Advertisement

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

  • Marcelo FarinaEmail author
  • Michael Aschner
Chapter
Part of the Advances in Neurobiology book series (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.

Keywords

Methylmercury Pro-oxidative events Oxidative stress Neurotoxicity 

Abbreviations and Synonyms

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

Notes

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).

References

  1. 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.CrossRefPubMedGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. Araie H, Shiraiwa Y. Selenium utilization strategy by microalgae. Molecules. 2009;14(12):4880–91. doi: 10.3390/molecules14124880.CrossRefPubMedGoogle Scholar
  5. Aschner M, Clarkson TW. Uptake of methylmercury in the rat brain: effects of amino acids. Brain Res. 1988;462(1):31–9.CrossRefPubMedGoogle Scholar
  6. Aschner M, Yao CP, Allen JW, Tan KH. Methylmercury alters glutamate transport in astrocytes. Neurochem Int. 2000;37(2–3):199–206.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. Aust AE, Eveleigh JF. Mechanisms of DNA oxidation. Proc Soc Exp Biol Med. 1999;222(3):246–52.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.
  15. Brigelius-Flohe R. Glutathione peroxidases and redox-regulated transcription factors. Biol Chem. 2006;387(10–11):1329–35. doi: 10.1515/BC.2006.166.PubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. Clarkson TW. The three modern faces of mercury. Environ Health Perspect. 2002;110(Suppl 1):11–23.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. Compeau GC, Bartha R. Sulfate-reducing bacteria: principal methylators of mercury in anoxic estuarine sediment. Appl Environ Microbiol. 1985;50(2):498–502.PubMedPubMedCentralGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefPubMedGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 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.
  38. Fonnum F. Glutamate: a neurotransmitter in mammalian brain. J Neurochem. 1984;42(1):1–11.CrossRefPubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 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.CrossRefPubMedGoogle Scholar
  44. 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.CrossRefPubMedGoogle Scholar
  45. 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.CrossRefPubMedGoogle Scholar
  46. Grandjean P, Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014;13(3):330–8. doi: 10.1016/S1474-4422(13)70278-3.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 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.CrossRefPubMedGoogle Scholar
  48. Hintelmann H. Organomercurials. Their formation and pathways in the environment. Met Ions Life Sci. 2010;7:365–401. doi: 10.1039/BK9781847551771-00365.CrossRefPubMedGoogle Scholar
  49. 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.CrossRefPubMedGoogle Scholar
  50. 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
  51. 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.CrossRefPubMedGoogle Scholar
  52. 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.CrossRefPubMedGoogle Scholar
  53. 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.CrossRefPubMedGoogle Scholar
  54. 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.CrossRefPubMedGoogle Scholar
  55. Kaur P, Aschner M, Syversen T. Biochemical factors modulating cellular neurotoxicity of methylmercury. J Toxicol. 2011;2011:721987. doi: 10.1155/2011/721987.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Kessler R. The Minamata convention on mercury: a first step toward protecting future generations. Environ Health Perspect. 2013;121(10):A304–9.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 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.CrossRefPubMedGoogle Scholar
  58. 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.CrossRefPubMedGoogle Scholar
  59. 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.CrossRefPubMedGoogle Scholar
  60. 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.CrossRefPubMedGoogle Scholar
  61. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 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.CrossRefPubMedGoogle Scholar
  63. 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.CrossRefPubMedGoogle Scholar
  64. 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.CrossRefPubMedGoogle Scholar
  65. Lu J, Holmgren A. Selenoproteins. J Biol Chem. 2009;284(2):723–7. doi: 10.1074/jbc.R800045200.CrossRefPubMedGoogle Scholar
  66. 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.PubMedGoogle Scholar
  67. 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.PubMedGoogle Scholar
  68. 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.CrossRefPubMedGoogle Scholar
  69. 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.CrossRefPubMedGoogle Scholar
  70. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 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.CrossRefPubMedGoogle Scholar
  72. 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.CrossRefPubMedGoogle Scholar
  73. Osawa M, Magos L. The chemical form of the methylmercury complex in the bile of the rat. Biochem Pharmacol. 1974;23(13):1903–5.CrossRefPubMedGoogle Scholar
  74. 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.CrossRefPubMedGoogle Scholar
  75. 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.CrossRefPubMedGoogle Scholar
  76. Rabenstein DL, Evans CA. The mobility of methylmercury in biological systems. Bioinorg Chem. 1978;8(2):107–101,104.CrossRefPubMedGoogle Scholar
  77. 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.CrossRefPubMedGoogle Scholar
  78. 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.PubMedGoogle Scholar
  79. 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.CrossRefPubMedGoogle Scholar
  80. Richardson RJ, Murphy SD. Effect of glutathione depletion on tissue deposition of methylmercury in rats. Toxicol Appl Pharmacol. 1975;31(3):505–19.CrossRefPubMedGoogle Scholar
  81. 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.CrossRefPubMedGoogle Scholar
  82. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 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.CrossRefPubMedGoogle Scholar
  84. 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.CrossRefPubMedGoogle Scholar
  85. Sakamoto M, Ikegami N, Nakano A. Protective effects of Ca2+ channel blockers against methyl mercury toxicity. Pharmacol Toxicol. 1996;78(3):193–9.CrossRefPubMedGoogle Scholar
  86. 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.PubMedGoogle Scholar
  87. 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.CrossRefPubMedGoogle Scholar
  88. 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.CrossRefPubMedGoogle Scholar
  89. 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.CrossRefPubMedGoogle Scholar
  90. 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.CrossRefPubMedGoogle Scholar
  91. 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.CrossRefPubMedGoogle Scholar
  92. 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.CrossRefPubMedGoogle Scholar
  93. 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.CrossRefPubMedGoogle Scholar
  94. 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.CrossRefPubMedGoogle Scholar
  95. Von Burg R, Northington FK, Shamoo A. Methylmercury inhibition of rat brain muscarinic receptors. Toxicol Appl Pharmacol. 1980;53(2):285–92.CrossRefGoogle Scholar
  96. 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.CrossRefPubMedGoogle Scholar
  97. 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.CrossRefPubMedGoogle Scholar
  98. 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.CrossRefPubMedGoogle Scholar
  99. 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.CrossRefPubMedGoogle Scholar
  100. 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.PubMedPubMedCentralGoogle Scholar
  101. 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.CrossRefPubMedGoogle Scholar
  102. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Departamento de Bioquímica, Centro de Ciências BiológicasUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  2. 2.Department of Molecular PharmacologyAlbert Einstein College of MedicineBronxUSA

Personalised recommendations