Methylmercury Neurotoxicity: A Synopsis of In Vitro Effects

  • Lucio G. Costa
  • Gennaro Giordano
Part of the Current Topics in Neurotoxicity book series (Current Topics Neurotoxicity, volume 2)


Following severe episodes of human poisoning, a large number of studies in experimental animals have confirmed that methylmercury (MeHg) is a potent developmental neurotoxicant. Furthermore, extensive research in vivo and in vitro has delineated the possible mechanisms underlying MeHg neurotoxicity. This chapter summarizes major findings on the effects of MeHg at the cellular level in both neuronal and glial cells in vitro. Given the multitude of information available, only major pathways of toxicity are discussed, with a focus on the ability of MeHg to cause apoptotic cell death, by mechanisms involving the perturbation of calcium homeostasis and the induction of oxidative stress.


Glial Cell Cerebellar Granule Cerebellar Granule Cell Cerebellar Granule Neuron MeHg Exposure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Work by the authors has been supported over the years by grants from the National Institutes of Health, the Environmental Protection Agency, the European Commission, and the Italian Ministry for Research (MIUR).


  1. Aschner M, Du YL, Gannon M, et al. Methylmercury-induced alterations in excitatory amino acid transport in rat primary astrocyte cultures. Brain Res. 1993;602:181–6.PubMedCrossRefGoogle Scholar
  2. Aschner M, Yao CP, Allen JW, et al. Methylmercury alters glutamate transport in astrocytes. Neurochem Int. 2000;37:199–206.PubMedCrossRefGoogle Scholar
  3. Atchison WD, Hare MF. Mechanisms of methylmercury-induced neurotoxicity. FASEB J. 1994;8: 622–8.PubMedGoogle Scholar
  4. Bakir F, Damluji SF, Amin-Zaki L, et al. Methylmercury poisoning in Iraq. Science. 1973;181: 230–41.PubMedCrossRefGoogle Scholar
  5. Belletti S, Orlandini G, Vettori MV, et al. Time course assessment of methylmercury effects on C6 glioma cells: submicromolar concentrations induce oxidative DNA damage and apoptosis. J Neurosci Res. 2002;70:703–11.PubMedCrossRefGoogle Scholar
  6. Castoldi AF, Barni S, Turin I, et al. Early acute necrosis, delayed apoptosis and cytoskeletal breakdown in cultured cerebellar granule neurons exposed to methylmercury. J Neurosci Res. 2000;59:775–87.PubMedCrossRefGoogle Scholar
  7. Castoldi AF, Coccini T, Ceccatelli S, Manzo L. Neurotoxicity and molecular effects of methylmercury. Brain Res Bull. 2001;55:197–203.PubMedCrossRefGoogle Scholar
  8. Castoldi AF, Onishchenko N, Johansson C, et al. Developmental neurotoxicity of methylmercury: laboratory animal data and their contribution to human risk assessment. Regul Toxicol Pharmacol. 2008;51:215–29.PubMedCrossRefGoogle Scholar
  9. Ceccatelli S, Daré E, Moors M. Methylmercury-induced neurotoxicity and apoptosis. Chem Biol Interact. 2010;188:301–8.PubMedCrossRefGoogle Scholar
  10. Clarkson TW, Magos L. The toxicology of mercury and its chemical compounds. Crit Rev Toxicol. 2006;36:609–62.PubMedCrossRefGoogle Scholar
  11. Costa LG. Contaminants in fish: risk-benefit considerations. Arch Ind Hyg Toxicol. 2007;58: 367–74.CrossRefGoogle Scholar
  12. Costa LG, Fattori V, Giordano G, et al. An in vitro approach to assess the toxicity of certain food contaminants: methylmercury and polychlorinated biphenyls. Toxicology. 2007;237:65–76.PubMedCrossRefGoogle Scholar
  13. Cuello S, Goya L, Madrid Y, et al. Molecular mechanisms of methylmercury-induced cell death in human HepG2 cells. Food Chem Toxicol. 2010;48:1405–11.PubMedCrossRefGoogle Scholar
  14. Daré E, Gotz ME, Zhivotovsky B, et al. Antioxidants J811 and 17β-estradiol protect cerebellar granule cells from methylmercury-induced apoptotic cell death. J Neurosci Res. 2000;62:557–65.PubMedCrossRefGoogle Scholar
