title: In Utero Cigarette Smoke Affects Allergic Airway Disease But Does Not Alter the Lung Methylome.
abstract: Prenatal and postnatal cigarette smoke exposure enhances the risk of developing asthma. Despite this as well as other smoking related risks, 11% of women still smoke during pregnancy. We hypothesized that cigarette smoke exposure during prenatal development generates long lasting differential methylation altering transcriptional activity that correlates with disease. In a house dust mite (HDM) model of allergic airway disease, we measured airway hyperresponsiveness (AHR) and airway inflammation between mice exposed prenatally to cigarette smoke (CS) or filtered air (FA). DNA methylation and gene expression were then measured in lung tissue. We demonstrate that HDM-treated CS mice develop a more severe allergic airway disease compared to HDM-treated FA mice including increased AHR and airway inflammation. While DNA methylation changes between the two HDM-treated groups failed to reach genome-wide significance, 99 DMRs had an uncorrected p-value < 0.001. 6 of these 99 DMRs were selected for validation, based on the immune function of adjacent genes, and only 2 of the 6 DMRs confirmed the bisulfite sequencing data. Additionally, genes near these 6 DMRs (Lif, Il27ra, Tle4, Ptk7, Nfatc2, and Runx3) are differentially expressed between HDM-treated CS mice and HDM-treated FA mice. Our findings confirm that prenatal exposure to cigarette smoke is sufficient to modify allergic airway disease; however, it is unlikely that specific methylation changes account for the exposure-response relationship. These findings highlight the important role in utero cigarette smoke exposure plays in the development of allergic airway disease.
authors.affiliation: Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado, United States of America.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Eyring
authors.affiliation: Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado, United States of America.
authors.forename: Brent S
authors.initials: BS
authors.lastname: Pedersen
authors.affiliation: Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado, United States of America.
authors.forename: Ivana V
authors.initials: IV
authors.lastname: Yang
authors.affiliation: Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado, United States of America.|Department of Immunology, School of Medicine, University of Colorado, Aurora, Colorado, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D001249:Asthma / Q000196:embryology* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008168:Lung / Q000196:embryology* / Q000473:pathology; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000473:pathology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D014028:Tobacco Smoke Pollution