Effects of Methylmercury on Cellular Signal Transduction Systems

  • Fusako Usuki
  • Masatake Fujimura
Part of the Current Topics in Neurotoxicity book series (Current Topics Neurotoxicity, volume 2)


Methylmercury (MeHg) is a major environmental toxicant that affects cellular functions including growth, differentiation, and migration. Dependent upon the cellular context and developmental phase of the cells, various cellular stress responses are induced and cell fate is determined in response to MeHg exposure. MeHg triggers the activation or suppression of cellular signaling pathways in a manner similar to other environmental stressors. Cellular signal transduction systems that are disturbed by MeHg exposure are potential therapeutic targets for MeHg cytotoxicity. This review focuses on the cellular signal transduction systems involved in responses to MeHg exposure, such as mitogen-activated protein kinase cascade, redox signaling pathway, Rho/ROCK signaling pathway, and Notch signaling pathway.


Neural Stem Cell Notch Signaling Axonal Degeneration Cellular Stress Response 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.


  1. Arimura K, Murai Y, Rosales RL, Izumo S. Spinal roots of rats poisoned with methylmercury: physiology and pathology. Muscle Nerve. 1988;11:762–8.PubMedCrossRefGoogle Scholar
  2. Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science. 1995;268:225–32.PubMedCrossRefGoogle Scholar
  3. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284:770–6.PubMedCrossRefGoogle Scholar
  4. Aschner M. Changes in axonally transported proteins in the mature and developing rat nervous system during early stages of methyl mercury exposure. Pharmacol Toxicol. 1987;60:81–5.PubMedCrossRefGoogle Scholar
  5. Belletti S, Oriandini 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;70:703–11.PubMedCrossRefGoogle Scholar
  6. Bito H, Furuyashiki T, Ishihara H, Shibasaki Y, Ohashi K, Mizuno K, Maekawa M, Ishizaki T, Narumiya S. A critical role for a Rho-associated kinase, p160ROCK, in determining axon outgrowth in mammalian CNS neurons. Neuron. 2000;26:431–41.PubMedCrossRefGoogle Scholar
  7. Bland C, Rand MD. Methylmercury induced activation of Notch signaling. Neurotoxicology. 2006;27:982–91.PubMedCrossRefGoogle Scholar
  8. Carvalho CM, Chew EH, Hashemy SI, Lu J, Holmgren A. Inhibition of the human thioredoxin system. A molecular mechanism of mercury toxicity. J Biol Chem. 2008;283:11913–23.PubMedCrossRefGoogle Scholar
  9. Choi BH, Lapham LW, Amin-Zaki L, Saleem T. Abnormal neuronal migration, deranged central cortical organization, and diffuse white matter astrocytosis of human fetal brain: a major effect of methylmercury poisoning in utero. J Neuropathol Exp Neurol. 1978;37:719–33.PubMedCrossRefGoogle Scholar
  10. Dare E, Li W, Zhivotovsky B, Yuan X, Ceccatelli S. Methylmercury and H(2)O(2) provoke lysosomal damage in human astrocytoma D384 cells followed by apoptosis. Free Radic Biol Med. 2001;30:1347–56.PubMedCrossRefGoogle Scholar
  11. Dickson TC, Vickers JC. The morphological phenotype of beta-amyloid plaques and associated neuritic changes in Alzheimer’s disease. Neuroscience. 2001;105:99–107.PubMedCrossRefGoogle Scholar
  12. Fujimura M, Usuki F, Sawada M, Rostene W, Godefroy D, Takashima A. Methylmercury exposure downregulates the expression of Racl and leads to neuritic degeneration and ultimately apoptosis in cerebrocortical neurons. Neurotoxicology. 2009a;30:16–22.PubMedCrossRefGoogle Scholar
  13. Fujimura M, Usuki F, Sawada M, Takashima A. Methylmercury induces neuropathological changes with tau hyperphosphorylation mainly through the activation of c-jun-N-terminal kinase pathway in the cerebral cortex, but not in the hippocampus of the mouse brain. Neurotoxicology. 2009b;30:1000–7.PubMedCrossRefGoogle Scholar
  14. Fujimura M, Usuki F, Kawamura M, Izumo S. Inhibition of the Rho/ROCK pathway prevents neuronal degeneration in vitro and in vivo following methylmercury exposure. Toxicol Appl Pharmacol. 2011;250:1–9.PubMedCrossRefGoogle Scholar
