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Size-Dependent Toxicity Differences of Intratracheally Instilled Manganese Oxide Nanoparticles: Conclusions of a Subacute Animal Experiment

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Abstract

Incomplete information on toxicological differences of micro- and nanometer-sized particles raised concerns about the effects of the latter on health and environment. Besides chemical composition, size and surface-to-volume ratio of nanoparticles (NPs) can affect toxicity. To investigate size-dependent toxicity differences, we used particles made of dioxide of the neurotoxic heavy metal manganese (Mn), typically found in inhaled metal fumes, in three size ranges (size A, 9.14 ± 1.98 nm; size B, 42.36 ± 8.06 nm; size C, 118.31 ± 25.37 nm). For modeling the most frequent route of exposure to Mn, NPs were given to rats for 6 weeks by intratracheal instillation. Of each NP size, 3 or 6 mg/kg body weight was given while control animals were vehicle treated. Neurotoxicity was assessed by measuring spontaneous locomotor activity in an open field and by recording spontaneous and evoked electrical activity from the somatosensory cortical area. Mn content of brain, lung, and blood, measured by ICP-MS, were correlated to the observed functional alterations to see the relationship between Mn load and toxic effects. Body weight gain and organ weights were measured as general toxicological indices. The toxicity of size A and size B NPs proved to be stronger compared to size C NPs, seen most clearly in decreased body weight gain and altered spontaneous cortical activity, which were also well correlated to the internal Mn dose. Our results showed strong effect of size on NP toxicity, thus, beyond inappropriateness of toxicity data of micrometer-sized particles in evaluation of NP exposure, differentiation within the nano range may be necessary.

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References

  1. Buzea C, Pacheco II, Robbie K (2007) Nanomaterials and nanoparticles: sources and toxicity. Biointerphases 2(4):MR17–MR172. doi:10.1116/1.2815690

    Article  PubMed  Google Scholar 

  2. Suh WH, Suslick KS, Stucky GD, Suh YH (2009) Nanotechnology, nanotoxicology, and neuroscience. Prog Neurobiol 87:133–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rajak S, Jamil K (2012) Acute and sub acute toxicity studies of manganese oxide nanomaterials as compared to bulk in rats with emphasis on changes in biochemical and haematological parameters. IJAST 2(6):ISSN 2249-9954. http://rspublication.com/ijst/index.html. Accessed 9 April 2014

  4. Zhang Y, Ling F, Zhu Q, Xiao Z, Zhao Z, Zhang Y, Zheng Y (2006) New development of study on the toxicity of nano materials. Nanoscience 11:137–141

    CAS  Google Scholar 

  5. US Environmental Protection Agency (2003) Impacts of manufactured nanomaterials on human health and the environment. http://www.epa.gov/ncer/rfa/current/2003_nano.html Accessed 26 June 2015

  6. European Agency for Safety and Health at Work (2009) Expert forecast on emerging chemical risks related to occupational safety and health. ISBN 978-92-9191-171-4

  7. Oberdörster G, Oberdörster E, Oberdörster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113:823–839

    Article  PubMed  PubMed Central  Google Scholar 

  8. Schrand AM, Rahman MF, Hussain SM, Schlager JJ, Smith DA, Syed AF (2010) Metal-based nanoparticles and their toxicity assessment. WIREs Nanomed Nanobiotechnol 2:544–568. doi:10.1002/wnan.103

    Article  CAS  Google Scholar 

  9. Li T, Shi T, Li X, Zeng S, Yin L, Pu Y (2014) Effects of nano-MnO2 on dopaminergic neurons and the spatial learning capability of rats. Int J Environ Res Public Health 11:7918–7930. doi:10.3390/ijerph110807918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang Z, Kleinstreuer C (2011) Computational analysis of airflow and nanoparticle deposition in a combined nasal–oral–tracheobronchial airway model. J Aerosol Sci 42:174–194

    Article  Google Scholar 

  11. ICRP (1994) Human respiratory tract model for radiological protection. A report of a task group of the ICRP. Annals of the International Commission on Radiation Protection, ICRP Publication 66. Pergamon Press, Oxford

