Effects of Methylmercury on the Developing Brain

  • Ben H. Choi
Chapter
Part of the Rochester Series on Environmental Toxicity book series (RSET)

Abstract

In an attempt to elucidate the mechanisms of methylmercury (MeHg) action on the developing brain, MeHg effects on neuronal migration and on proliferative neuroepithelial germinal cells within the ventricular zone of telencephalic vesicles were investigated in C57BL/6J mice. 3H-thymidine autoradiographic studies following acute and chronic MeHg intoxication in embryonic mice showed that heavily labeled neurons (generated on E-16) within specified regions of the cerebral cortex of prenatally intoxicated offspring were distributed irregularly throughout layers II and III, whereas those in controls were tightly clustered within the upper part of layer II. These findings support the hypothesis that prenatal MeHg poisoning results in anomalous cytoarchitectonic patterning of the cerebral cortex, and provide a possible morphological basis for some of the neurobehavioral abnormalities that may follow sublethal prenatal MeHg intoxication. Whether the irregular distribution of labeled neurons was due to the effects of MeHg on the dividing neuroepithelial germinal cells, on the process of neuronal migration, or on the final positioning of postmigratory neurons within the cerebral cortex remained unclear. Ultrastructural studies of telencephalic vesicles during acute phases of MeHg intoxication revealed the presence of acute degenerative changes within ventricular cells, characterized by spongy change and vacuolization of the cytoplasmic matrix and by loss of microtubules. 3H-thymidine autoradiography demonstrated features suggestive of disturbed interkinetic nuclear migration. Also noted were reduction of the mitotic indices of neuroepithelial germinal cells at the ventricular surface at 4 to 12 hours and early-phase mitotic arrest. These findings suggest that MeHg exerts significant effects on proliferating neuroepithelial germinal cells during the acute phases of MeHg poisoning, and may eventually affect the architectonic makeup of the cortical plate as the brain matures. Additional studies in our laboratory demonstrated 1) a failure of histotypic re-organization of dissociated embryonic cerebral cortical cells in rotation-mediated re-aggregation culture, 2) disturbances in neural cell adhesion molecule expression in PC12 cells, 3) modifications in the density of excitatory neurotransmitter L-glutamate receptors, 4) marked disturbances in the glutamate uptake mechanism of fetal astrocytes in vitro, and 5) reductions in cholinoceptive muscarinic receptor (M1 and M2) binding in selected regions of the cerebrum. Thus, MeHg may affect the developing brain through diverse pathogenetic pathways. Possible effects of mercurial compounds on the interaction between certain serine proteases and protease inhibitors during brain development are also discussed.

Keywords

Neural Cell Adhesion Molecule Neuronal Migration Minamata Disease Fetal Astrocyte Interkinetic Nuclear Migration 
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References

