiolation during the respiratory burst in human monocytes. A reversible post-translational modification with potential for buffering the effects of oxidant stress. J Immunol. 1996;156(5):1973–80.

    CAS  PubMed  Google Scholar 

  • Shanker G, Syversen T, Aschner JL, Aschner M. Modulatory effect of glutathione status and antioxidants on methylmercury-induced free radical formation in primary cultures of cerebral astrocytes. Brain Res Mol Brain Res. 2005;137(1–2):11–22. doi:10.1016/j.molbrainres.2005.02.006.

    Article  CAS  PubMed  Google Scholar 

  • Shen AN, Cummings C, Hoffman D, Pope D, Arnold M, Newland MC. Aging, motor function, and sensitivity to calcium channel blockers: an investigation using chronic methylmercury exposure. Behav Brain Res. 2016;315:103–14. doi:10.1016/j.bbr.2016.07.049.

    Article  CAS  PubMed  Google Scholar 

  • Soares FA, Farina M, Santos FW, Souza D, Rocha JB, Nogueira CW. Interaction between metals and chelating agents affects glutamate binding on brain synaptic membranes. Neurochem Res. 2003;28(12):1859–65.

    Article  CAS  PubMed  Google Scholar 

  • Stringari J, Nunes AK, Franco JL, Bohrer D, Garcia SC, Dafre AL, Milatovic D, Souza DO, Rocha JB, Aschner M, Farina M. Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain. Toxicol Appl Pharmacol. 2008;227(1):147–54. doi:10.1016/j.taap.2007.10.010.

    Article  CAS  PubMed  Google Scholar 

  • Suda I, Takahashi H. Degradation of methyl and ethyl mercury into inorganic mercury by other reactive oxygen species besides hydroxyl radical. Arch Toxicol. 1992;66(1):34–9.

    Article  CAS  PubMed  Google Scholar 

  • Theunissen PT, Pennings JL, Robinson JF, Claessen SM, Kleinjans JC, Piersma AH. Time-response evaluation by transcriptomics of methylmercury effects on neural differentiation of murine embryonic stem cells. Toxicol Sci. 2011;122(2):437–47. doi:10.1093/toxsci/kfr134.

    Article  CAS  PubMed  Google Scholar 

  • Usuki F, Fujimura M. Decreased plasma thiol antioxidant barrier and selenoproteins as potential biomarkers for ongoing methylmercury intoxication and an individual protective capacity. Arch Toxicol. 2016;90(4):917–26. doi:10.1007/s00204-015-1528-3.

    Article  CAS  PubMed  Google Scholar 

  • Usuki F, Yamashita A, Fujimura M. Post-transcriptional defects of antioxidant selenoenzymes cause oxidative stress under methylmercury exposure. J Biol Chem. 2011;286(8):6641–9. doi:10.1074/jbc.M110.168872.

    Article  CAS  PubMed  Google Scholar 

  • Von Burg R, Northington FK, Shamoo A. Methylmercury inhibition of rat brain muscarinic receptors. Toxicol Appl Pharmacol. 1980;53(2):285–92.

    Article  Google Scholar 

  • Wagner C, Sudati JH, Nogueira CW, Rocha JB. In vivo and in vitro inhibition of mice thioredoxin reductase by methylmercury. Biometals. 2010;23(6):1171–7. doi:10.1007/s10534-010-9367-4.

    Article  CAS  PubMed  Google Scholar 

  • Watanabe C, Yin K, Kasanuma Y, Satoh H. In utero exposure to methylmercury and se deficiency converge on the neurobehavioral outcome in mice. Neurotoxicol Teratol. 1999;21(1):83–8.

    Article  CAS  PubMed  Google Scholar 

  • Wormser U, Brodsky B, Milatovic D, Finkelstein Y, Farina M, Rocha JB, Aschner M. Protective effect of a novel peptide against methylmercury-induced toxicity in rat primary astrocytes. Neurotoxicology. 2012;33(4):763–8. doi:10.1016/j.neuro.2011.12.004.

    Article  CAS  PubMed  Google Scholar 

  • Yin Z, Milatovic D, Aschner JL, Syversen T, Rocha JB, Souza DO, Sidoryk M, Albrecht J, Aschner M. Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes. Brain Res. 2007;1131(1):1–10. doi:10.1016/j.brainres.2006.10.070.

    Article  CAS  PubMed  Google Scholar 

  • Yin Z, Jiang H, Syversen T, Rocha JB, Farina M, Aschner M. The methylmercury-L-cysteine conjugate is a substrate for the L-type large neutral amino acid transporter. J Neurochem. 2008;107(4):1083–90. doi:10.1111/j.1471-4159.2008.05683.x.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zemolin AP, Meinerz DF, de Paula MT, Mariano DO, Rocha JB, Pereira AB, Posser T, Franco JL. Evidences for a role of glutathione peroxidase 4 (GPx4) in methylmercury induced neurotoxicity in vivo. Toxicology. 2012;302(1):60–7. doi:10.1016/j.tox.2012.07.013.

    Article  CAS  PubMed  Google Scholar 

  • Zimmer B, Schildknecht S, Kuegler PB, Tanavde V, Kadereit S, Leist M. Sensitivity of dopaminergic neuron differentiation from stem cells to chronic low-dose methylmercury exposure. Toxicol Sci. 2011;121(2):357–67. doi:10.1093/toxsci/kfr054.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The author would like to thank the colleagues/coauthors who have contributed to several studies referenced in this chapter. These studies were funded in part by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC).

Author information

Authors and Affiliations

  1. Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

    Marcelo Farina

  2. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA

    Michael Aschner

Authors
  1. Marcelo Farina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Aschner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marcelo Farina .

Editor information

Editors and Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA

    Michael Aschner

  2. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA

    Lucio G. Costa

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Farina, M., Aschner, M. (2017). Methylmercury-Induced Neurotoxicity: Focus on Pro-oxidative Events and Related Consequences. In: Aschner, M., Costa, L. (eds) Neurotoxicity of Metals. Advances in Neurobiology, vol 18. Springer, Cham. https://doi.org/10.1007/978-3-319-60189-2_13

Download citation

Publish with us

Policies and ethics

Search

Navigation