Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease

Journal of Neuroinflammation

Michelle L Block²  Jacob McDonald¹  Michael J Surace²  Shannon Levesque² 

[1] Lovelace Respiratory Research Institute, Albuquerque, NM, 87108, USA;Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, VA 23298, USA

关键词: Aβ42;    TNFα;    α synuclein;    Tau hyperphosphorylation;    midbrain;    diesel exhaust;    Air pollution;   

Others  :  1213171
DOI  :  10.1186/1742-2094-8-105

 received in 2011-05-11, accepted in 2011-08-24,  发布年份 2011

【 摘 要 】

Background

Increasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood.

Objective

We explored the central nervous system consequences of subchronic exposure to diesel exhaust (DE) and addressed the minimum levels necessary to elicit neuroinflammation and markers of early neuropathology.

Methods

Male Fischer 344 rats were exposed to DE (992, 311, 100, 35 and 0 μg PM/m³) by inhalation over 6 months.

Results

DE exposure resulted in elevated levels of TNFα at high concentrations in all regions tested, with the exception of the cerebellum. The midbrain region was the most sensitive, where exposures as low as 100 μg PM/m³ significantly increased brain TNFα levels. However, this sensitivity to DE was not conferred to all markers of neuroinflammation, as the midbrain showed no increase in IL-6 expression at any concentration tested, an increase in IL-1β at only high concentrations, and a decrease in MIP-1α expression, supporting that compensatory mechanisms may occur with subchronic exposure. Aβ42 levels were the highest in the frontal lobe of mice exposed to 992 μg PM/m³ and tau [pS199] levels were elevated at the higher DE concentrations (992 and 311 μg PM/m³) in both the temporal lobe and frontal lobe, indicating that proteins linked to preclinical Alzheimer's disease were affected. α Synuclein levels were elevated in the midbrain in response to the 992 μg PM/m³ exposure, supporting that air pollution may be associated with early Parkinson's disease-like pathology.

Conclusions

Together, the data support that the midbrain may be more sensitive to the neuroinflammatory effects of subchronic air pollution exposure. However, the DE-induced elevation of proteins associated with neurodegenerative diseases was limited to only the higher exposures, suggesting that air pollution-induced neuroinflammation may precede preclinical markers of neurodegenerative disease in the midbrain.