  1. Abe, T., Haga, T. and Kurokawa, M., 1975. Blockage of axoplasmic transport and depolymerication of reassembled microtubules by methylmercury. Brain Res. 86:504–508.PubMedCrossRefGoogle Scholar
  2. Amin-Zaki, L., Elhassani, S., Majeed, M. A., Clarkson, T. W., Doherty, R. A. and Greenwood, M. S., 1974. Intra-uterine methylmercury poisoning in Iraq. Pediat. 54:587–595.Google Scholar
  3. Amin-Zaki, L., Elhassani, S., Majeed, M. A., Clarkson, T. W., Greenwood, M. S. and Giovanoli-Jakubezak, T., 1976. Perinatal methylmercury poisoning in Iraq. Amer. J. Dis. Child 130:1070–1076.PubMedGoogle Scholar
  4. Baker, J. B., Low, D. A., Simmer, R. L. and Cunningham, D. D., 1980. Proteasenexin: a cellular component that links thrombin and plasminogen activator and mediates their binding to cells. Cell 21:37–45.PubMedCrossRefGoogle Scholar
  5. Brookes, N., 1988. Specificity and reversibility of the inhibition by HgCl2 of glutamate transport in astrocyte cultures. J. Neurochem. 50:1117–1122.PubMedCrossRefGoogle Scholar
  6. Cavanaugh, K., Kurwitz, D., Cunningham, D. and Bradshaw, R., 1990. Reciprocal modulation of astrocyte stellation by thrombin and protease nexin-1. J. Neurochem. 54:1735–1743.PubMedCrossRefGoogle Scholar
  7. Chang, L. W. and Hartmann, H. A., 1972. Blood-brain barrier dysfunction in experimental mercury intoxication. Acta Neuropathol. (Berl.) 21:179–184.CrossRefGoogle Scholar
  8. Chang, L. W., Reuhl, K. R., and Lee, G. W., 1977. Degenerative changes in the developing nervous system as a result of in utero exposure to methylmercury. Environ. Res. 14:414–423.PubMedCrossRefGoogle Scholar
  9. Choi, B. H., 1981. Radial glia of developing human fetal spinal cord: Golgi, immunohistochemical and electron microscopic study. Dev. Brain Res. 1:249–267.CrossRefGoogle Scholar
  10. Choi, B. H., 1984. Cellular and subcellular demonstration of mercury in situ by modified sulfide-silver technique and photoemulsion histochemistry. Exp. Mol. pathol. 40:109–121.PubMedCrossRefGoogle Scholar
  11. Choi, B. H., 1986. Glial fibrillary acidic protein in radial glia of early human fetal cerebrum: A light and electron microscopic immunoperoxidase study. J. Neuropathol. Exp. Neurol. 45:408–418.PubMedCrossRefGoogle Scholar
  12. Choi, B. H., 1988a. Developmental events during the early stages of cerebral cortical neurogenesis in man: A correlative light, electron microscopic, immunohistochemical and Golgi study. Acta Neuropath. (Berl.) 75:441–447.CrossRefGoogle Scholar
  13. Choi, B. H., 1988b. Effects of methylmercury on developing fetal astrocytes. In: The biochemical pathology of astrocytes. M. D. Norenberg, L. Hertz, and A. Schousboe, eds. Alan R. Liss, Inc., New York, pp. 219–230.Google Scholar
  14. Choi, B. H., 1989. The effects of methylmercury on the developing brain. Prog. Neurobiol. 32:447–470.PubMedCrossRefGoogle Scholar
  15. Choi, B. H., 1991. Effects of methylmercury on neuroepithelial germinal cells in the developing telencephalic vesicles of mice. Acta Neuropath. 81:359–365.PubMedCrossRefGoogle Scholar
  16. Choi, B. H. and Ahn, B. T., 1989. Effects of methylmercury upon dissociated embryonic rat brain cells in rotation-mediated re-aggregation culture. Fed. Proc. 3:A291.Google Scholar
  17. Choi, B. H. and Lapham, L. W., 1978. Radial glia in the human fetal cerebrum: A combined Golgi, electron microscopic and immunofluorescent study. Brain Res. 148:295–311.PubMedCrossRefGoogle Scholar
  18. Choi, B. H. and Lapham, L. W., 1981. Effects of meso-2–3-dimercaptosuccinic acid on methylmercury-injured human fetal astrocytes in vitro. Exp. Mol. Pathol. 34:25–53.CrossRefGoogle Scholar
  19. Choi, B. H. and Simpkins, H., 1986. Changes in the molecular structure of mouse fetal astrocyte produced in vitro by methylmercury chloride. Environ. Res. 39:321–330.PubMedCrossRefGoogle Scholar
  20. Choi, B. H., Cho, K. H. and Lapham, L. W., 1981. Effects of methylmercury on human fetal neurons and astrocytes in vitro: A time-lapse cinematographic, phase and electron microscopic study. Environ. Res. 24:61–74.PubMedCrossRefGoogle Scholar
  21. Choi, B. H., Lapham, L. W., Amin-Zaki, L. and Saleem, T., 1978. Abnormal neuronal migration, deranged cerebral cortical organization, and diffuse white matter astrocytosis of human fetal brain: A major effect of methylmercury poisoning in utero. J. Neuropathol Exper. Neurol. 37:719–733.CrossRefGoogle Scholar
  22. Choi, B. H., Lincoln, J. and Amodei, P., 1988. Effects of methylmercury on excitatory amino acid receptors in the mouse cerebrum. Soc. for Neurosci 14:886.Google Scholar
