Skip to main content
SpringerLink
Log in
Book cover

Advances in Mercury Toxicology pp 315–337Cite as

Effects of Methylmercury on the Developing Brain

  • Chapter

Part of the book series: Rochester Series on Environmental Toxicity ((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.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abe, T., Haga, T. and Kurokawa, M., 1975. Blockage of axoplasmic transport and depolymerication of reassembled microtubules by methylmercury. Brain Res. 86:504–508.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Brookes, N., 1988. Specificity and reversibility of the inhibition by HgCl2 of glutamate transport in astrocyte cultures. J. Neurochem. 50:1117–1122.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Chang, L. W. and Hartmann, H. A., 1972. Blood-brain barrier dysfunction in experimental mercury intoxication. Acta Neuropathol. (Berl.) 21:179–184.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Choi, B. H., 1981. Radial glia of developing human fetal spinal cord: Golgi, immunohistochemical and electron microscopic study. Dev. Brain Res. 1:249–267.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • Choi, B. H., 1989. The effects of methylmercury on the developing brain. Prog. Neurobiol. 32:447–470.

    Article  PubMed  CAS  Google Scholar 

  • Choi, B. H., 1991. Effects of methylmercury on neuroepithelial germinal cells in the developing telencephalic vesicles of mice. Acta Neuropath. 81:359–365.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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.

    CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Clarkson, T. W., 1987. Metal toxicity in the central nervous system. Environ. Heatlh Perspect. 75:59–64.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Edelman, G., 1984. Cell adhesion and morphogenesis: The regulator hypothesis. Proc. Natl. Acad. Sci. U.S.A. 81:1460–1464.

    Article  PubMed  CAS  Google Scholar 

  • Fuyuta, M., Fujimoto, T. and Hirata, S., 1978. Embryotoxic effects of methylmercury chloride administered to mice and rats during organogenesis. Teratol. 18:353–366.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Harada, M., 1976. Minamata Disease, Chronology and Medial Report. Bulletin of the Constitutional Medicine. Kumamoto University Press, Japan, pp. 1–78.

    Google Scholar 

  • Harada, M., 1978. Congenital Minamata disease: Intrauterine methylmercury poisoning. Teratol. 18:285–288.

    Article  CAS  Google Scholar 

  • Harris, S. B., Wilson, J. G. and Prinz, R. H., 1972. Embryotoxicity of methylmercuric chloride in golden hamster. Teratol. 6:139–142.

    Article  CAS  Google Scholar 

  • Honegger, P. and Richelson, E., 1977. Biochemical differentiation of aggregating cell cultures of different fetal rat brain regions. Brain Res. 109:335–354.

    Article  Google Scholar 

  • Inouye, M. and Kajiwara, Y., 1988. Developmental disturbances of the fetal brain in guinea-pigs caused by methylmercury. Toxicol. 7:227–232.

    Google Scholar 

  • Inouye, M. and Kajiwara, Y., 1990. Strain difference of the mouse in manifestation of hydrocephalus following prenatal methylmercury exposure. Teratol. 41:205–210.

    Article  CAS  Google Scholar 

  • Kim, P. and Choi, B. H., 1990. Effects of mercury on glutamate uptake in cultured mouse astrocytes. Fed. Proc. 4:A1014.

    Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Margolis, R. L. and Wilson, L., 1981. Microtubule treadmills-possible molecular machinery. Nature 293:705–711.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Miura, K., Suzuki, K. and Imura, N., 1978. Effects of methylmercury on mitotic mouse glioma cells. Environ. Res. 17:453–471.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Murakami, U., 1972. The effects of organic mercury on intrauterine life. Adv. Exp. Med. Biol. 27:310–336, 1972.

    Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Rakic, P., 1972. Mode of cell migration to the superficial layers of fetal monkey neocortex. J. Comp. Neurol. 145:61–84.

    Article  PubMed  CAS  Google Scholar 

  • Ramel, C., 1969. Methyl mercury as a mitosis disturbing agent. J. Japan Med. Assn. 61:1072–1077.

    CAS  Google Scholar 

  • Reuhl, K. R. and Chang, L. W., 1979. Effects of methylmercury on the development of the nervous system. Neurotoxicol. 1:21–55.

    CAS  Google Scholar 

  • 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.

    Chapter  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Sager, P. R., Doherty, R. A., and Rodier, P. M., 1982. Effects of methylmercury on developing mouse cerebellar cortex. Exp. Neurol. 77:179–193.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Spyker, J. M. and Smithberg, M., 1972. Effects of methylmercury on prenatal development in mice. Teratology 5:181–190.

    Article  PubMed  CAS  Google Scholar 

  • Steinwall, O. and Olsson, Y., 1969. Impairment of the blood-brain barrier in mercury poisoning. Acta Neurol. Scandinav. 45:351–361.

    Article  CAS  Google Scholar 

  • Su, M. and Okita, G., 1976. Embryocidal and teratogenic effects of methylmercury in mice. Toxicol. Appl. Pharmacol. 38:207–216.

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi, T., 1977. Pathology of fetal Minamata disease. Pediatrician 6:69–87.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Neuropathology, Department of Pathology, University of California, Irvine, CA, USA

    Ben H. Choi

Authors
  1. Ben H. Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Tokyo, Tokyo, Japan

    Tsuguyoshi Suzuki

  2. Kitasoto University, Tokyo, Japan

    Nobumasa Imura

  3. University of Rochester School of Medicine, Rochester, New York, USA

    Thomas W. Clarkson

Rights and permissions

Reprints and permissions

Copyright information

© 1991 Springer Science+Business Media New York

About this chapter

Cite this chapter

Choi, B.H. (1991). Effects of Methylmercury on the Developing Brain. In: Suzuki, T., Imura, N., Clarkson, T.W. (eds) Advances in Mercury Toxicology. Rochester Series on Environmental Toxicity. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-9071-9_20

Download citation

  • DOI: https://doi.org/10.1007/978-1-4757-9071-9_20

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4757-9073-3

  • Online ISBN: 978-1-4757-9071-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation