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Oxidative stress is induced in the rat brain following repeated inhalation exposure to manganese sulfate

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Abstract

Eight-week-old rats inhaled manganese (Mn) in the form of MnSO4 at 0, 0.03, 0.3, or 3.0 mg Mn/m3 for 6 h/d for 7 d/wk (14 consecutive exposures). Brain manganese concentrations in these animals were reported by Dorman et al. in 2001, noting the following rank order: olfactory bulb>striatum>cerebellum. We assessed biochemical end points indicative of oxidative stress in these three brain regions, as well as the hypothalamus and hippocampus. Glutamine synthetase (GS) protein levels and total glutathione (GSH) levels were determined for all five regions. GS mRNA and metallothionein (MT) mRNA levels were also evaluated for the cerebellum, hypothalamus, and hippocampus. Statistically significant increases (p<0.05) in GS protein were observed in the olfactory bulb upon exposure to the medium and high manganese doses. In the hypothalamus, statistically significant (p<0.05) but more modest increases were also noted in the medium and high manganese dose. Total GSH levels significantly (p<0.05) decreased only in the hypothalamus (high manganese dose), and MT mRNA significantly increased in the hypothalamus (medium manganese dose). No significant changes were noted in any of the measured parameters in the striatum, although manganese concentrations in this region were also increased. These results demonstrate that the olfactory bulb and hypothalamus represent potentially sensitive areas to oxidative stress induced by exceedingly high levels of inhaled manganese sulfate and that other regions, and especially the striatum, are resistant to manganese-induced oxidative stress despite significant accumulation of this metal.

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References

  1. K. Nelson, J. Golnick, T. Korn, et al., C. Angle, Manganese encephalopathy: utility of early magnetic resonance imaging, Br. J. Ind. Med. 50, 510–513 (1993).

    PubMed  CAS  Google Scholar 

  2. S. S. Schochet and J. Nelson, Exogenous toxic-metabolic diseases including vitamin deficiency, in Textbook of Neuropathology, 2nd ed., R. L. Davis and D. M. Robertson, eds., Williams & Wilkins, Baltimore, MD, p. 450 (1991).

    Google Scholar 

  3. D. B. Calne, N. S. Chu, C. C. Huang, et al., Manganism and idiopathic parkinsonism: similarities and difference, Neurology 44, 1583–1586 (1994).

    PubMed  CAS  Google Scholar 

  4. N. Molders, P. J. Schilling, J. Wong, et al., X-ray fluorescence mapping and micro-XANES spectroscopic characterization of exhaust particulates emitted from auto engines burning MMT-added gasoline, Environ. Sci. Technol. 35, 3122–3129 (2001).

    Article  PubMed  CAS  Google Scholar 

  5. T. Ressler, J. Wong, and J. Roos, Manganese speciation in exhaust particulates of automobiles using MMT containing gasoline, J. Synchrotron Radiat. 6, 656–658 (1999).

    Article  PubMed  CAS  Google Scholar 

  6. J. Zayed, A. Vyskocil, and G. Kennedy, Environmental contamination and human exposure to manganese—contribution of methylcyclopentadienyl manganese tricarbonyl in unleaded gasoline, Int. Arch. Occup. Environ. Health 72, 7–13 (1999).

    Article  PubMed  CAS  Google Scholar 

  7. D. C. Dorman, M. F. Struve, R. A. James, et al., Influence of particle solubility of the delivery of inhaled manganese to the rat brain: manganese sulfate and manganese tetroxide pharmacokinetics following repeated (14-day) exposure, Toxicol. Appl. Pharmacol. 170, 79–87 (2001).

    Article  PubMed  CAS  Google Scholar 

  8. M. Aschner, Manganese neurotoxicity and oxidative damage, in Metals and Oxidative Damage in Neurological Disorders, J. R. Connor, ed., Plenum, New York, pp. 77–93 (1997).

    Google Scholar 

  9. W. N. Sloot, J. Korf, J. F. Koster, et al., Manganese-induced hydroxyl radical formation in rat striatum is not attenuated by dopamine depletion or iron chelation in vivo, Exp. Neurol. 138, 236–245 (1996).

    Article  PubMed  CAS  Google Scholar 

  10. P. Galvani, P. Fumagalli, and A. Santagostino, Vulnerability of mitochondrial complex I in PC12 cells exposed to manganese, Eur. J. Pharmacol. 293, 377–383 (1995).