  15. Fukata M, Nakagawa M, Kaibuchi K. Roles of Rho-family GTPases in cell polarization and directional migration. Curr Opin Cell Biol. 2003;15:590–7.PubMedCrossRefGoogle Scholar
  16. Götz ME, Koutsilieri E, Riederer P, Ceccatelli S, Daré E. Methylmercury induces neurite degeneration in primary culture of mouse dopaminergic mesencephalic cells. J Neural Transm. 2002;109: 597–605.PubMedCrossRefGoogle Scholar
  17. Hall A. Rho GTPases and the actin cytoskeleton. Science. 1998;279:509–14.PubMedCrossRefGoogle Scholar
  18. Heidemann SR, Lamourex P, Atchison WD. Inhibition of axonal morphogenesis by nonlethal, submicromolar concentration of methylmercury. Toxicol Appl Pharmacol. 2001;174:49–59.PubMedCrossRefGoogle Scholar
  19. Holmgren A, Lu J. Thioredoxin and thioredoxin reductase: current research with special reference to human disease. Biochem Biophys Res Commun. 2010;396:120–4.PubMedCrossRefGoogle Scholar
  20. Hunter D, Russel DS. Focal cerebral and cerebellar atrophy in a human subject due to organic mercury compounds. J Neurol Neurosurg Psychiatry. 1954;17:235–41.PubMedCrossRefGoogle Scholar
  21. Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997;275:90–4.PubMedCrossRefGoogle Scholar
  22. Igata A. Neurological aspects of methylmercury poisoning in Minamata. In: Tsubaki T, Takahashi H, editors. Recent advances in Minamata disease studies. Tokyo: Kodansha Ltd; 1986. pp. 41–57.Google Scholar
  23. InSug O, Datar S, Koch CJ, Shapiro IM, Shenker BJ. Mercuric compounds inhibit human monocyte function by inducing apoptosis: evidence for formation of reactive oxygen species, development of mitochondrial membrane permeability transition and loss of reductive reserve. Toxicology. 1997;124:211–24.PubMedCrossRefGoogle Scholar
  24. Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Wataneba N, Saito Y, Kakizuka A, Morii N, Narumiya S. The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J. 1996;15:1885–93.PubMedGoogle Scholar
  25. Jackson M, Gentleman S, Lennox G, Ward L, Gray T, Randall K, Morrell K, Lowe J. The cortical neuritic pathology of Huntington’s disease. Neuropathol Appl Neurobiol. 1995;21:18–26.PubMedCrossRefGoogle Scholar
  26. Kubo T, Yamashita T. Rho-ROCK inhibitors for the treatment of CNS injury. Recent Pat CNS Drug Discov. 2007;2:173–9.PubMedCrossRefGoogle Scholar
  27. Kubo T, Tamaguchi A, Iwata N, Yamashita T. The therapeutic effects of Rho-ROCK inhibitors on CNS disorders. Ther Clin Risk Manag. 2008;4:605–15.PubMedGoogle Scholar
  28. Kunimoto M. Methylmercury induces apoptosis of rat cerebellar neurons in primary culture. Biochem Biophys Res Commun. 1994;204:310–7.PubMedCrossRefGoogle Scholar
  29. Kuo TC. The influence of methylmercury on the nitric oxide production of alveolar macrophages. Toxicol Ind Health. 2008;24:531–8.PubMedCrossRefGoogle Scholar
  30. Lei K, Nimnual A, Zong WX, Kennedy NJ, Flavell RA, Thompson CB, Bar-Sagi D, Davix RJ. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH2-terminal kinase. Mol Cell Biol. 2002;22:4929–42.PubMedCrossRefGoogle Scholar
  31. Leung T, Manser E, Tan L, Lim L. A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem. 1995;270: 29051–4.PubMedCrossRefGoogle Scholar
  32. Luo L. Rho GTPases in neuronal morphogenesis. Nat Rev Neurosci. 2000;1:173–80.PubMedCrossRefGoogle Scholar
  33. Masutani H, Ueda S, Yodoi J. The thioredoxin system in retroviral infection and apoptosis. Cell Death Differ. 2005;12:991–8.PubMedCrossRefGoogle Scholar
  34. Matsui T, Amano M, Yamamoto T, Chihara K, Nakafuku M, Ito M, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J. 1996;15:2208–16.PubMedGoogle Scholar
  35. Matsukawa J, Matsuzawa A, Takeda K, Ichijo H. The ASK1-MAP kinase cascades in mammalian stress response. J Biochem. 2004;136:261–5.PubMedCrossRefGoogle Scholar
