Skip to main content
Log in

An ultrastructural study on the blood-brain barrier dysfunction following mercury intoxication

  • Original Investigations
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Summary

Methyl mercuric chloride (CH3HgCl) was administered in a single intraperitoneal injection to adult male rats at a dosage of 10 mg/kg body weight. Horseradish peroxidase was systemically injected into these animals at various time intervals following methyl mercury administration. Horseradish peroxidase activity as demonstrated by 3,3′-diaminobenzidene conjugation was used as a tracer to study blood-brain barrier dysfunction induced by methyl mercury. Permeation of tracer into the parenchyma of the central nervous system was observed ultrastructurally as early as 4–6 hrs following methyl mercury administration. Examination of capillary regions in the calcarine cortex and cerebellum at this time also revealed many endothelial cells with mitochondrial injury, increased pinocytotic transport of tracer, and in several instances, widening of lateral leaflet spaces without disruption of tight junctions. 6 hrs after the intoxication, many astrocytic end-feet abutting these injured capillaries displayed swelling and tracer accumulation. Horseradish peroxidase activity could be localized within neuronal and glial elements after 10–12 hrs of methyl mercury treatment. A newly developed electron microscopic histochemical technique utilizing an ammonium sulfide reaction was also employed to study the distribution of mercury within the blood-brain barrier structures. Localization of mercury corresponded with observed sites of cellular injury and tracer extravasation. It is believed that the observed blood-brain barrier dysfunction was due to the impairment of endothelial cells and astrocytic end-feet by mercury ions.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Ackefors, H., Lofroth, G., Rosen, C. G.: A survey of the mercury pollution problem in Sweden with special reference to fish. Oceanogr. Marine Biol. Ann. Rev.8, 203–224 (1970)

    Google Scholar 

  • Berlin, M., Ullberg, S.: Accumulation and retention of mercury in mouse. III. An autoradiographic comparison of methyl mercuric dicyadiamide with inorganic mercury. Arch. environm. Hlth6, 610–616 (1963)

    Google Scholar 

  • Broman, T., Steinwall, O.: Blood-brain barrier. In: Pathology of the nervous system. J. Minckler (Ed.), Vol. 1, Chapt. 33. New York: Blakiston 1967

    Google Scholar 

  • Brown, I. A.: Chronic mercurialism: amyotrophic lateral sclerosis. Arch. Neurol. Psychiat. (Chic.)72, 672–685 (1954)

    Google Scholar 

  • Brown, W. J., Yoshida, N.: Organic mercurial encephalopathy—an experimental electron microscopic study. Advanc. Neurol. Sci. (Tokyo)9, 34–42 (1965)

    Google Scholar 

  • Brown, J. R., Jose, F. R., Kulkarni, M. V.: Studies of the toxicity and metabolism of mercury and its compounds. Med. Sci. J. Can.23, 1089–1110 (1967)

    Google Scholar 

  • Cassano, G. B., Viola, P. L., Ghetti, B., Amaducci, L.: The distribution of inhaled mercury vapor in brain of rats and mice. J. Neuropath. exp. Neurol.28, 308–320 (1969)

    Google Scholar 

  • Cavanagh, J. B., Chen, F. C. K.: Amino acid incorporation in protein during the “silent phase” before organo-mercury andp-bromophenylacetylurea neuropathy in the rat. Acta neuropath. (Berl.)19, 216–224 (1971)

    Google Scholar 

  • Chang, L. W., Hartmann, H. A.: Ultrastructural studies of the nervous system after mercury intoxication. I. Pathological changes in the nerve cell bodies. Acta neuropath. (Berl.)20, 122–138 (1972a)

    Google Scholar 

  • Chang, L. W., Hartmann, H. A.: Ultrastructural studies of the nervous system after mercury intoxication. II. Pathological changes of nerve fibers. Acta neuropath. (Berl.)20, 316–334 (1972b)

    Google Scholar 

  • Chang, L. W., Hartmann, H. A.: Electron microscopic histochemical study on the localization and distribution of mercury in the nervous system after mercury intoxication. Exp. Neurol.35, 122–137 (1972c)

    Google Scholar 

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

    Google Scholar 

  • Chang, L. W., Dudley, A. W., Jr., Ware, R. A.: Mitochondrial changes in neurons following mercury intoxication. J. Neuropath. exp. Neurol.33, 175–176 (1974a)

    Google Scholar 

  • Chang, L. W., Ware, R. A., Desnoyers, P. A.: A histochemical study on some enzyme changes in the kidney, liver and brain after chronic mercury intoxication in the rat. Fd. Cosmet. Toxicol.11, 283–286 (1973)