  15. Daré E, Gorman AM, Ahlbom E, et al. Apoptotic morphology does not always require caspase activity in rat cerebellar granule neurons. Neurotox Res. 2001a;3:501–14.PubMedCrossRefGoogle Scholar
  16. Daré E, Li W, Zhivotovsky B, et al. Methylmercury and H2O2 provoke lysosomal damage in human astrocytoma D384 cells followed by apoptosis. Free Radic Biol Med. 2001b;30:1347–56.PubMedCrossRefGoogle Scholar
  17. Fang SC, Fallin E. The binding of various mercurial compounds to serum proteins. Bull Environ Contam Toxicol. 1976;15:110–7.PubMedCrossRefGoogle Scholar
  18. Gatti R, Belletti S, Uggeri J, et al. Methylmercury cytotoxicity in PC12 cells is mediated by primary glutathione depletion independent of excess reactive oxygen species generation. Toxicology. 2004;204:175–85.PubMedCrossRefGoogle Scholar
  19. Giordano G, Kavanagh TJ, Costa LG. Neurotoxicity of a polybrominated diphenyl ether mixture (DE-71) in mouse neurons and astrocytes is modulated by intracellular glutathione levels. Toxicol Appl Pharmacol. 2008;232:161–8.PubMedCrossRefGoogle Scholar
  20. Grandjean P, Weihe P, White RF, et al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol. 1997;19:417–28.PubMedCrossRefGoogle Scholar
  21. Harada M. Minamata disease: methylmercury poisoning in Japan caused by environmental pollution. Crit Rev Toxicol. 1995;25:1–24.PubMedCrossRefGoogle Scholar
  22. Hare MF, Atchison WD. Methylmercury mobilizes Ca++ from intracellular stores sensitive to inositol 1,4,5-trisphosphate in NG108-15 cells. J Pharmacol Exp Ther. 1995;272:1016–23.PubMedGoogle Scholar
  23. Kaur P, Aschner M, Syversen T. Glutathione modulation influences methyl mercury induced neurotoxicity in primary cultures of neurons and astrocytes. Neurotoxicology. 2006;27:492–500.PubMedCrossRefGoogle Scholar
  24. Kaur P, Aschner M, Syversen T. Role of glutathione in determining the differential sensitivity between cortical and cerebellar regions towards mercury-induced oxidative stress. Toxicology. 2007;230:164–77.PubMedCrossRefGoogle Scholar
  25. Kunimoto M. Methylmercury induces apoptosis of rat cerebellar neurons in primary culture. Biochem Biophys Res Commun. 1994;204:310–7.PubMedCrossRefGoogle Scholar
  26. Limke TL, Bearss JJ, Atchison WD. Acute exposure to methylmercury causes Ca2+ dysregulation and neuronal death in rat cerebellar granule cells through an M3 muscarinic receptor-linked pathway. Toxicol Sci. 2004;80:60–8.PubMedCrossRefGoogle Scholar
  27. Marty MS, Atchison WD. Pathways mediating Ca2+ entry in rat cerebellar granule cells following I vitro exposure to methyl mercury. Toxicol Appl Pharmacol. 1997;147:319–30.PubMedCrossRefGoogle Scholar
  28. Marty MS, Atchison WD. Elevations of intracellular Ca2+ as a probable contributor to decreased viability in cerebellar granule cells following acute exposure to methylmercury. Toxicol Appl Pharmacol. 1998;150:98–105.PubMedCrossRefGoogle Scholar
  29. Meacham CA, Freudenrich TM, Anderson WL, et al. Accumulation of methylmercury and polychlorinated biphenyls in in vitro models of rat neuronal tissue. Toxicol Appl Pharmacol. 2005;295:177–87.CrossRefGoogle Scholar
  30. Morken TS, Sonnewald U, Aschner M, et al. Effects of methylmercury on primary brain cells in mono-and co-culture. Toxicol Sci. 2005;87:169–75.PubMedCrossRefGoogle Scholar
  31. Ni M, Li X, Yin Z, et al. Methylmercury induces acute oxidative stress, altering Nrf2 protein level in primary microglial cells. Toxicol Sci. 2010;116:590–603.PubMedCrossRefGoogle Scholar
  32. Nishioku T, Takai N, Miyamoto KI, et al. Involvement of caspase 3-like protease in methylmercury-induced apoptosis in primary cultured rat cerebral microglia. Brain Res. 2000;871: 160–4.PubMedCrossRefGoogle Scholar
  33. Orrenius S, Nicotera P. The calcium ion and cell death. J Neural Transm. 1994;43:1–11.Google Scholar
  34. Sakaue M, Okazaki M, Hara S. Very low levels of methylmercury induce cell death of cultured rat cerebellar neurons via calpain activation. Toxicology. 2005;213:97–106.PubMedCrossRefGoogle Scholar