    Google Scholar 

  12. Warheit DB, Webb TR, Sayes CM, Colvin WL, Reed KL (2006) Pulmonary instillation studies with nanoscale TiO2 rods and dots in rats: toxicity is not dependent upon particle size and surface area. Toxicol Sci 91:227–236. doi:10.1093/toxsci/kfj140

    Article  CAS  PubMed  Google Scholar 

  13. Ferraz HB, Bertolucci PH, Pereira JS, Lima JG, Andrade LA (1988) Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication. Neurology 38:550–553

    Article  CAS  PubMed  Google Scholar 

  14. Ma R, Bando Y, Zhang L, Sasaki T (2004) Layered MnO2 nanobelts: hydrothermal synthesis and electrochemical measurement. Adv Mater 16:918–922

    Article  CAS  Google Scholar 

  15. Cheng FY, Zhao JZ, Song W, Li C, Ma H, Chen J, Shen P (2006) Facile controlled synthesis of MnO2 nanostructures of novel shapes and their application in batteries. Inorg Chem 45:2038–2044. doi:10.1021/ic051715b

    Article  CAS  PubMed  Google Scholar 

  16. Cao J, Mao QH, Shi L, Qian YT (2011) Fabrication of γ-MnO2/α-MnO2 hollow core/shell structures and their application to water treatment. J Mater Chem 21:16210–16215

    Article  CAS  Google Scholar 

  17. Flynn MR, Susi P (2009) Neurological risks associated with manganese exposure from welding operations—a literature review. Int J Hyg Environ Health 212:459–469

    Article  CAS  PubMed  Google Scholar 

  18. Stefanescu DM, Khoshnan A, Patterson PH, Hering JG (2009) Neurotoxicity of manganese oxide nanomaterials. J Nanopart Res 11:1957–1969. doi:10.1007/s11051-008-9554-1

    Article  CAS  Google Scholar 

  19. Rofsky NM, Earls JP (1996) Mangafopidir trisodium injection (Mn-DPDP). A contrast agent for abdominal MR imaging. Magn Reson Imaging Clin N Am 4:73–85

    CAS  PubMed  Google Scholar 

  20. Zhen Z, Xie J (2012) Development of manganese-based nanoparticles as contrast probes for magnetic resonance imaging. Theranostics 2:45–54. doi:10.7150/thno.3448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Quintanar L (2008) Manganese neurotoxicity: a bioinorganic chemist’s perspective. Inorg Chim Acta 361:875–884

    Article  CAS  Google Scholar 

  22. Dobson AW, Erikson KM, Aschner M (2004) Manganese neurotoxicity. Ann N Y Acad Sci 1012:115–129

    Article  CAS  PubMed  Google Scholar 

  23. Aschner M, Lukey B, Tremblay A (2006) The Manganese Health Research Program (MHRP): status report and future research needs and directions. Neurotoxicology 27:733–736. doi:10.1016/j.neuro.2005.10.005

    Article  CAS  PubMed  Google Scholar 

  24. Erikson KM, Aschner M (2003) Manganese neurotoxicity and glutamate-GABA interaction. Neurochem Int 43:475–480

    Article  CAS  PubMed  Google Scholar 

  25. Pal PK, Samii A, Calne DB (1999) Manganese neurotoxicity: a review of clinical features, imaging and pathology. Neurotoxicology 20:227–238

    CAS  PubMed  Google Scholar 

  26. Michalke B, Lucio M, Berthele A, Kanawati B (2013) Manganese speciation in paired serum and CSF samples using SEC-DRC-ICP-MS and CE-ICP-DRC-MS. Anal Bioanal Chem 405:2301–2309. doi:10.1007/s00216-012-6662-7

    Article  CAS  PubMed  Google Scholar 

  27. Singh SP, Kumari M, Kumari SI, Rahman MF, Mahboob M, Grover P (2013) Toxicity assessment of manganese oxide micro and nanoparticles in Wistar rats after 28 days of repeated oral exposure. J Appl Toxicol 33:1165–1179

    Article  CAS  PubMed  Google Scholar 

  28. Kreyling WG, Semmler-Behnke M, Möller W (2006) Ultrafine particle–lung interactions: does size matter? J Aerosol Med 19:74–83