    Google Scholar 

  • Chang, L. W., Yamaguchi, S., Dudley, A. W., Jr.: Neurological changes in cats following long-term diet of mercury contaminated tuna. Acta neuropath. (Berl.)27, 171–176 (1974b)

    Google Scholar 

  • Clarkson, T. W.: The pharmacology of mercury compounds 6545. Ann. Rev. Pharmacol.12, 375–406 (1972)

    Google Scholar 

  • Crone, C.: Facilitated transfer of glucose from blood to brain. J. Physiol. (Lond.)181, 103–113 (1965)

    Google Scholar 

  • De Robertis, E., Gerschenfeld, H. M.: Submicroscopic morphology of glial cells. Int. Rev. Neurobiol.3, 1–65 (1961)

    Google Scholar 

  • Desnoyers, P. A., Chang, L. W.: Pathological changes in hepatocytes after acute mercury intoxication. Fed. Proc.32, 838 (1973)

    Google Scholar 

  • Dobbing, J.: The blood-brain barrier: Some recent developments. Guy Hosp. Rep.112, 267–286 (1963)

    Google Scholar 

  • Edstrom, R.: Recent developments of the blood-brain barrier concept. Int. Rev. Neurobiol.7, 153–190 (1964)

    Google Scholar 

  • Gritzka, T. L., Trump, B. F.: Renal tubular lesions caused by mercuric chloride. Amer. J. Path.52, 1225–1277 (1968)

    Google Scholar 

  • Hammond, A. L.: Mercury in the environment: natural and human factors. Science26, 788–789 (1971)

    Google Scholar 

  • Hunter, D.: Industrial toxicology. Quart. J. Med.12, 185–258 (1943)

    Google Scholar 

  • Hunter, D., Bomford, R. R., Russell, D. S.: Poisoning by methyl mercury compounds. Quart. J. Med.9, 193–213 (1940)

    Google Scholar 

  • Hunter, D., Russell, D. S.: Focal cerebral and cerebellar atrophy in human subjects due to organic mercury compounds. J. Neurol. Neurosurg. Psychiat.17, 235–241 (1954)

    Google Scholar 

  • It, Y.: An autopsy case of chronic organic mercury poisoning. Acta path. jap.16, 411–420 (1966)

    Google Scholar 

  • Katsuki, S., Hirai, S., Terao, T.: On the disease of central nervous system in Minamata District with unknown etiology, with special references to the clinical observations. Kumamoto Igakkai Zasshi31, Suppl. 23, 110–121 (1957)

    Google Scholar 

  • Klein, R., Herman, S. P. Brubaker, P. E., Lucier, G. W., Krigman, M. R.: A model of methyl mercury intoxication in rats. Arch. Path.93, 408–418 (1972)

    Google Scholar 

  • Lajtha, A.: The brain barrier system. In: Neurochemistry. K. A. C. Elliot, I. H. Page and J. H. Quastel (Eds.), 2nd Ed., pp. 399–430. Springfield, Ill. Ch. C. Thomas 1962

    Google Scholar 

  • Lajtha, A.: Cerebral transport as a control mechanism of cerebral metabolote levels. Progr. Brain Res.29, 201–216 (1967)

    Google Scholar 

  • Leonhardt, H.: Die Neurohypophyse, ein Resorptionsorgan. Acta neuroveg. (Wien)12, 1–12 (1955)

    Google Scholar 

  • Miyakawa, T., Deshimaru, M.: Electron microscopic study of experimentally induced poisoning due to organic mercury compound. Acta neuropath. (Berl.)14, 126–136 (1969)

    Google Scholar 

  • Miyakawa, T., Deshimaru, M., Sumiyoshi, S., Tersoka, A., Tatetsu, S.: Experimental organic mercury poisoning regeneration of peripheral nerves. Acta neuropath. (Berl.)17, 6–13 (1971)

    Google Scholar 

  • Miyakawa, T., Deshimaru, M., Udo, N., Hattori, E., Tatetsu, S.: Experimental organic mercury poisoning patholog icalchanges in peripheral nerves. Acta neuropath. (Berl.)15, 45–55 (1970)

    Google Scholar 

  • Montague, K., Montague, P.: Mercury. San Francisco-New York: Sierra Club 1971

    Google Scholar 

  • Morikawa, N.: Pathological studies on organic mercury poisoning. Kumamoto med. J.14, 71–86 (1961)

    Google Scholar 

  • Neal, P. A., Jones, R. R.: Chronic mercurialism in the hatters' fur-cutting industry. J. Amer. med. Ass.10, 337–343 (1938)

    Google Scholar 

  • Okinaka, S.: Encephalomyelopathy due to an organic mercury compound. Neurology (Minneap.)14, 69–76 (1964)

    Google Scholar 

  • Passow, H., Rothstein, A., Clarkson, T. W.: The general pharmacology of the heavy metals. Pharmacol. Rev.13, 185–224 (1961)