  36. Mattila PM, Rinne JO, Helenius H, Rőyttä M. Neuritic degeneration in the hippocampus and amygdala in Parkinson’s disease in relation to Alzheimer pathology. Acta Neuropathol. 1999;98:157–64.PubMedCrossRefGoogle Scholar
  37. Mueller BK, Mack H, Teusch N. Rho kinase, a promising drug target for neurological disorders. Nat Rev Drug Discov. 2005;4:387–98.PubMedCrossRefGoogle Scholar
  38. Nagashima K, Fujii Y, Tsukamoto T, Nukuzuma S, Satoh M, Fujita M, Fujioka Y, Akagi H. Apoptotic process of cerebellar degeneration in experimental methylmercury intoxication of rats. Acta Neuropathol. 1996;91:72–7.PubMedCrossRefGoogle Scholar
  39. Narumiya S, Yasuda S. Rho GTPases in animal cell mitosis. Curr Opin Cell Biol. 2006;18: 199–205.PubMedCrossRefGoogle Scholar
  40. Narumiya S, Ishizaki T, Watanabe N. Rho effectors and reorganization of actin cytoskeleton. FEBS Lett. 1997;410:68–72.PubMedCrossRefGoogle Scholar
  41. Negishi M, Katoh H. Rho family GTPases as key regulators for neuronal network formation. J Biochem (Tokyo). 2002;132:157–66.CrossRefGoogle Scholar
  42. Nishimoto S, Nishida E. MAPK signaling: ERK5 versus ERK1/2. EMBO Rep. 2006;7:782–6.PubMedCrossRefGoogle Scholar
  43. Nishioku T, Takai N, Miyamoto K, Murao K, Hara C, Yamamoto K, Nakanishi H. Involvement of caspase 3-like protease in methylmercury-induced apoptosis of primary cultured rat cerebral microglia. Brain Res. 2000;871:160–4.PubMedCrossRefGoogle Scholar
  44. Park ST, Lim KT, Chung YT, Kim SU. Methylmercury-induced neurotoxicity in cerebral neuron culture is blocked by antioxidants and NMDA receptor antagonists. Neurotoxicology. 1996;17:37–45.PubMedGoogle Scholar
  45. Parran DK, Barone Jr S, Mundy WR. Methylmercury inhibits TrkA signaling through the ERK1/2 cascade after NGF stimulation of PC12 cells. Brain Res Dev Brain Res. 2004;149:53–61.PubMedCrossRefGoogle Scholar
  46. Peckham NH, Choi BH. Abnormal neuronal distribution within the cerebral cortex after prenatal methylmercury intoxication. Acta Neuropathol. 1988;76:222–6.PubMedCrossRefGoogle Scholar
  47. Posser T, Dunkley PR, Dickson PW, Franco JL. Human neuroblastoma cells transfected with tyrosine hydroxylase gain increased resistance to methylmercury-induced cell death. Toxicol In Vitro. 2010;24:1498–503.PubMedCrossRefGoogle Scholar
  48. Rand MD, Bland CE, Bond J. Methylmercury activates enhancer-of-split and bearded complex genes independent of the notch receptor. Toxicol Sci. 2008;104:163–76.PubMedCrossRefGoogle Scholar
  49. Riento K, Ridley AJ. Rocks: multifunctional kinases in cell behavior. Nat Rev Mol Cell Biol. 2003;4:446–56.PubMedCrossRefGoogle Scholar
  50. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998;17:2596–606.PubMedCrossRefGoogle Scholar
  51. Shanker G, Aschner M. Methylmercury-induced reactive oxygen species formation in neonatal cerebral astrocytic cultures is attenuated by antioxidants. Brain Res Mol Brain Res. 2003;110:85–91.PubMedCrossRefGoogle Scholar
  52. Shenker BJ, Guo TL, Shapiro IM. Low-level methylmercury exposure causes human T-cells to undergo apoptosis: evidence of mitochondrial dysfunction. Environ Res. 1998;77:149–59.PubMedCrossRefGoogle Scholar
  53. Su M, Kakita A, Wakabayashi K, Yamada M, Takahashi H, Ikuta F. Degeneration of spinal dorsal root ganglia in adult rats treated with methylmercury: chronological observations on the cell bodies, centrally directed axons and presynaptic terminals. Neuropathology. 1997;17:201–7.CrossRefGoogle Scholar
  54. Suriyo T, Thiantanawat A, Chaiyaroj SC, Parkpian P, Satayavivad J. Involvement of the lymphocytic muscarinic acetylcholine receptor in methylmercury-induced c-Fos expression and apoptosis in human leukemic T cells. J Toxicol Environ Health A. 2008;71:1109–23.PubMedCrossRefGoogle Scholar
  55. Takeuchi T., Eto K. Pathology of Minamata Disease. In: Takeuchi T, Eto K, Nakayama H, Sumiyshi A, editors. The pathology of Minamata disease. A tragic story of water pollution. Kyushu University Press, Inc. 1999;53–78.Google Scholar
