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Toluene-induced oxidative stress in several brain regions and other organs

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Molecular and Chemical Neuropathology

Abstract

The in vivo dose-response relationship between toluene and reactive oxygen species (ROS) formation in rat brain, liver, kidney, and lung, and the time-course of these effects has been characterized. The rate of oxygen radical formation was measured using the probe 2′,7′-dichlorofluorescin diacetate. In vivo exposure to various doses of toluene (0.5, 1.0, and 1.5 g/kg ip) elicited a dose-dependent elevation of ROS generation within crude mitochondrial fractions obtained from rat lung and kidney, and within crude synaptosomal fractions from cerebellum. ROS formation in crude mitochondrial fractions from liver, and crude synaptosomal fractions from striatum and hippocampus, reached a maximum value at relatively low doses of toluene. Of the brain regions, the hippocampus had the highest induced levels of ROS. In vivo exposure to a single dose of toluene (1.5 g/kg ip), revealed that toluene-induced ROS reached a peak within 2 h, which correlated directly with measured toluene blood levels. This elevated oxidative activity was maintained throughout the next 24 h, even though blood values of toluene decreased to negligible amounts. These results demonstrate that exposure to toluene results in broad systemic elevation in the normal rate of oxygen radical generation, with such effects persisting in the tissues despite a rapid decline in toluene blood levels. Acute exposure to toluene may lead to extended ROS-related changes, and this may account for some of the clinical observations made in chronic toluene abusers.

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References

  • Agency for Toxic Substances and Disease Registry. (December, 1989)Toxicologic Profile for Toluene. U.S. Public Health Service.

  • Bakke O. M. and Scheline R. (1970) Hydroxylation of aromatic hydrocarbons in the rat.Toxicol. Appl. Pharmacol. 16, 691.

    Article  PubMed  CAS  Google Scholar 

  • Bass D. A., Parce J. W., Dechatelet L. R., Szejda P., Seeds M. C., and Thomas M. (1983) Flow cytometric studies of oxidative product formation by neutrophils: A graded dose response to membrane stimulation.J. Immunol. 130, 1910–1917.

    PubMed  CAS  Google Scholar 

  • Baud L. and Ardaillou R. (1986) Reactive oxygen species: production and role in the kidney.Am. J. Physiol.,251, F765-F776.

    PubMed  CAS  Google Scholar 

  • Benignus V. A. (1981) Health effects of toluene: A review.Neurotoxicology 2, 567–588.

    PubMed  CAS  Google Scholar 

  • Bjornaes S. and Naaslund L. U. (1988) Biochemical changes in different brain areas after toluene inhalation.Toxicology 49, 367–374.

    Article  PubMed  CAS  Google Scholar 

  • Boor J. W. and Hurtig H. I. (1977) Persistent cerebellar ataxia after exposure to toluene.Ann. Neurol. 2, 440–442.

    Article  PubMed  CAS  Google Scholar 

  • Bruckner J. V. and Peterson R. G. (1981) Evaluation of toluene and acetone inhalant abuse. I. Pharmacology and Pharmacodynamics.Toxicol. Appl. Pharmacol. 61, 27–38.

    Article  PubMed  CAS  Google Scholar 

  • Chacon E. and Acosta D. (1991) Mitochondrial regulation of superoxide by Ca2+: An alternate mechanism for the cardiotoxicity of Doxorubicin.Toxicol. Appl. Pharmacol. 107, 117–128.

    Article  PubMed  CAS  Google Scholar 

  • Cohr K. H. and Stokholm J. (1979) Toluene: a toxicologic review.Scand. J. Work Environ. Health. 5, 71–86, 1979.

    PubMed  CAS  Google Scholar 

  • Dodd P. R., Hardy J. A., Oakley A. E., Edwardson J. A., Perry E. K., and Delaunoy J. P. (1981) A rapid method for preparing synaptosomes: Comparison with alternative procedures.Brain Res. 226, 107–118.

    Article  PubMed  CAS  Google Scholar 

  • Fornazzari L., Wilkinson D. A., Kapur B. M., and Carlen P. L. (1983) Cerebellar, cortical and functional impairment in toluene abusers.Acta Neurol. Scand. 67, 319–329.

    Article  PubMed  CAS  Google Scholar 

  • Gerarde H. W. and Ahlstrom D. B. (1966) Toxicologic studies on hydrocarbons: XI: Influence of dose on the metabolism of mono-n-alkyl derivatives of benzene.Toxicol. Appl. Pharmacol. 9, 185–191.