    Google Scholar 

  • Peters, A., Palay, S. L., Webster, H. de F.: The fine struture of the nervous system. The cells and their processes. New York-Evanston-London: Harper and Row 1970

    Google Scholar 

  • Reese, T. S., Karnovsky, M. J.: Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol.34, 207–219 (1967)

    Google Scholar 

  • Rothstein, A.: Cell membrane and site of heavy metals. Fed. Proc.18, 1026–1035 (1959)

    Google Scholar 

  • Sahaphong, S., Trump, B. F.: Studies of cellular injury in isolated kidney tubules of the flounder. V. Effects of inhibiting sulfhydryl groups of plasma membranes with the organic mercurials PCMB (parachloromercuribnnzoste) and PCMBS (parachloromercuribenzenesulfonate). Amer. J. Path.63, 277–297 (1971)

    Google Scholar 

  • Somjen, G. G., Herman, S. P., Klein, R., Brubaker, P. E., Briner, W. H., Goodrich, J. K., Krigman, M. R., Haseman, J. K.: The uptake of methyl mercury (203 Hg) in different tissues related to its neurotoxic effect. J. Pharmacol. exp. Ther.87, 602–611 (1974)

    Google Scholar 

  • Steinwall, O.: Transport mechanisms in certain blood-brain barrier phenomena—a hypothesis. Acta psychiat. scand.150, 314–318 (1961)

    Google Scholar 

  • Steinwall, O., Brain uptake of Se75-selenomethionine after damage to blood-brain barrier by mercuric ions. Acta neurol. scand.45, 362–368 (1969)

    Google Scholar 

  • Steinwall, O., Klatzo, I.: Selective vulnerability of the blood-brain barrier to chemically induced lesions. J. Neuropath. exp. Neurol.25, 542–559 (1969)

    Google Scholar 

  • Steinwall, O., Olsson, Y.: Impairment of the blood-brain barrier in mercury poisoning. Acta neurol. scand.45, 351–361 (1969)

    Google Scholar 

  • Steinwall, O., Snyder, H.: Brain uptake of C14-cycloleucine after damage to the blood-brain barrier by mercury ions. Acta neurol. scand.45, 369–375 (1969)

    Google Scholar 

  • Swensson, A.: Investigation on the toxicity of some organic mercury compounds which are used as seed disinfectants. Acta med. scand.143, 365–384 (1952)

    Google Scholar 

  • Takeuchi, T.: Pathological studies on encephalopathy from unknown cause in Minamata District of Kumamoto prepecture (so-called Minamata disease) in Japan. Acta path. jap.7, Suppl. 607, 1–15 (1957)

    Google Scholar 

  • Takeuchi, T., Matsumoto, H., Sasaki, M., Kambara, T., Shiraishi, Y., Hirata, Y., Nobuhiro, M., Ito, H.: Pathology of Mianamata diseases. Kumamoto med. J.34, 521–530 (1968)

    Google Scholar 

  • Takeuchi, T., Shiraishi, Y.: A study of Minamata disease in Japan. Acta neuropath. (Berl.)2, 40–57 (1962)

    Google Scholar 

  • Tokuomi, H.: Minamata disease, unusual neurological disorder accuring in Minamata, Japan. Kumamoto med. J.14, 47–64 (1961)

    Google Scholar 

  • Truex, R. C., Carpenter, M. B.: Human neuroanatomy, 6th ed. Baltimore: Williams and Wilkins 1968

    Google Scholar 

  • Ware, R. A., Burkholder, P. B., Chang, L. W.: Time-dependent distribution of organic and inorganic mercury compounds in rats following chronic and acute intoxication. Fed. Proc.33, 227 (1974a)

    Google Scholar 

  • Ware, R. A., Burkholder, P. B., Chang, L. W.: Pathological effects of experimental mercury intoxication on renal function. Amer. J. Path.74, 21a (1974b)

    Google Scholar 

  • Ware, R. A., Chang, L. W., Burkholder, P. M.: Ultrastructural pathology of the kiney after chronic mercury intoxication. Fed. Proc.32, 823 (1973)

    Google Scholar 

  • Yoshino, Y., Mozai, T., Nakao, K.: Biochemical changes in the brain in rats poisoned with an alkylmercuric compound, with special reference to the inhibition of protein synthesis in brain cortex slices. J. Neurochem.13, 1223–1230 (1966)

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ware, R.A., Chang, L.W. & Burkholder, P.M. An ultrastructural study on the blood-brain barrier dysfunction following mercury intoxication. Acta Neuropathol 30, 211–224 (1974). https://doi.org/10.1007/BF00688922

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00688922

Key words

Navigation