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ToxSci Advance Access originally published online on November 27, 2007
Toxicological Sciences 2008 102(1):76-81; doi:10.1093/toxsci/kfm290
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Combined Inhaled Diesel Exhaust Particles and Allergen Exposure Alter Methylation of T Helper Genes and IgE Production In Vivo

Jinming Liu*, Manisha Ballaney*, Umaima Al-alem*, Chunli Quan{dagger}, Ximei Jin{dagger}, Frederica Perera{ddagger}, Lung-Chi Chen{dagger} and Rachel L. Miller*,1

* Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032 {dagger} Environmental Health Sciences, New York University, Tuxedo, New York 10987 {ddagger} Joseph L. Mailman School of Public Health, Columbia University, New York, New York 10032

1 To whom correspondence should be addressed at PH8C, Columbia University College of Physicians and Surgeons, 630 W. 168th St, NY, NY 10032. Fax: (212) 305-2277. E-mail: rlm14{at}columbia.edu.

Received September 21, 2007; accepted November 20, 2007


  Abstract

Changes in methylation of CpG sites at the interleukin (IL)-4 and interferon (IFN)-{gamma} promoters are associated with T helper (Th) 2 polarization in vitro. No previous studies have examined whether air pollution or allergen exposure alters methylation of these two genes in vivo. We hypothesized that diesel exhaust particles (DEP) would induce hypermethylation of the IFN-{gamma} promoter and hypomethylation of IL-4 in CD4+ T cells among mice sensitized to the fungus allergen Aspergillus fumigatus. We also hypothesized that DEP-induced methylation changes would affect immunoglobulin (Ig) E regulation. BALB/c mice were exposed to a 3-week course of inhaled DEP exposure while undergoing intranasal sensitization to A. fumigatus. Purified DNA from splenic CD4+ cells underwent bisulfite treatment, PCR amplification, and pyrosequencing. Sera IgE levels were compared with methylation levels at several CpG sites in the IL-4 and IFN-{gamma} promoter. Total IgE production was increased following intranasal sensitization A. fumigatus. IgE production was augmented further following combined exposure to A. fumigatus and DEP exposure. Inhaled DEP exposure and intranasal A. fumigatus induced hypermethylation at CpG–45, CpG–53, CpG–205 sites of the IFN-{gamma} promoter and hypomethylation at CpG–408 of the IL-4 promoter. Altered methylation of promoters of both genes was correlated significantly with changes in IgE levels. This study is the first to demonstrate that inhaled environmental exposures influence methylation of Th genes in vivo, supporting a new paradigm in asthma pathogenesis.

Key Words: environmental exposure; respiratory sensitization; cytokines; inhalation toxicology; epigenetic modification.


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