    Article  PubMed  CAS  Google Scholar 

  • Gospe S. M. and Calaban M. J. (1988) Central nervous system distribution of inhaled toluene.Fund. Appl. Toxicol. 11, 540–545.

    Article  CAS  Google Scholar 

  • Guertin D. L. and Gerarde H. W. (1959) Toxicological studies on hydrocarbons.AMA Arch. Ind. Health 20, 262–265.

    CAS  Google Scholar 

  • Halliwell B. and Gutteridge J. M. C. (1985)Free Radicals in Biology and Medicine. Clarendon, Oxford.

    Google Scholar 

  • Hansson E., von Euler G., Fuxe K., and Hansson T. (1988) Toluene induces changes in the morphology of astroglia and neurons in striatal primary cell cultures.Toxicology 49, 155–163.

    Article  PubMed  CAS  Google Scholar 

  • Ikeda M. and Ohtsuji H. (1971) Phenobarbital-induced protection against toxicity of toluene and benzene in the rat.Toxicol. Appl. Pharmacol. 20, 30–43.

    Article  PubMed  CAS  Google Scholar 

  • Jerina D. M. and Daly J. W. (1974) Arene oxides: a new aspect of drug metabolism.Science 185, 573–575.

    Article  PubMed  CAS  Google Scholar 

  • Kelly T. W. (1975) Prolonged cerebellar dysfunction associated with paint sniffing.Pediatrics 56, 605–608.

    PubMed  CAS  Google Scholar 

  • Korpela M. and Tahti H. (1988) The effect of in vivo and in vitro toluene exposure on rat erythrocyte and synaptosome membrane integral enzymes.Pharmacol. Toxicol. 63, 30–32.

    Article  PubMed  CAS  Google Scholar 

  • Kyrklund T., Kjellstrand P., and Haglid K. (1987) Brain lipid changes in rats exposed to xylene and toluene.Toxicology 45, 123–133.

    Article  PubMed  CAS  Google Scholar 

  • Ladefoged O., Strange P., Moller A., Lam H. R., Ostergaard G., Larsen J. J., and Arlien-Soborg P. (1991) Irreversible effects in rats of toluene (inhalation) exposure for six months.Pharmacol. Toxicol. 68, 384–391.

    Article  PubMed  CAS  Google Scholar 

  • Laham S. (1970) Metabolism of industrial solvents.Industrial Med. 39, 237–242.

    CAS  Google Scholar 

  • LeBel C. P. and Bondy S. C. (1990) Sensitive and rapid quantitation of oxygen reactive species formation in rat synaptosomes.Neurochem. Int. 17, 435–440.

    Article  CAS  PubMed  Google Scholar 

  • LeBel C. P. and Schatz R. A. (1988) Toluene-induced alterations in rat synaptosomal membrane composition and function.J. Biochem. Toxicol. 3, 279–293.

    Article  CAS  Google Scholar 

  • LeBel C. P. and Schatz R. A. (1989) Effect of toluene on rat synaptosomal phospholipid methylation and membrane fluidity.Biochem. Pharmacol. 38, 4005–4011.

    Article  PubMed  CAS  Google Scholar 

  • LeBel C. P. and Schatz R. A. (1990) Altered synaptosomal phospholipid metabolism after toluene. Possible relationship with membrane fluidity, Na+, K+-adenosine triphosphate and phospholipid methylation.J. Pharmacol. Exp. Ther. 253, 1189–1197.

    PubMed  CAS  Google Scholar 

  • Malm G. and Lying T. U. (1980) Cerebellar dysfunction related to toluene sniffing.Acta Neurol. Scand. 62, 188–190.

    PubMed  CAS  Google Scholar 

  • Mason R. P. (1982) Free radical intermediates in the metabolism of toxic chemicals, inFree Radicals in Biology (Pryor, W. A. ed.), pp. 161, Academic, New York.

    Google Scholar 

  • Mattia C. J., LeBel C. P., and Bondy S. C. (1991) Effects of toluene and its metabolites on cerebral reactive oxygen species generation.Biochem. Pharmacol. 42, 879–882.

    Article  PubMed  CAS  Google Scholar 

  • Meister A. and Anderson M. E. (1983) Glutathione.Ann. Rev. Biochem. 52, 711–60.

    Article  PubMed  CAS  Google Scholar 

  • Mihara M., Uchiyama M., and Fukazawa K. (1980) Thiobarbituric acid value of fresh homogenate of rat as a parameter of lipid peroxidation in aging, CCI4 intoxication and Vitamin E deficiency.Biochem. Med. 23, 302–311.

