Objective-To determine the impact of environmental exposures (diesel exhaust particle (DEP), environmental tobacco smoke (ETS), and mold) that may contribute to oxidative stress on persistent wheezing in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort and to determine how the impact of these exposures is modified by the GST-P1 Ile105Val polymorphism.Study design-A land-use regression model was used to derive an estimate of each child's DEP exposure. ETS exposure was determined by questionnaire data. Each child's home was evaluated for visible mold by a trained professional. Children in the CCAAPS cohort were genotyped for the GST-P1 polymorphism (N=570). Persistent wheezing was defined as wheezing at both 12 and 24 months.Results-High DEP exposure conferred increased risk for wheezing phenotypes but only among the Val 105 allele carriers. Infants with multiple exposures were significantly more likely to persistently wheeze despite their genotype.Conclusion-There is evidence for an environmental effect of DEP among carriers of the GST-P1 Val 105 allele in the development of persistent wheezing in children. The protective effect of the © 2008 Mosby, Inc. All rights reserved.Correspondence should be addressed to: Gurjit K. Khurana Hershey, M.D., Ph.D., Institute for Personalized and Predictive Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 7037, Cincinnati, Phone: (513) Fax: (513) 636-1657; E-mail: Gurjit.Hershey@cchmc.org . Edited by Padbury and WFBPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Delineating the factors that are contributory or protective to persistent wheezing in early childhood is critical to advance our understanding of asthma. There is limited information about how genetic and environmental factors interact to influence longitudinal asthmatic/wheezing status over time. DEP, ETS, and mold exposures are common and each has been shown to aggravate respiratory symptoms. The gene-environment effect related to these individual and/ or combined exposures has not been evaluated with regard to longitudinal wheezing status. The purpose of this study was to investigate whether exposure to DEP, ETS, and/or mold uniquely modifies wheezing and persistent wheezing in young children, especially among those with the GST-P1 I105V polymorphism. Our study evaluates the modified effect of this polymorphism upon exposure to not only ETS and mold, but distinctively DEP exposure associated with traffic and their combined exposures utilizing the well-characterized Cincinnati Childhood Allergy and Air Pol...

Allergic sensitization is prevalent even among children who do not have a personal or family history of asthma, allergic rhinitis, or atopic dermatitis and who have no evidence of current, even subtle effects from this sensitization on allergic disease-related quality of life. African-American children are at greater risk for presence of sensitization, especially to outdoor allergens.

Background Glutathione S-transferase Pi (GSTPi) is the predominant redox regulator in the lung. While evidence implicates an important role for GSTPi in asthma, the mechanism for this has remained elusive. Objectives To determine how GSTPi is regulated in asthma and to elucidate its role in maintaining redox homeostasis. Methods We elucidated the regulation of GSTPi in children with asthma and utilized murine models of asthma to determine the role of GSTPi in redox homeostasis. Measurements and Main Results Our findings demonstrate that GSTPi transcript levels are markedly down-regulated in allergen and IL-13 treated mouse models of asthma via STAT6 dependent and independent pathways. Nuclear factor-erythroid 2 related factor 2 (Nrf2) was also down-regulated in these models. The decrease in GSTPi expression was associated with decreased total GST activity in the lungs of mice. Examination of cystine intermediates uncovered a functional role for GSTPi in regulating Cys oxidation, whereby GSTPi-deficient mice exhibited increased oxidative stress (increase in % cystine) compared with wild-type mice following allergen challenge. GSTPi expression was similarly down-regulated in children with asthma. Conclusions These data collectively suggest that down-regulation of GSTPi following allergen challenge may contribute to the asthma phenotype due to disruption of redox homeostasis and increased oxidative stress. Furthermore, GSTPi may be an important therapeutic target for asthma, and evaluation of GSTPi expression may prove beneficial in identifying individuals who would benefit from therapy targeting this pathway.