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Biological Trace Element Research

, Volume 95, Issue 1, pp 1–10 | Cite as

Astrocyte-mediated methylmercury neurotoxicity

  • Gouri Shanker
  • Tore Syversen
  • Michael Aschner
Article

Abstract

Methylmercury (MeHg) is a potent neurotoxicant. Any source of environmental mercury represents a potential risk for human MeHg poisoning, because the methylation of inorganic mercury to MeHg in waterways results ultimately in its accumulation in the sea food chain, which represents the most prevalent source for human consumption. A small amount of MeHg accumulates in the central nervous system (CNS), particularly in astrocytes. Astrocytic swelling, excitatory amino acid (EAA) release and uptake inhibition, as well as EAA transporter expression inhibition are known sequelae of MeHg exposure. Herein, we review the effect of MeHg on additional transport systems (for cystine and cysteine) as well as arachidonic acid (AA) release and cytosolic phospholipase A2 (cPLA2) regulation and attempt to integrate the effects of MeHg in astrocytes within a mechanistic hypothesis that explains the inability of these cells to maintain control of the proper milieu of the extracellular fluid and, in turn, leads to neuronal demise.

Index Entries

Astrocytes methylmercury cystine cysteine cytosolic phospholipase A2 in vitro 

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References

  1. 1.
    T. Kjellstrom, P. Kennedy, S. Wallis, et al., Physical and mental development of children with prenatal exposure to mercury from fish. Stage II: interviews and psychological tests at age 6. National Swedish Environmental Protection Board Report 3642, Solna, Sweden (1989).Google Scholar
  2. 2.
    P. Grandjean, P. Weihe, R. F. White, et al., Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury, Neurotoxicol. Teratol. 19, 417–428 (1997).PubMedCrossRefGoogle Scholar
  3. 3.
    P. W. Davidson, G. J. Myers, C. Cox, et al., Effects of prenatal and postnatal methylmercury exposure from fish consumption on neurodevelopment: outcomes at 66 months of age in the Seychelles child development study, JAMA 280, 701–707 (1998).PubMedCrossRefGoogle Scholar
  4. 4.
    M. Aschner and H. K. Kimelberg, eds., The Role of Glia in Neurotoxicity, CRC, Boca Raton, FL (1996).Google Scholar
  5. 5.
    S. Murphy, ed., Astrocytes: Pharmacology and Function, Academic, New York (1995).Google Scholar
  6. 6.
    H. Kettenmann and B. R. Ransom, eds., Neuroglia, Oxford University Press, New York (1995).Google Scholar
  7. 7.
    M. Aschner, J. W. Allen, H. K. Kimelberg, R. M. LoPachin, and J. W. Streit, Glial cells in neurotoxicity development, Annu. Rev. Pharmacol. Toxicol. 39, 151–173 (1999).PubMedCrossRefGoogle Scholar
  8. 8.
    M. Aschner, N. B. Eberle, S. Goderie, and H. K. Kimelberg, Methylmercury uptake in rat primary astrocyte cultures: the role of the neutral amino acid transport system, Brain Res. 521, 221–228 (1990).PubMedCrossRefGoogle Scholar
  9. 9.
    V. Dave, K. J. Mullaney, S. Godorie, H. K. Kimelberg, and M. Aschner, Astrocytes as mediators of methylmercury neurotoxicity: effects on d-aspartate and serotonin uptake, Dev. Neurosci. 16, 222–231 (1994).PubMedGoogle Scholar
  10. 10.
    N. Brookes, In vitro evidence for the role of glutamate in the CNS toxicity of mercury, Toxicology 76, 245–256 (1992).PubMedCrossRefGoogle Scholar
  11. 11.
    E. Matyja and J. Albrecht, Ultrastructural evidence that mercuric chloride lowers the threshold for glutamate neurotoxicity in an organotypic culture of rat cerebellum, Neurosci. Lett. 158, 155–158 (1993).PubMedCrossRefGoogle Scholar
  12. 12.
    R. H. Garman, B. Weiss, and H. L. Evans, Alkylmercurial encephalopathy in the monkey: a histopathologic and autoradiographic study, Acta Neuropathol. (Berlin) 32, 61–74 (1975).CrossRefGoogle Scholar
  13. 13.
    M. Aschner, D. Vitarella, J. W. Allen, D. R. Conklin, and K. S. Cowan, Methylmercury-induced inhibition of regulatory volume decrease in astrocytes: characterization of osmoregulator efflux and its reversal by amiloride, Brain Res. 811, 133–142 (1998).PubMedCrossRefGoogle Scholar
  14. 14.
    M. E. Anderson and A. Meister, Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis, Proc. Natl. Acad. Sci. USA 80, 707–711 (1983).PubMedCrossRefGoogle Scholar
  15. 15.