    Article  CAS  PubMed  Google Scholar 

  29. Sárközi L, Horváth E, Kónya Z, Kiricsi I, Szalay B, Vezér T, Papp A (2009) Subacute intratracheal exposure of rats to manganese nanoparticles: behavioral, electrophysiological and general toxicological effects. Inhal Toxicol 21:83–91

    Article  PubMed  Google Scholar 

  30. Máté Z, Szabó A, Paulik E, Jancsó Z, Hermesz E, Papp A (2011) Electrophysiological and biochemical response in rats on intratracheal instillation of manganese. Central Eur J Biol 6:925–932

    Google Scholar 

  31. Horváth E, Máté Z, Takács S, Pusztai P, Sápi A, Kónya Z, Nagymajtényi L, Papp A (2012) General and electrophysiological toxic effects of manganese in rats following subacute administration in dissolved and nanoparticle form. Sci World J 2012:Article ID 520632. doi:10.1100/2012/520632

  32. Filho WJ, Fontinele RG, de Souza RR (2014) Reference database of lung volumes and capacities in Wistar rats from 2 to 24 months. Curr Aging Sci 7:220–228

    Article  PubMed  Google Scholar 

  33. US Environmental Protection Agency Integrated Risk Information System—Manganese. http://www.epa.gov/iris/subst/0373.htm Accessed 26 June 2015

  34. Oka Y, Mitsui M, Kitahashi T, Sakamoto A, Kusuoka O, Tsunoda T, Mori T, Tsutsumi M (2006) A reliable method for intratracheal instillation of materials to the entire lung in rats. J Toxicol Pathol 19:107–109

    Article  Google Scholar 

  35. Schärer K (1977) The effect of chronic underfeeding on organ weights of rats. Toxicology 7:45–56

    Article  PubMed  Google Scholar 

  36. Vezér T, Papp A, Hoyk Z, Varga C, Náray M, Nagymajtényi L (2005) Behavioral and neurotoxicological effects of subchronic manganese exposure in rats. Environ Toxicol Pharmacol 19:797–810

    Article  PubMed  Google Scholar 

  37. Koblin DD (2002) Urethane: help or hindrance? Anesth Analg 94:241–242

    PubMed  Google Scholar 

  38. Papp A, Vezér T, Institóris L (2001) An attempt to interpret the fatigue of the somatosensory cortical evoked potential during a stimulus train as a possible biomarker of neurotoxic exposure. Centr Eur J Occup Environ Med 7:176–281

    Google Scholar 

  39. Papp A, Pecze L, Vezér T (2004) Dynamics of central and peripheral evoked electrical activity in the nervous system of rats exposed to xenobiotics. Centr Eur J Occup Environ Med 10:52–59

    Google Scholar 

  40. Tracey DJ, Waite PME (1995) Somatosensory system. In: Paxinos G (ed) The rat nervous system, 4th edn. Academic Press, San Diego, pp 689–704

    Google Scholar 

  41. Zilles K (1984) The cortex of the rat: a stereotaxic atlas. Springer, Berlin

    Google Scholar 

  42. Kandel ER, Schwartz JH (1985) Principles of neural science. Elsevier, New York, pp 643–644

    Google Scholar 

  43. Dési I, Nagymajtényi L (1999) Electrophysiological biomarkers of an organophosphorous pesticide, dichlorvos. Toxicol Lett 107:55–64

    Article  PubMed  Google Scholar 

  44. Máté Z, Horváth E, Kovács K, Tombácz E, Papp A, Nagymajtényi L, Szabó A (2014) Subacute exposure of rats to chromium containing nanoparticles via the airways: neurological and general toxicological effects. Central Eur J Occup Environ Med 20:87–101

    Google Scholar 

  45. Oszlánczi G, Vezér T, Sárközi L, Horváth E, Kónya Z, Papp A (2010) Functional neurotoxicity of Mn-containing nanoparticles in rats. Ecotoxicol Environ Saf 73:2004–2009

    Article  PubMed  Google Scholar 

  46. Lundborg M, Eklund A, Lind DB, Camner P (1985) Dissolution of metals by human and rabbit alveolar macrophages. Br J Ind Med 42:642–645