    Article  PubMed  CAS  Google Scholar 

  11. C. E. Gavin, K. K. Gunter, and T. E. Gunter, Manganese and calcium transport in mitochondria: implications for manganese toxicity, Neurotoxicology 20, 445–453 (1999).

    PubMed  CAS  Google Scholar 

  12. F. S. Archibald and C. Tyree, Manganese poisoning and the attack of trivalent manganese upon catecholamines, Arch. Biochem. Biophys. 256, 638–650 (1987).

    Article  PubMed  CAS  Google Scholar 

  13. S. F. Ali, H. M. Duhart, G. D. Newport, et al., Manganese-induced reactive oxygen species: comparison between Mn+2 and Mn+3, Neurodegeneration 4, 329–334 (1995).

    Article  PubMed  CAS  Google Scholar 

  14. J. Y. Chen, G. C. Tsao, Q. Zhao, et al., Differential cytotoxicity of Mn(II) and Mn(III): special reference to mitochondrial [Fe-S] containing enzymes, Toxicol. Appl. Pharmacol. 175, 160–168 (2001).

    Article  PubMed  CAS  Google Scholar 

  15. D. HaMai, A. Campbell, and S. C. Bondy, Modulation of oxidative events by multivalent manganese complexes in brain tissue, Free Radical Biol. Med. 31, 763–768 (2001).

    Article  CAS  Google Scholar 

  16. V. Anantharam, M. Kitazawa, J. Wagner, et al., Caspase-3-dependent proteolytic cleavage of protein kinase C delta is essential for oxidative stress-mediated dopaminergic cell death after exposure to methylcyclopentadienyl manganese tricarbonyl, J. Neurosci. 22, 1738–1751 (2002).

    PubMed  CAS  Google Scholar 

  17. K. A. Brenneman, R. C. Cattley, S. F. Ali, et al., Manganese-induced developmental neurotoxicity in the CD rat: is oxidative damage a mechanism of action? Neurotoxicology 20, 477–487 (1999).

    PubMed  CAS  Google Scholar 

  18. J. C. Ball, A. M. Straccia, W. C. Young, et al., The formation of reactive oxygen species catalyzed by neutral, aqueous extracts of NIST ambient particulate matter and diesel engine particles, J. Air Waste Manag. Assoc. 50, 1897–1903 (2000).

    PubMed  CAS  Google Scholar 

  19. H. Oubrahim, E. R. Stadtman, and P. B. Chock, Mitochondria play no roles in Mn(II)-induced apoptosis in HeLa cells, Proc. Natl. Acad Sci. USA 98, 9505–9510 (2001).

    Article  PubMed  CAS  Google Scholar 

  20. S. Weber, D. C. Dorman, L. H. Lash, et al., Effects of manganese (Mn) on the developing rat brain: oxidative-stress related endpoints, Neurotoxicology, 23, 169–175 (2003).

    Article  Google Scholar 

  21. A. Takeda, S. Ishiwatari, and S. Okada, Manganese uptake into rat brain during development and aging, J. Neurosci. Res. 56, 93–98 (1999).

    Article  PubMed  CAS  Google Scholar 

  22. C. L. Dupont and Y. Tanaka, Blood manganese levels in children with convulsive disorder, Biochem. Med. 33, 246–255 (1985).

    Article  PubMed  CAS  Google Scholar 

  23. A. Spencer, Whole blood manganese levels in pregnancy and the neonate, Nutrition 15, 731–734 (1999).

    Article  PubMed  CAS  Google Scholar 

  24. National Research Council, Guide for the Care and Use of Laboratory Animals, National Academic Press, Washington, DC (1996).

    Google Scholar 

  25. V. Barbu and F. Dautry, Northern blot normalization with a 28S rRNA oligonucleotide probe, Nucleic Acids Res. 17, 7115 (1989).

    Article  PubMed  CAS  Google Scholar 

  26. M. W. Fariss and D. J. Reed, High-performance liquid chromatography of thiols and disulfides: dinitrophenol derivatives, Methods Enzymol. 143, 101–109 (1987).

    Article  PubMed  CAS  Google Scholar 

  27. L. H. Lash and J. J. Tokarz, Oxidative stress in isolated rat renal proximal and distal tubular cells, Am. J. Physiol. 259, F338–F347 (1990).

    PubMed  CAS  Google Scholar 

  28. L. H. Lash and E. B. Woods, Cytotoxicity of alkylating agents in isolated rat kidney proximal tubular and distal tubular cells, Arch. Biochem. Biophys. 286, 46–56 (1991).