  56. Tamm C, Duckworth J, Hermanson O, Ceccatelli S. High susceptibility of neural stem cells to methylmercury toxicity: effects on cell survival and neuronal differentiation. J Neurochem. 2006;97:69–78.PubMedCrossRefGoogle Scholar
  57. Tamm C, Duckworth JK, Hermanson O, Ceccatelli S. Methylmercury inhibits differentiation of rat neural stem cells via Notch signaling. Neuroreport. 2008;12:339–43.CrossRefGoogle Scholar
  58. Tomasevic N, Jia Z, Russell A, Fujii T, Hartman JJ, Clancy S, Wang M, Beraud C, Wood KW, Sakowicz R. Differential regulation of WASP and N-WASP by Cdc42, Rac1, NCK, and PI (4,5) P2. Biochemistry. 2007;46:3494–502.PubMedCrossRefGoogle Scholar
  59. Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y, Yoshioka K, Masuyama N, Gotoh Y. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J. 2004;23:1889–99.PubMedCrossRefGoogle Scholar
  60. Usuki F, Ishiura S. Expanded CTG repeats in myotonin protein kinase increase susceptibility to oxidative stress. Neuroreport. 1998;9:2291–6.PubMedCrossRefGoogle Scholar
  61. Usuki F, Yasutake A, Matsumoto M, Umehara F, Higuci I. The effect of methylmercury on skeletal muscle in the rat: a histopathological study. Toxicol Lett. 1998;94:227–32.PubMedCrossRefGoogle Scholar
  62. Usuki F, Takahashi N, Sasagawa N, Ishiura S. Differential signaling pathways following oxidative stress in mutant myotonin protein kinase cDNA-transfected C2C12 cell lines. Biochem Biophys Res Commun. 2000;267:739–43.PubMedCrossRefGoogle Scholar
  63. Usuki F, Yasutake A, Umehara F, Tokunaga H, Matsumoto M, Eto K, Ishiura S, Higuchi I. In vivo protection of a water-soluble derivative of vitamin E, Trolox, against methylmercury-intoxication. Neurosci Lett. 2001;304:199–203.PubMedCrossRefGoogle Scholar
  64. Usuki F, Yasutake A, Umehara F, Higuchi I. Beneficial effects of mild lifelong dietary restriction on skeletal muscle: prevention of age-related mitochondrial damage, morphological changes, and vulnerability to a chemical toxin. Acta Neuropathol. 2004;108:1–9.PubMedCrossRefGoogle Scholar
  65. Usuki F, Fujita E, Sasagawa N. Methylmercury activates ASK1/JNK signaling pathways, leading to apoptosis due to both mitochondria- and endoplasmic reticulum (ER)-generated processes in myogenic cell lines. Neurotoxicology. 2008;29:22–30.PubMedCrossRefGoogle Scholar
  66. Usuki F, Yamashita A, Fujimura M. Posttranscriptional defects of antioxidant seleno-enzymes cause oxidative stress under methyl- mercury exposure. J Biol Chem. 2011;286:6641–9.PubMedCrossRefGoogle Scholar
  67. Ventura JJ, Hubner A, Zhang C, Flavell RA, Shokat KM, Davis RJ. Chemical genetic analysis of the time course of signal transduction by JNK. Mol Cell. 2006;2:701–10.CrossRefGoogle Scholar
  68. Wilke RA, Kolbert CP, Rahimi RA, Windebank AJ. Methylmercury induces apoptosis in cultured rat dorsal root ganglion neurons. Neurotoxicology. 2003;24:369–78.PubMedCrossRefGoogle Scholar
  69. Willison DT, Polunas MA, Zhou R, Halladay AK, Lowndes HE, Reuhl KR. Methylmercury alters Eph and ephrin expression during neuronal differentiation of P19 embryonal carcinoma cells. Neurotoxicology. 2005;26:661–74.CrossRefGoogle Scholar
  70. Xu M, Yan C, Tian Y, Yuan X, Shen X. Effect s of low level of methylmercury on proliferation of cortical progenitor cells. Brain Res. 2010;1359:272–80.PubMedCrossRefGoogle Scholar
  71. Yee S, Choi BH. Methylmercury poisoning induces oxidative stress in the mouse brain. Exp Mol Pathol. 1994;60:188–96.PubMedCrossRefGoogle Scholar
  72. Yee S, Choi BH. Oxidative stress in neurotoxic effects of methylmercury poisoning. Neuro­toxicology. 1996;17:17–26.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC  2012

Authors and Affiliations

  1. 1.Department of Clinical MedicineNational Institute for Minamata DiseaseMinamata CityJapan
  2. 2.Department of Basic Medical SciencesNational Institute for Minamata DiseaseMinamata CityJapan

Personalised recommendations