    S. J. Stohs and D. Bagchi, Oxidative mechanisms in the toxicity of metal ions, Free Radical Biol. Med. 18, 321–336 (1995).CrossRefGoogle Scholar
  16. 16.
    M. Aschner, K. J. Mullaney, D. Wagoner, L. H. Lash, and H. K. Kimelberg, Intracellular glutathione (GSH) levels modulate mercuric chloride (MC)- and methylmercuric chloride (MeHgCl)-induced amino acid release from neonatal rat primary astrocytes cultures, Brain Res. 664, 133–140 (1994).PubMedCrossRefGoogle Scholar
  17. 17.
    J. Sagara, K. Miura, and S. Bannai, Maintenance of neuronal glutathione by glial cells, J. Neurochem. 61, 1672–1676 (1993).PubMedCrossRefGoogle Scholar
  18. 18.
    S. F. Ali, C. P. LeBel, and S. C. Bondy, Reactive oxygen species formation as a biomarker of methylmercury and trimethyltin neurotoxicity, Neurotoxicology 13, 637–648 (1992).PubMedGoogle Scholar
  19. 19.
    O. Sorg, B. Schilter, P. Honegger, and F. Monnet-Tschudi, Increased vulnerability of neurons and glial cells to low concentrations of methylmercury in a prooxidant situation, Acta Neuropathol. (Berlin) 96, 621–627 (1998).CrossRefGoogle Scholar
  20. 20.
    S. Bannai and N. Tateishi, Role of membrane transport in metabolism and function of glutathione in mammals, J. Membr. Biol. 89, 1–8 (1986).PubMedCrossRefGoogle Scholar
  21. 21.
    M. A. Dichter, Rat cortical neurons in cell culture: culture methods, cell morphology, electrophysiology and synapse formation, Brain Res. 149, 279–293 (1978).PubMedCrossRefGoogle Scholar
  22. 22.
    R. Dringen, B. Pfeiffer, and B. Hamprecht, Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione, J. Neurosci. 19, 562–569 (1999).PubMedGoogle Scholar
  23. 23.
    K. Miura and T. W. Clarkson, Reduced methylmercury accumulation in a methylmercury-resistant rat pheochromocytoma PC12 cell line, Toxicol. Appl. Pharmacol. 118, 39–45 (1993).PubMedCrossRefGoogle Scholar
  24. 24.
    B. H. Choi, S. Yee, and M. Robles, The effects of glutathione glycoside in methylmercury poisoning, Toxicol. Appl. Pharmacol. 141, 357–364 (1996).PubMedCrossRefGoogle Scholar
  25. 25.
    K. J. Mullaney, M. N. Fehm, D. Vitarella, D. E. Wagoner, Jr., and M. Aschner, The role of -SH groups in methylmercuric chloride induced d-aspartate and rubidium release from rat primary astrocyte cultures, Brain Res. 641, 1–9 (1994).PubMedCrossRefGoogle Scholar
  26. 26.
    S. T. Park, K. T. Lim, Y. T. Chung, and S. U. Kim, Methylmercury-induced neurotoxicity in cerebral neuron culture is blocked by antioxidants and NMDA receptor antagonists, Neurotoxicology 17, 37–46 (1996).PubMedGoogle Scholar
  27. 27.
    E. O’Connor, A. Devesa, C. Garcia, I. R. Puertes, A. Pellin, and J. R. Vina, Biosynthesis and maintenance of GSH in primary astrocyte cultures: role of l-cystine and ascorbate, Brain Res. 680, 157–163 (1995).PubMedCrossRefGoogle Scholar
  28. 28.
    J. Sagara, K. Miura, and S. Bannai, Cystine uptake and glutathione level in fetal brain cells in primary culture and in suspension, J. Neurochem. 61, 1667–1671 (1993).PubMedCrossRefGoogle Scholar
  29. 29.
    X. F. Wang and M. S. Cyander, Astrocytes provide cysteine in neurons by releasing glutathione, J. Neurochem. 74, 1434–1442 (2000).PubMedCrossRefGoogle Scholar
  30. 30.
    J. W. Allen, G. Shanker, and M. Aschner, Methylmercury inhibits the in vitro uptake of the glutathione precursor, cystine, in astrocytes, but not in neurons, Brain Res. 894, 131–140 (2001).PubMedCrossRefGoogle Scholar
  31. 31.
    G. Shanker and M. Aschner, Identification and characterization of uptake systems for cystine and cysteine in cultured astrocytes and neurons: evidence for methylmercury-targeted disruption of astrocytic transport, J. Neurosci. Res. 66, 998–1002 (2001).PubMedCrossRefGoogle Scholar
  32. 32.
    T. H. Murphy, R. L. Schnaar, and J. T. Coyle, Immature cortical neurons are uniquely sensitive to glutamate sensitivity by inhibition of cystine uptake, FASEB J. 4, 1624–1633 (1990).PubMedGoogle Scholar
  33. 33.
    Y. Sagara and D. Schubert, The activation of metabotropic glutamate receptors protects nerve cells from oxidative stress, J. Neurosci. 18, 6662–6671 (1998).PubMedGoogle Scholar
  34. 34.
    H. Sato, M. Tamba, T. Ishii, and S. Bannai, Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins, J. Biol. Chem. 274, 11,455–11,458 (1999).Google Scholar
  35. 35.