  23. Choi, B. H., Suzuki, M., Kim, T., Wagner, S. L. and Cunningham, D. D., 1990. Protease nexin-1: Localization in human brain suggests a protective role against extravasated serine proteases. Amer. J.Pathol. 137:741–747.Google Scholar
  24. Chuong, C. and Edelman, G. M., 1984. Alterations in neural cell adhesion molecules during development of different regions of the nervous system. J. Neurosci. 4:2354–2368.PubMedGoogle Scholar
  25. Clarkson, T. W., 1987. Metal toxicity in the central nervous system. Environ. Heatlh Perspect. 75:59–64.CrossRefGoogle Scholar
  26. Eaton, D. L. and Baker, J. B., 1983. Evidence that a varieyt of cultured cells secrete protease nexin and produce a distinct cytoplasmic serine protease-binding factor. J. Cell Physiol. 117:175–182.PubMedCrossRefGoogle Scholar
  27. Edelman, G., 1984. Cell adhesion and morphogenesis: The regulator hypothesis. Proc. Natl. Acad. Sci. U.S.A. 81:1460–1464.PubMedCrossRefGoogle Scholar
  28. Fuyuta, M., Fujimoto, T. and Hirata, S., 1978. Embryotoxic effects of methylmercury chloride administered to mice and rats during organogenesis. Teratol. 18:353–366.CrossRefGoogle Scholar
  29. Gloor, S., Odink, K., Guenther, J., Nick, H. and Monard, D., 1986. A glia-derived neurite promoting factor with protease inhibitory activity belongs to the proteasee nexins. Cell 47:687–693.PubMedCrossRefGoogle Scholar
  30. Harada, Y., 1968. Clinical investigations of Minamata disease: C. congenital (or fetal) Minamata disease. In: Minamata Disease. M. Kutsuna, ed. Kumamoto University Press, Japan, pp. 93–117.Google Scholar
  31. Harada, M., 1976. Minamata Disease, Chronology and Medial Report. Bulletin of the Constitutional Medicine. Kumamoto University Press, Japan, pp. 1–78.Google Scholar
  32. Harada, M., 1978. Congenital Minamata disease: Intrauterine methylmercury poisoning. Teratol. 18:285–288.CrossRefGoogle Scholar
  33. Harris, S. B., Wilson, J. G. and Prinz, R. H., 1972. Embryotoxicity of methylmercuric chloride in golden hamster. Teratol. 6:139–142.CrossRefGoogle Scholar
  34. Honegger, P. and Richelson, E., 1977. Biochemical differentiation of aggregating cell cultures of different fetal rat brain regions. Brain Res. 109:335–354.CrossRefGoogle Scholar
  35. Inouye, M. and Kajiwara, Y., 1988. Developmental disturbances of the fetal brain in guinea-pigs caused by methylmercury. Toxicol. 7:227–232.Google Scholar
  36. Inouye, M. and Kajiwara, Y., 1990. Strain difference of the mouse in manifestation of hydrocephalus following prenatal methylmercury exposure. Teratol. 41:205–210.CrossRefGoogle Scholar
  37. Kim, P. and Choi, B. H., 1990. Effects of mercury on glutamate uptake in cultured mouse astrocytes. Fed. Proc. 4:A1014.Google Scholar
  38. Kleinschuster, S. J., Yoneyama, M. and Sharma, R. P., 1983. A cell aggregation model for the protective effect of selenium and vitamin E on methylmercury toxicity. Toxicol. 26:1–9.CrossRefGoogle Scholar
  39. Kostyniak, P. J., 1982. Mobilization and removal of methylmercury in the dog during extracorporeal complexing hemodialysis with 2,3-dimercaptosuccinic acid (DMSA). J. Pharmacol. Exp. Ther. 221:63–68.PubMedGoogle Scholar
  40. Lu, E. J., Brown, W. J., Cole, R. and deVellis, J., 1980. Ultrastructural differentiation and synaptogenesis in aggregating rotation cultures of rat cerebral cells. J. Neurosci. Res. 5:447–463.PubMedCrossRefGoogle Scholar
  41. Magos, L., 1976. The effects of dimercaptosuccinic acid on the excretion and distribution of mercury in rats and mice treated with mercuric chloride and methylmercury chloride. Br. J. Pharm. 56:479–484.CrossRefGoogle Scholar
  42. Margolis, R. L. and Wilson, L., 1981. Microtubule treadmills-possible molecular machinery. Nature 293:705–711.PubMedCrossRefGoogle Scholar
  43. Marsh, D. O., Myers, G. J., Clarkson, T. W., Amin-Zaki, L., Tikriti, S. and Majeed, M. A., 1980. Fetal methylmercury poisoning: clinical and toxicological data on 29 cases. Ann. Neurol. 7:348–353.PubMedCrossRefGoogle Scholar
  44. McGrogan, M., Kennedy, J., Li, M. P., Hsu, C., Scott, R. W., Simonsen, C. C. and Baker, J. B., 1988. Molecular cloning and expression of two forms of human protease nexin 1. Bio/Technol. 6:172–177.CrossRefGoogle Scholar
  45. Miura, K., Suzuki, K. and Imura, N., 1978. Effects of methylmercury on mitotic mouse glioma cells. Environ. Res. 17:453–471.PubMedCrossRefGoogle Scholar