【 授权许可】

   
2011 Levesque et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Block ML, Zecca L, Hong JS: Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007, 8:57-69.
• [2]Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH: Mechanisms underlying inflammation in neurodegeneration. Cell 2010, 140:918-934.
• [3]Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG: Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener 2009, 4:47. BioMed Central Full Text
• [4]Carvey PM, Punati A, Newman MB: Progressive dopamine neuron loss in Parkinson's disease: the multiple hit hypothesis. Cell Transplant 2006, 15:239-250.
• [5]Horowitz MP, Greenamyre JT: Gene-environment interactions in Parkinson's disease: the importance of animal modeling. Clin Pharmacol Ther 2010, 88:467-474.
• [6]Liu B, Gao HM, Hong JS: Parkinson's disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: role of neuroinflammation. Environ Health Perspect 2003, 111:1065-1073.
• [7]Akimoto H: Global air quality and pollution. Science 2003, 302:1716-1719.
• [8]National Ambient Air Quality Standards [http://www.epa.gov/air/criteria.html] webcite
• [9]Mauderly JL, Burnett RT, Castillejos M, Ozkaynak H, Samet JM, Stieb DM, Vedal S, Wyzga RE: Is the air pollution health research community prepared to support a multipollutant air quality management framework? Inhal Toxicol 2010, 22(Suppl 1):1-19.
• [10]Block ML, Calderon-Garciduenas L: Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci 2009, 32:506-516.
• [11]Kipen H, Rich D, Huang W, Zhu T, Wang G, Hu M, Lu SE, Ohman-Strickland P, Zhu P, Wang Y, Zhang JJ: Measurement of inflammation and oxidative stress following drastic changes in air pollution during the Beijing Olympics: a panel study approach. Ann N Y Acad Sci 2010, 1203:160-167.
• [12]Campen MJ, Lund AK, Knuckles TL, Conklin DJ, Bishop B, Young D, Seilkop S, Seagrave J, Reed MD, McDonald JD: Inhaled diesel emissions alter atherosclerotic plaque composition in ApoE(-/-) mice. Toxicol Appl Pharmacol 2010, 242:310-317.
• [13]Calderon-Garciduenas L, Mora-Tiscareno A, Ontiveros E, Gomez-Garza G, Barragan-Mejia G, Broadway J, Chapman S, Valencia-Salazar G, Jewells V, Maronpot RR, et al.: Air pollution, cognitive deficits and brain abnormalities: a pilot study with children and dogs. Brain Cogn 2008, 68:117-127.
• [14]Calderon-Garciduenas L, Reed W, Maronpot RR, Henriquez-Roldan C, Delgado-Chavez R, Calderon-Garciduenas A, Dragustinovis I, Franco-Lira M, Aragon-Flores M, Solt AC, et al.: Brain inflammation and Alzheimer's-like pathology in individuals exposed to severe air pollution. Toxicol Pathol 2004, 32:650-658.
• [15]Mateen FJ, Brook RD: Air pollution as an emerging global risk factor for stroke. JAMA 2011, 305:1240-1241.
• [16]Finkelstein MM, Jerrett M: A study of the relationships between Parkinson's disease and markers of traffic-derived and environmental manganese air pollution in two Canadian cities. Environ Res 2007, 104:420-432.
• [17]TE M, DA D, N I, JA T, D S, Z N, W K, Y H, NA W, J C, et al.: Glutamatergic Neurons in Rodent Models Respond to Nanoscale Particulate Urban Air Pollutants In Vivo and In Vitro. Environ Health Perspect 2011.
• [18]Levesque S, Taetzsch T, Lull ME, Kodavanti U, Stadler K, Wagner A, Johnson J, Duke L, Kodavanti P, Surace M, Block ML: Diesel Exhaust Activates & Primes Microglia: Air Pollution, Neuroinflammation, & Regulation of Dopaminergic Neurotoxicity. Environ Health Perspect, in press.
• [19]Santiago-Lopez D, Bautista-Martinez JA, Reyes-Hernandez CI, Aguilar-Martinez M, Rivas-Arancibia S: Oxidative stress, progressive damage in the substantia nigra and plasma dopamine oxidation, in rats chronically exposed to ozone. Toxicol Lett 2010, 197:193-200.
• [20]Antonini JM, Sriram K, Benkovic SA, Roberts JR, Stone S, Chen BT, Schwegler-Berry D, Jefferson AM, Billig BK, Felton CM, et al.: Mild steel welding fume causes manganese accumulation and subtle neuroinflammatory changes but not overt neuronal damage in discrete brain regions of rats after short-term inhalation exposure. Neurotoxicology 2009, 30:915-925.
• [21]Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A, Ito Y, Finkelstein J, Oberdorster G: Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect 2006, 114:1172-1178.
• [22]McDonald JD, Barr EB, White RK, Chow JC, Schauer JJ, Zielinska B, Grosjean E: Generation and characterization of four dilutions of diesel engine exhaust for a subchronic inhalation study. Environ Sci Technol 2004, 38:2513-2522.
• [23]Pronk A, Coble J, Stewart PA: Occupational exposure to diesel engine exhaust: a literature review. J Expo Sci Environ Epidemiol 2009, 19:443-457.
• [24]Mauderly JL: Diesel emissions: is more health research still needed? Toxicol Sci 2001, 62:6-9.
• [25]Cruts B, van Etten L, Tornqvist H, Blomberg A, Sandstrom T, Mills NL, Borm PJ: Exposure to diesel exhaust induces changes in EEG in human volunteers. Part Fibre Toxicol 2008, 5:4. BioMed Central Full Text
• [26]Suzuki T, Oshio S, Iwata M, Saburi H, Odagiri T, Udagawa T, Sugawara I, Umezawa M, Takeda K: In utero exposure to a low concentration of diesel exhaust affects spontaneous locomotor activity and monoaminergic system in male mice. Part Fibre Toxicol 2010, 7:7. BioMed Central Full Text
