ToxSci Advance Access published online on January 11, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn006
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Published by Oxford University Press 2008.
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Increased Transcription of Immune and Metabolic Pathways in Naïve and Allergic Mice Exposed to Diesel Exhaust
* Curriculum of Toxicology, University of North Carolina, Chapel Hill, NC 27599
Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory
Air Pollution and Prevention Control Division, National Risk Management Research Laboratory
Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, 27711
Address correspondence to: Dr. M. Ian Gilmour, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 USA. Telephone: (919) 541-0015. Fax: (919) 541-0026. E-mail: gilmour.ian{at}epa.gov, Research Triangle Park, NC 27709 USA
Received October 19, 2007; revision received January 3, 2008; accepted January 7, 2008
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Abstract |
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Diesel exhaust (DE) has been shown to enhance allergic sensitization in animals following high dose instillation or chronic inhalation exposure scenarios. The purpose of this study was to determine if short term exposures to diluted DE enhance allergic immune responses to antigen, and identify possible mechanisms using microarray technology. BALB/c mice were exposed to filtered air or diluted DE to yield particle concentrations of 500 or 2000 µg/m3 4 hr/day on days 0-4. Mice were immunized intranasally with ovalbumin (OVA) antigen or saline on days 0-2, challenged on day 18 with OVA or saline, and all mice were challenged with OVA on day 28. Mice were necropsied either 4 hrs after the last DE exposure on day 4, or 18, 48, and 96 hrs after the last challenge. Immunological endpoints included OVA-specific serum IgE, biochemical and cellular profiles of bronchoalveolar lavage (BAL), and cytokine production in the BAL. OVA-immunized mice exposed to both concentrations of DE had increased eosinophils, neutrophils, lymphocytes, and IL-6 post-challenge compared to OVA control, while DE/saline exposure yielded increases in neutrophils at the high dose only. Transcriptional microarray analysis 4 hrs after the last DE exposure demonstrated distinct gene expression profiles for the high dose DE/OVA and DE/saline groups. DE/OVA induced oxidative stress and metabolism pathways while DE in the absence of immunization modulated cell cycle control, growth and differentiation, G-proteins, and cell adhesion pathways. This study shows for the first time early changes in gene expression induced by the combination of diesel exhaust inhalation and mucosal immunization, which resulted in stronger development of allergic eosinophilia.
Key Words: Diesel; Genomics; Mice; Lung; Allergy.