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ayres JG, Borm P, Cassee FR, Castranova V, Donaldson K, Ghio A, Harrison RM, Hider R, Kelly F, Kooter IM (2008) Evaluating the toxicity of airborne particulate matter and nanoparticles by measuring oxidative stress potential—a workshop report and consensus statement. Inhal Toxicol 20:75–99

    Article  CAS  PubMed  Google Scholar 

  48. Xia T, Kovochich M, Brant J, Hotze M, Sempf J, Oberley T, Sioutas C, Yeh JI, Wiesner MR, Nel AE (2006) Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Lett 6:1794–1807. doi:10.1021/nl061025k

    Article  CAS  PubMed  Google Scholar 

  49. Guerra-Araiza C, Álvarez-Mejía AL, Sánchez-Torres S, Farfan-García E, Mondragón-Lozano R, Pinto-Almazán R, Salgado-Ceballos H (2013) Effect of natural exogenous antioxidants on aging and on neurodegenerative diseases. Free Rad Res 47:451–462

    Article  CAS  Google Scholar 

  50. Alexander GE, Crutcher MD, DeLong MR (1990) Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res 85:119–146

    Article  CAS  PubMed  Google Scholar 

  51. Alexi T, Borlongan CV, Faull RLM, Williams CE, Clark RG, Gluckmann PD, Hughes PE (2000) Neuroprotective strategies for basal ganglia degeneration: Parkinson’s and Huntington’s diseases. Prog Neurobiol 60:409–470

    Article  CAS  PubMed  Google Scholar 

  52. Hazell AS, Norenberg MD (1997) Manganese decreases glutamate uptake in cultured astrocytes. Neurochem Res 22:1443–1447

    Article  CAS  PubMed  Google Scholar 

  53. Lee E, Sidoryk-Wegrzynowicz M, Farina M, Rocha JBT, Aschner M (2013) Estrogen attenuates manganese-induced glutamate transporter impairment in rat primary astrocytes. Neurotox Res 23:124–130. doi:10.1007/s12640-012-9347-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695

    Article  CAS  PubMed  Google Scholar 

  55. Patki G, Solanki N, Atrooz F, Allam F, Salim S (2013) Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress. Brain Res 1539:73–86. doi:10.1016/j.brainres.2013.09.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Harris RBS, Zhou J, Youngblood BD, Rybkin II, Smagin GN, Ryan DH (1998) Effect of repeated stress on body weight and body composition of rats fed low- and high-fat diets. Am J Physiol 275:R1928–R1938

    CAS  PubMed  Google Scholar 

  57. Van de Giessen E, de Bruin K, la Fleur SE, van den Brink W, Booij J (2012) Triple monoamine inhibitor tesofensine decreases food intake, body weight, and striatal dopamine D2/D3 receptor availability in diet-induced obese rats. Eur Neuropsychopharmacol 22:290–299. doi:10.1016/j.euroneuro.2011.07.015

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Gábor Galbács and his colleagues at the Department of Inorganic and Analytical Chemistry, University of Szeged Faculty of Science and Informatics, for the metal level determinations.

This publication is supported by the European Union and co-financed by the European Social Fund. Project number: TÁMOP4.2.2.A-11/1/KONV-2012-0035. Project title: “Interaction of environmental and genetic factors in the development of immune-mediated and oncological diseases.”

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Public Health, University of Szeged Faculty of Medicine, 6720, Szeged, Dóm tér 10., Hungary

    Zsuzsanna Máté, Edina Horváth, Edit Paulik, András Papp & Andrea Szabó

  2. Department of Applied and Environmental Chemistry, University of Szeged Faculty of Science and Informatics, Szeged, Hungary

    Gábor Kozma, Tímea Simon & Zoltán Kónya

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  1. Zsuzsanna Máté
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  2. Edina Horváth
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  3. Gábor Kozma
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Correspondence to Zsuzsanna Máté.

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Máté, Z., Horváth, E., Kozma, G. et al. Size-Dependent Toxicity Differences of Intratracheally Instilled Manganese Oxide Nanoparticles: Conclusions of a Subacute Animal Experiment. Biol Trace Elem Res 171, 156–166 (2016). https://doi.org/10.1007/s12011-015-0508-z

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