title: A mouse model links asthma susceptibility to prenatal exposure to diesel exhaust.
abstract: BACKGROUND
  Most asthma begins in the first years of life. This early onset cannot be attributed merely to genetic factors because the prevalence of asthma is increasing. Epidemiologic studies have indicated roles for prenatal and early childhood exposures, including exposure to diesel exhaust. However, little is known about the mechanisms. This is largely due to a paucity of animal models.
  
  
  OBJECTIVE
  We aimed to develop a mouse model of asthma susceptibility through prenatal exposure to diesel exhaust.
  
  
  METHODS
  Pregnant C57BL/6 female mice were given repeated intranasal applications of diesel exhaust particles (DEPs) or PBS. Offspring underwent suboptimal immunization and challenge with ovalbumin (OVA) or received PBS. Pups were examined for features of asthma; lung and liver tissues were analyzed for transcription of DEP-regulated genes.
  
  
  RESULTS
  Offspring of mice exposed to DEPs were hypersensitive to OVA, as indicated by airway inflammation and hyperresponsiveness, increased serum OVA-specific IgE levels, and increased pulmonary and systemic TH2 and TH17 cytokine levels. These cytokines were primarily produced by natural killer (NK) cells. Antibody-mediated depletion of NK cells prevented airway inflammation. Asthma susceptibility was associated with increased transcription of genes known to be specifically regulated by the aryl hydrocarbon receptor and oxidative stress. Features of asthma were either marginal or absent in OVA-treated pups of PBS-exposed mice.
  
  
  CONCLUSIONS
  We created a mouse model that linked maternal exposure to DEPs with asthma susceptibility in offspring. Development of asthma was dependent on NK cells and associated with increased transcription from aryl hydrocarbon receptor- and oxidative stress-regulated genes.
authors.affiliation: Department of Medicine, Division of Allergy and Clinical Immunology, National Jewish Health, Denver, Colo.
authors.forename: Sarah
authors.initials: S
authors.lastname: Manners
authors.affiliation: Department of Medicine, Division of Allergy and Clinical Immunology, National Jewish Health, Denver, Colo; Department of Medicine, Division of Allergy and Clinical Immunology, University of Colorado Denver, Aurora, Colo.
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
authors.affiliation: Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colo.
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
authors.affiliation: Department of Medicine, Division of Allergy and Clinical Immunology, National Jewish Health, Denver, Colo; Department of Medicine, Division of Allergy and Clinical Immunology, University of Colorado Denver, Aurora, Colo. Electronic address: gorskam@njhealth.org.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Gorska
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D018811:Maternal Exposure / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D000393:Air Pollutants; D020381:Interleukin-17; D018336:Receptors, Aryl Hydrocarbon; D001335:Vehicle Emissions; D007073:Immunoglobulin E; D010047:Ovalbumin
keywords: IL-13; IL-17; IL-5; Prenatal exposure; aryl hydrocarbon receptor; asthma; diesel exhaust particles; mouse model; natural killer cells