    H. Sato, M. Tamba, K. Kuriyama-Matsumura, S. Okuno, and S. Bannai, Molecular cloning and expression of human xCT, the light chain of amino acid transport system Xc-, Antioxid. Redox Signal 2, 665–671 (2000).PubMedCrossRefGoogle Scholar
  36. 36.
    A. Y. Shih and T. H. Murphy, xCT cystine transporter expression in HEK293 cells: pharmacology and localization, Biochem. Biophys. Res. Commun. 282, 1132–1137 (2001).PubMedCrossRefGoogle Scholar
  37. 37.
    M. T. Bassi, E. Gasol, M. Manzoni, et al., Identification and characterization of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc-, Pflugers Arch. 442, 286–296 (2001).PubMedCrossRefGoogle Scholar
  38. 38.
    J. Y. Kim, Y. Kanai, A. Chairoungdua, et al., Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells, Biochim. Biophys. Acta 1512, 335–344 (2001).PubMedCrossRefGoogle Scholar
  39. 39.
    J. Flynn and G. J. McBean, Kinetic and pharmacological analysis of L-[35S]-cystine transport into rat brain synaptosomes, Neurochem. Int. 36, 513–521 (2000).PubMedCrossRefGoogle Scholar
  40. 40.
    A. S. Bender, W. Reichelt, and M. D. Norenberg, Characterization of cystine uptake in cultured astrocytes, Neurochem. Int. 37, 269–276 (2000).PubMedCrossRefGoogle Scholar
  41. 41.
    G. Shanker, J. W. Allen, L. A. Mutkus, and M. Aschner, The uptake of cysteine in cultured primary astrocytes and neurons, Brain Res. 902, 156–163 (2001).PubMedCrossRefGoogle Scholar
  42. 42.
    D. M. Bukowski, S. M. Deneke, R. A. Lawrence, and S. G. Jenkinson, A non-inducible cystine transport system in rat alveolar type II cells, Am. J. Physiol. 268, L21-L26 (1995).PubMedGoogle Scholar
  43. 43.
    G. Shanker, J. W. Allen, L. A. Mutkus, and M. Aschner, Methyl-mercury inhibits cysteine uptake in cultured primary astrocytes, but not in neurons, Brain Res. 914, 159–165 (2001).PubMedCrossRefGoogle Scholar
  44. 44.
    M. Aschner, C. P. Yao, J. W. Allen, and K. H. Tan, Methylmercury alters glutamate transport in astrocytes, Neurochem. Int. 37, 199–206 (2000).PubMedCrossRefGoogle Scholar
  45. 45.
    J. S. Charleston, R. L. Body, R. P. Bolander, N. K. Mottet, M. E. Vahter, and T. M. Burbacher, Changes in the number of astrocytes and microglia in the thalamus of the monkey Macaca fascicularis following long-term subclinical methylmercury exposure, Neurotoxicology 17, 127–138 (1996).PubMedGoogle Scholar
  46. 46.
    T. A. Sarafian, D. E. Bredesen, and M. A. Verity, Cellular resistance to methylmercury, 17, 27–36 (1996).Google Scholar
  47. 47.
    A. Sapirstein, R. A. Spech, R. Witzgall, and J. V. Bonventre, Cytosolic phospholipase A2 (cPLA2), but not secretory PLA2, potentiates hydrogen peroxide cytotoxicity in kidney epithelial cells, J. Biol. Chem. 271, 21,505–21,513 (1996).Google Scholar
  48. 48.
    J. A. Clemens, D. T. Stephenson, E. B. Smalstig, et al., Reactive glia express cytosolic phospholipase A2 after transient global forebrain ischemia in the rats, Stroke 27, 527–535 (1996).PubMedGoogle Scholar
  49. 49.
    D. Trotti, N. C. Danbolt, and A. Volterra, Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends Pharmacol. Sci. 19, 328–334 (1998).PubMedCrossRefGoogle Scholar
  50. 50.
    G. Shanker, L. A. Mutkus, S. J. Walker, and M. Aschner, Methylmercury enhances arachidonic acid release and cytosolic phospholipase A2 expression in primary cultures of neonatal astrocytes, Mol. Brain Res. 106, 1–11 (2002).PubMedCrossRefGoogle Scholar
  51. 51.
    W. J. Lukiw and N. G. Bazan, Neuro-inflammatory signaling upregulation in Alzheimer’s disease, Neurochem. Res. 25, 1173–1184 (2000).PubMedCrossRefGoogle Scholar
  52. 52.
    Z. Wu, D. R. Turner, and D. B. Oliveira, IL-4 gene expression up-regulated by mercury in rat mast cells: a role of oxidant stress in IL-4 transcription, Int. Immunol. 13, 297–304 (2001).PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Gouri Shanker
    • 1
  • Tore Syversen
    • 3
  • Michael Aschner
    • 1
    • 2
  1. 1.Department of Physiology and PharmacologyWake Forest University School of Medicine, Medical Center BoulevardWinston-Salem
  2. 2.Interdisciplinary Program in NeuroscienceWake Forest University School of Medicine, Medical Center BoulevardWinston-Salem
  3. 3.Department of NeuroscienceNorwegian University of Science and TechnologyTrondheimNorway

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