    Article  PubMed  CAS  Google Scholar 

  29. A. Martinez-Hernandez, K. P. Bell, and M. D. Norenberg, Glutamine synthetase: glial localization in brain, Science 195, 1356–1358 (1977).

    Article  PubMed  CAS  Google Scholar 

  30. U. Sonnewald, N. Westergaard, and A. Schousboe, Glutamate transport and metabolism in astrocytes, Glia 21, 56–63 (1997).

    Article  PubMed  CAS  Google Scholar 

  31. E. R. Stadtman, Protein oxidation and aging, Science 257, 1220–1224 (1992).

    Article  PubMed  CAS  Google Scholar 

  32. F. C. Wedler and R. B. Denman, Glutamine synthetase: the major Mn (II) enzyme in mammalian brain, Curr. Topics. Cell. Regul. 24, 153–169 (1984).

    CAS  Google Scholar 

  33. F. C. Wedler, M. C. Vichnin, B. W. Ley, et al., Effects of Ca (II) ions on Mn (II) dynamics in chick glia and rat astrocytes: potential regulation of glutamine synthetase, Neurochem. Res. 19, 145–151 (1994).

    Article  PubMed  CAS  Google Scholar 

  34. P. Hainut and J. Milner, Redox modulation of p53 conformation and sequence-specific DNA binding in vitro, Cancer Res. 53, 4469–4473 (1993).

    Google Scholar 

  35. M. A. Levy, Y. H. Tsai, A. Reaume, et al., Cellular response of antioxidant metalloproteins in Cu/Zn SOD transgenic mice exposed to hyperoxia, Am. J. Physiol. Lung Cell. Mol. Physiol. 281, 172–182 (2001).

    Google Scholar 

  36. S. Hussain, W. Slikker, Jr., and S. F. Ali, Role of metallothionein and other antioxidants in scavenging superoxide radicals and their possible role in neuroprotection, Neurochem. Int. 29, 145–152 (1996).

    Article  PubMed  CAS  Google Scholar 

  37. Z. Zhou, X. Sun, and Y. James Kang, Metallothionein protection against alcoholic liver injury through inhibition of oxidative stress, Exp. Biol. Med. 227, 214–222 (2002).

    CAS  Google Scholar 

  38. M. Kondoh, Y. Inoue, S. Atagi, et al., Specific induction of metallothionein synthesis by mitochondrial oxidative stress, Life Sci. 69, 2137–2146 (2001).

    Article  PubMed  CAS  Google Scholar 

  39. M. Aschner, J. R. Connor, D. C. Dorman, et al., Manganese. in Neurotoxicology Handbook, Volume 1, Neurotoxicity of Synthesized and Natural Chemical Substances, E. F. Massaro, ed., Humana Totowa, NJ, pp. 195–209 (2001).

    Google Scholar 

  40. G. Gianutsos, G. R. Morrow, and J. B. Morris, Accumulation of manganese in rat brain following intranasal administration, Fundam. Appl. Toxicol. 37, 102–105 (1997).

    Article  PubMed  CAS  Google Scholar 

  41. J. Henriksson, J. Tallkvist, and H. Tjälve, Transport of manganese via the olfactory pathway in rats: dosage dependency of the uptake and subcellular distribution of the metal in the olfactory epithelium and brain, Toxicol. Appl. Pharmacol. 156, 119–128 (1999).

    Article  PubMed  CAS  Google Scholar 

  42. K. A. Brenneman, B. A. Wong, M. A. Buccellato, et al., Direct olfactory transport of inhaled manganese (54MnCl2) to the rat brain: toxicokinetic investigations in a unilateral nasal occlusion model, Toxicol. Appl. Pharmacol. 169, 238–248 (2000).

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, and Interdisciplinary Program in Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC

    Allison W. Dobson, Sarah Weber, Keith M. Erikson & Michael Aschner

  2. CIIT Centers for Health Research, Research Triangle Park, NC

    David C. Dorman

  3. Department of Pharmacology, Wayne State University, Detroit, MI

    Lawrence K. Lash

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  1. Allison W. Dobson
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  2. Sarah Weber
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  3. David C. Dorman
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  5. Keith M. Erikson
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  6. Michael Aschner
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Dobson, A.W., Weber, S., Dorman, D.C. et al. Oxidative stress is induced in the rat brain following repeated inhalation exposure to manganese sulfate. Biol Trace Elem Res 93, 113–125 (2003). https://doi.org/10.1385/BTER:93:1-3:113

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  • DOI: https://doi.org/10.1385/BTER:93:1-3:113

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