  46. Miura, K., Inokawa, M. and Imura, N., 1984. Effects of methylmercury and some metal ions on microtubule networks in mouse glioma cells and in vitro tubulin polymerization. Toxicol. Appl. Pharmacol. 73:218–231.PubMedCrossRefGoogle Scholar
  47. Mottet, N. K., Shaw, C. and Burbacher, T. M., 1987. The pathological lesions of methylmercury intoxication in monkeys. In: The Toxicity of Methyl Mercury. C. U. Eccles, and Z. Annau, eds. Johns Hopkins University Press, Baltimore, pp. 73–103.Google Scholar
  48. Murakami, U., 1972. The effects of organic mercury on intrauterine life. Adv. Exp. Med. Biol. 27:310–336, 1972.Google Scholar
  49. Olson, F. C. and Massaro, E. J., 1977. Effects of methyl mercury on murine fetal amino acid uptake, protein synthesis and palate closure. Teratology 16:187–194.PubMedCrossRefGoogle Scholar
  50. Orkand, P. M., Linder, J. and Schachner, M., 1984. Specificity of histiotypic organization and synaptogenesis in reaggregating cell cultures of mouse cerebellum. Dev. Brain Res. 16:119–134.CrossRefGoogle Scholar
  51. Peckham, N. J. and Choi, B. H., 1986. Surface charge alterations in mouse fetal astrocytes due to methylmercury: An ultrastructural study with cationized ferritin. Exp. Mol. Pathol. 44:230–234.PubMedCrossRefGoogle Scholar
  52. Peckham, N. H. and Choi, B. H., 1988. Abnormal neuronal distribution within the cerebral cortex after prenatal methylmercury intoxication. Acta Neuropath. (Berl.) 76:222–226.CrossRefGoogle Scholar
  53. Rakic, P., 1972. Mode of cell migration to the superficial layers of fetal monkey neocortex. J. Comp. Neurol. 145:61–84.PubMedCrossRefGoogle Scholar
  54. Ramel, C., 1969. Methyl mercury as a mitosis disturbing agent. J. Japan Med. Assn. 61:1072–1077.Google Scholar
  55. Reuhl, K. R. and Chang, L. W., 1979. Effects of methylmercury on the development of the nervous system. Neurotoxicol. 1:21–55.Google Scholar
  56. Rodier, P. M., 1983. Critical processes in CNS development and the pathogenesis of early injuries. In: Reproductive and Developmental Toxicity of Metals. T. W. Clarkson, G. F. Nordberg and P. R. Sager, eds. Plenum Press, New York and London, pp. 455–471, 1983.CrossRefGoogle Scholar
  57. Rodier, P. M., Aschner, M. and Sager, P. M., 1984. Mitotic arrest in the developing CNS after prenatal exposure to methylmercury. Neurobehav. Toxicol. Teratol. 6:379–385.PubMedGoogle Scholar
  58. Rosenblatt, D. E., Cotman, C. W., Nieto-Sampedro, M., Rowe, J. W. and Knauer, D. J., 1987. Identification of a protease inhibitor produced by astrocytes that is structurally and functionally homologous to human protease nexin-1. Brain Res. 415:40–48.PubMedCrossRefGoogle Scholar
  59. Sager, P. R., Doherty, R. A., and Rodier, P. M., 1982. Effects of methylmercury on developing mouse cerebellar cortex. Exp. Neurol. 77:179–193.PubMedCrossRefGoogle Scholar
  60. Shen, V., Amodei, P. and Choi, B. H., 1989. Expression of neural cell adhesion molecule in PC12 cells following methylmercury exposure: immunofluorescent, phase and EM study. Fed. Proc. 3:A29.Google Scholar
  61. Spyker, J. M. and Smithberg, M., 1972. Effects of methylmercury on prenatal development in mice. Teratology 5:181–190.PubMedCrossRefGoogle Scholar
  62. Steinwall, O. and Olsson, Y., 1969. Impairment of the blood-brain barrier in mercury poisoning. Acta Neurol. Scandinav. 45:351–361.CrossRefGoogle Scholar
  63. Su, M. and Okita, G., 1976. Embryocidal and teratogenic effects of methylmercury in mice. Toxicol. Appl. Pharmacol. 38:207–216.PubMedCrossRefGoogle Scholar
  64. Takeuchi, T., 1977. Pathology of fetal Minamata disease. Pediatrician 6:69–87.Google Scholar
  65. Trapp, B. D., Honegger, P., Richeson, E. and DeF. Webster, H., 1979. Morphological differentiation of mechanically dissociated fetal rat brain in aggregating cell cultures. Brain Res. 160:117–130.PubMedCrossRefGoogle Scholar
  66. Vogel, D. G., Margolis, R. L. and Mottet, N. K. 1985. The effects of methyl mercury binding to microtubules. Toxicol. Appl. Pharmacol. 80:473–486.PubMedCrossRefGoogle Scholar
  67. Wagner, S. L., Gdeeds, J. W., Cotman, C. W., Lau, A. L., Gurwitz, D., Isackson, P. L. and Cunningham, D. D. 1989. Protease nexin-1, an antithrombin with neurite outgrowth activity is reduced in Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 86:8284–8288.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Ben H. Choi
    • 1
  1. 1.Division of Neuropathology, Department of PathologyUniversity of CaliforniaIrvineUSA

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