    Article  PubMed  CAS  Google Scholar 

  • Naaslund L. U. (1986) Hippocampal EEG in rats after chronic toluene inhalation.Acta Pharmacol. Toxicol. 59, 325–332.

    Google Scholar 

  • Press E. and Done A. K. (1967) Solvent sniffing. Physiological effects and community control measures for intoxication from intentional inhalation of organic solvents.Pediatrics 39, 451–461.

    PubMed  CAS  Google Scholar 

  • Rees D. C., Wood R. W., and Laties V. G. (1989) Evidence of tolerance following repeated exposure to toluene in the rat.Pharmacol. Biochem. Behav. 32, 283–291.

    Article  PubMed  CAS  Google Scholar 

  • Sato A., Nakajima T., Fujiwara Y., and Hirosawa K. (1974) Pharmacokinetics of benzene and toluene.Int. Arch. Arbeitsmed. 33, 169–182.

    Article  PubMed  CAS  Google Scholar 

  • Savolainen H. (1977) Some effects of the mechanisms by which industrial solvents produce neurotoxic effects.Chem-Biol. Interactions 18, 1–10.

    Article  CAS  Google Scholar 

  • Savolainen H. (1978) Distribution and nervous system binding of intraperitoneally injected toluene.Acta Pharmacol. Toxicol. 43, 78–80.

    CAS  Google Scholar 

  • Suleiman S. A. (1987) Petroleum hydrocarbon toxicity in vitro: Effect of n-alkanes, benzene and toluene on pulmonary alveolar macrophages and lysosomal enzymes of the lung.Arch. Toxicol. 59, 402–407.

    Article  PubMed  CAS  Google Scholar 

  • Sutherland G., Bose R., Louw D., and Pinsky C. (1991) Global elevation of brain superoxide dismutase activity following forebrain ischemia in rat.Neurosci. Lett. 128, 169–172.

    Article  PubMed  CAS  Google Scholar 

  • Taher S. M., Anderson R. J., McCartney R., Popovtzer M. M., and Schrier R. W. (1974) Renal tubular acidosis associated with toluene “sniffing.”New Engl. J. Med. 290, 765–768.

    Article  PubMed  CAS  Google Scholar 

  • Trush M. A., Mimnaugh E. G., and Gram T. E. (1982) Activation of pharmacologic agents to radical intermediates. Implications for the role of free radicals in drug action and toxicity.Biochem. Pharmacol. 31, 3335–3346.

    Article  PubMed  CAS  Google Scholar 

  • Uchiyama M. and Mihara M. (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test.Anal. Biochem. 86, 271–278.

    Article  PubMed  CAS  Google Scholar 

  • Utley H. G., Bernheimm F., and Hochstein P. (1967) Effect of sulfhydryl reagents on peroxidation in microsomes.Arch. Biochem. Biophys. 118, 29–32.

    Article  CAS  Google Scholar 

  • Vazquez-Nin G. H., Zipitria D., Echeverria O. M., Bermudez-Rattoni F., Cruz-Morales S. E., and Prado-Alcals R. A. (1980) Early neuronal alterations caused by experimental thinner inhalation in young rats.Neurobehav. Toxicol. 2, 25–31.

    PubMed  CAS  Google Scholar 

  • von Euler G., Fuxe K., Hansson T., and Gustafsson J. (1988) Effects of toluene treatment in vivo and in vitro on the binding characteristics of (3H)-neurotensin in rat striatal membranes.Toxicology 49, 149–154.

    Article  Google Scholar 

  • von Euler G., Fuxe K., and Bondy S. C. (1990) Ganglioside GM1 prevents and reverses toluene-induced increases in membrane fluidity and calcium levels in rat brain synaptosomes.Brain Res. 508, 210–214.

    Article  Google Scholar 

  • Walsh T. J. and Emerich D. F. (1988) The hippocampus as a common target of neurotoxic agents.Toxicology 49, 137–140.

    Article  PubMed  CAS  Google Scholar 

  • Yamawaki S., Segawa T., and Sarai K. (1982) Effects of acute and chronic toluene inhalation on behaivor and (3H)-serotonin binding in rat.Life Sci. 30, 1997–2002.

    Article  PubMed  CAS  Google Scholar 

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Mattia, C.J., Ali, S.F. & Bondy, S.C. Toluene-induced oxidative stress in several brain regions and other organs. Molecular and Chemical Neuropathology 18, 313–328 (1993). https://doi.org/10.1007/BF03160122

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