• [27]Yokota S, Mizuo K, Moriya N, Oshio S, Sugawara I, Takeda K: Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice. Neurosci Lett 2009, 449:38-41.
• [28]Gerlofs-Nijland ME, van Berlo D, Cassee FR, Schins RP, Wang K, Campbell A: Effect of prolonged exposure to diesel engine exhaust on proinflammatory markers in different regions of the rat brain. Part Fibre Toxicol 2010, 7:12. BioMed Central Full Text
• [29]van Berlo D, Albrecht C, Knaapen AM, Cassee FR, Gerlofs-Nijland ME, Kooter IM, Palomero-Gallagher N, Bidmon HJ, van Schooten FJ, Krutmann J, Schins RP: Comparative evaluation of the effects of short-term inhalation exposure to diesel engine exhaust on rat lung and brain. Arch Toxicol 2010, 84:553-562.
• [30]Reed MD, Gigliotti AP, McDonald JD, Seagrave JC, Seilkop SK, Mauderly JL: Health effects of subchronic exposure to environmental levels of diesel exhaust. Inhal Toxicol 2004, 16:177-193.
• [31]Seagrave J, McDonald JD, Reed MD, Seilkop SK, Mauderly JL: Responses to subchronic inhalation of low concentrations of diesel exhaust and hardwood smoke measured in rat bronchoalveolar lavage fluid. Inhal Toxicol 2005, 17:657-670.
• [32]Boothe VL, Shendell DG: Potential health effects associated with residential proximity to freeways and primary roads: review of scientific literature, 1999-2006. J Environ Health 2008, 70:33-41. 55-36
• [33]McDonald JD, Campen MJ, Harrod KS, Seagrave J, Seilkop SK, Mauderly JL: Engine Operating Load Influences Diesel Exhaust Composition and Cardiopulmonary and Immune Responses. Environ Health Perspect 2011.
• [34]Abramoff M, Magelhaes PJ, Ram S: Image processing with ImageJ. Biophotonics Int 2004, 11:36-42.
• [35]Barnum CJ, Tansey MG: The duality of TNF signaling outcomes in the brain: Potential mechanisms? Exp Neurol 2011.
• [36]McCoy MK, Ruhn KA, Blesch A, Tansey MG: TNF: a key neuroinflammatory mediator of neurotoxicity and neurodegeneration in models of Parkinson's disease. Adv Exp Med Biol 2011, 691:539-540.
• [37]Kimura T, Ono T, Takamatsu J, Yamamoto H, Ikegami K, Kondo A, Hasegawa M, Ihara Y, Miyamoto E, Miyakawa T: Sequential changes of tau-site-specific phosphorylation during development of paired helical filaments. Dementia 1996, 7:177-181.
• [38]Maurage CA, Sergeant N, Ruchoux MM, Hauw JJ, Delacourte A: Phosphorylated serine 199 of microtubule-associated protein tau is a neuronal epitope abundantly expressed in youth and an early marker of tau pathology. Acta Neuropathol 2003, 105:89-97.
• [39]Sironi F, Trotta L, Antonini A, Zini M, Ciccone R, Della Mina E, Meucci N, Sacilotto G, Primignani P, Brambilla T, et al.: alpha-Synuclein multiplication analysis in Italian familial Parkinson disease. Parkinsonism Relat Disord 2010, 16:228-231.
• [40]Chiba-Falek O, Lopez GJ, Nussbaum RL: Levels of alpha-synuclein mRNA in sporadic Parkinson disease patients. Mov Disord 2006, 21:1703-1708.
• [41]Chahine LM, Stern MB: Diagnostic markers for Parkinson's disease. Curr Opin Neurol 2011.
• [42]Calderon-Garciduenas L, Franco-Lira M, Henriquez-Roldan C, Osnaya N, Gonzalez-Maciel A, Reynoso-Robles R, Villarreal-Calderon R, Herritt L, Brooks D, Keefe S, et al.: Urban air pollution: influences on olfactory function and pathology in exposed children and young adults. Exp Toxicol Pathol 2010, 62:91-102.
• [43]Portelius E, Mattsson N, Andreasson U, Blennow K, Zetterberg H: Novel Abeta Isoforms in Alzheimer s Disease - Their Role in Diagnosis and Treatment. Curr Pharm Des 2011.
• [44]Thomas A, Ballard C, Kenny RA, O'Brien J, Oakley A, Kalaria R: Correlation of entorhinal amyloid with memory in Alzheimer's and vascular but not Lewy body dementia. Dement Geriatr Cogn Disord 2005, 19:57-60.
• [45]McCoy MK, Tansey MG: TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 2008, 5:45. BioMed Central Full Text
• [46]Campbell A, Araujo JA, Li H, Sioutas C, Kleinman M: Particulate matter induced enhancement of inflammatory markers in the brains of apolipoprotein E knockout mice. J Nanosci Nanotechnol 2009, 9:5099-5104.
• [47]Tonelli LH, Postolache TT: Airborne inflammatory factors: "from the nose to the brain". Front Biosci (Schol Ed) 2010, 2:135-152.
• [48]Oberdorster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C: Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol 2004, 16:437-445.
• [49]Savchenko VL, McKanna JA, Nikonenko IR, Skibo GG: Microglia and astrocytes in the adult rat brain: comparative immunocytochemical analysis demonstrates the efficacy of lipocortin 1 immunoreactivity. Neuroscience 2000, 96:195-203.
• [50]Lucas SM, Rothwell NJ, Gibson RM: The role of inflammation in CNS injury and disease. Br J Pharmacol 2006, 147(Suppl 1):S232-240.
• [51]Spooren A, Kolmus K, Laureys G, Clinckers R, De Keyser J, Haegeman G, Gerlo S: Interleukin-6, a mental cytokine. Brain Res Rev 2011.
• [52]Cheung G, Kann O, Kohsaka S, Faerber K, Kettenmann H: GABAergic activities enhance macrophage inflammatory protein-1alpha release from microglia (brain macrophages) in postnatal mouse brain. J Physiol 2009, 587:753-768.
• [53]Metcalfe MJ, Figueiredo-Pereira ME: Relationship between tau pathology and neuroinflammation in Alzheimer's disease. Mt Sinai J Med 2010, 77:50-58.