  35. Sanfeliu C, Sebastia J, Ki SU. Methylmercury neurotoxicity in cultures of human neurons, astrocytes, neuroblastoma cells. Neurotoxicology. 2001;22:317–27.PubMedCrossRefGoogle Scholar
  36. Sanfeliu C, Sebastia J, Cristofol R, et al. Neurotoxicity of organomercurial compounds. Neurotox Res. 2003;5:283–305.PubMedCrossRefGoogle Scholar
  37. Sarafian TA. Methyl mercury increases intracellular Ca2+ and inositol phosphate levels in cultured cerebellar granule neurons. J Neurochem. 1993;61:648–57.PubMedCrossRefGoogle Scholar
  38. Sarafian TA, Verity MA. Oxidative mechanisms underlying methyl mercury neurotoxicity. Int J Dev Neurosci. 1991;9:147–53.PubMedCrossRefGoogle Scholar
  39. Sarafian TA, Verity MA. Changes in protein phosphorylation in cultured neurons after exposure to methylmercury. Ann N Y Acad Sci. 1992;679:65–77.CrossRefGoogle Scholar
  40. Shanker G, Aschner M. Identification and characterization of uptake systems for cystine and cysteine in cultured astrocytes and neurons: evidence for methylmercury-targeted disruption of astrocyte transport. J Neurosci Res. 2001;66:998–1002.PubMedCrossRefGoogle Scholar
  41. Shanker G, Aschner M. Methylmercury-induced reactive oxygen species formation in neonatal cerebral astrocytic cultures is attenuated by antioxidants. Mol Brain Res. 2003;110:85–91.PubMedCrossRefGoogle Scholar
  42. Shanker G, Syversen T, Aschner M. Astrocyte-mediated methylmercury neurotoxicity. Biol Trace Elem Res. 2003;95:1–10.PubMedCrossRefGoogle Scholar
  43. Shanker G, Aschner JL, Syversen T, et al. Free radical formation in cerebral cortex astrocytes in culture induced by methylmercury. Mol Brain Res. 2004;128:48–57.PubMedCrossRefGoogle Scholar
  44. Shikiri M, Takanezawa Y, Uchida K, et al. Protection of cerebellar granule cells by tocopherols and tocotrienols against methylmercury toxicity. Brain Res. 2007;1182:106–15.CrossRefGoogle Scholar
  45. Soldin OP, O’Mara DM, Aschner M. Thyroid hormones and methylmercury toxicity. Biol Trace Elem Res. 2008;126:1–12.PubMedCrossRefGoogle Scholar
  46. Takser L, Mergler D, Baldwin M, et al. Thyroid hormones in pregnancy in relation to environmental exposure to organochlorine compounds and mercury. Environ Health Perspect. 2006;113: 1039–45.CrossRefGoogle Scholar
  47. Tamm C, Duckworth J, Hermanson O, et al. High susceptibility of neural stem cells to methylmercury toxicity: effects on cell survival and neuronal differentiation. J Neurochem. 2006;97: 69–78.PubMedCrossRefGoogle Scholar
  48. Toimela T, Tahti H. Mitochondrial viability and apoptosis induced by aluminum, mercuric mercury and methylmercury in cell lines of neural origin. Arch Toxicol. 2004;78:565–74.PubMedCrossRefGoogle Scholar
  49. Vendrell I, Carrascal M, Vilano MT, et al. Cell viability and proteomic analysis in cultured neurons exposed to methylmercury. Hum Exp Toxicol. 2007;26:263–72.PubMedCrossRefGoogle Scholar
  50. Wang L, Jiang H, Yin Z, et al. Methylmercury toxicity and Nrf2-dependent detoxification in astrocytes. Toxicol Sci. 2009;107:135–43.PubMedCrossRefGoogle Scholar
  51. Watanabe J, Nakamachi T, Ogawa T, et al. Characterization of antioxidant protection of cultured neural progenitor cells (NPC) against methylmercury (MeHg) toxicity. J Toxicol Sci. 2009;34:315–25.PubMedCrossRefGoogle Scholar
  52. Yin Z, Milatovic D, Aschner JL, et al. Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes. Brain Res. 2007;1131:1–10.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC  2012

Authors and Affiliations

  1. 1.Department of Environmental and Occupational Health SciencesUniversity of WashingtonSeattleUSA
  2. 2.Department of Human Anatomy, Pharmacology and Forensic ScienceUniversity of Parma Medical SchoolParmaItaly

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