title: Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells.
abstract: BACKGROUND
  Evidence suggests that exposure to polycyclic aromatic hydrocarbons (PAHs) increases atopy; it is unclear how PAH exposure is linked to increased severity of atopic diseases.
  
  
  OBJECTIVE
  We hypothesized that ambient PAH exposure is linked to impairment of immunity in atopic children (defined as children with asthma and/or allergic rhinitis) from Fresno, California, an area with elevated ambient PAHs.
  
  
  METHODS
  We recruited 256 subjects from Fresno, CA. Ambient PAH concentrations (ng/m(3) ) were measured using a spatial-temporal regression model over multiple time periods. Asthma diagnosis was determined by current NHLBI criteria. Phenotyping and functional immune measurements were performed from isolated cells. For epigenetic measurements, DNA was isolated and pyrosequenced.
  
  
  RESULTS
  We show that higher average PAH exposure was significantly associated with impaired Treg function and increased methylation in the forkhead box protein 3 (FOXP3) locus (P < 0.05), conditional on atopic status. These epigenetic modifications were significantly linked to differential protein expression of FOXP3 (P < 0.001). Methylation was associated with cellular functional changes, specifically Treg dysfunction, and an increase in total plasma IgE levels. Protein expression of IL-10 decreased and IFN-γ increased as the extent of PAH exposure increased. The strength of the associations generally increased as the time window for average PAH exposure increased from 24 hr to 1 year, suggesting more of a chronic response. Significant associations with chronic PAH exposure and immune outcomes were also observed in subjects with allergic rhinitis.
  
  
  CONCLUSIONS
  Collectively, these results demonstrate that increased ambient PAH exposure is associated with impaired systemic immunity and epigenetic modifications in a key locus involved in atopy: FOXP3, with a higher impact on atopic children. The results suggest that increased atopic clinical symptoms in children could be linked to increased PAH exposure in air pollution.
authors.affiliation: Department of Pediatric Allergy and Immunology, Stanford University, Stanford, CA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Hew
authors.forename: A I
authors.initials: AI
authors.lastname: Walker
authors.forename: A
authors.initials: A
authors.lastname: Kohli
authors.forename: M
authors.initials: M
authors.lastname: Garcia
authors.forename: A
authors.initials: A
authors.lastname: Syed
authors.forename: C
authors.initials: C
authors.lastname: McDonald-Hyman
authors.forename: E M
authors.initials: EM
authors.lastname: Noth
authors.forename: J K
authors.initials: JK
authors.lastname: Mann
authors.forename: B
authors.initials: B
authors.lastname: Pratt
authors.forename: J
authors.initials: J
authors.lastname: Balmes
authors.forename: S Katharine
authors.initials: SK
authors.lastname: Hammond
authors.forename: E A
authors.initials: EA
authors.lastname: Eisen
authors.forename: K C
authors.initials: KC
authors.lastname: Nadeau
mesh_terms: D000397:Air Pollution / Q000009:adverse effects*; D001249:Asthma / Q000139:chemically induced / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000187:drug effects / Q000276:immunology; D004781:Environmental Exposure / Q000009:adverse effects*; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D007073:Immunoglobulin E / Q000276:immunology; D007223:Infant; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D008297:Male; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D065631:Rhinitis, Allergic / Q000139:chemically induced / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C573415:IFNG protein, human; C508609:IL10 protein, human; D011084:Polycyclic Aromatic Hydrocarbons; D016753:Interleukin-10; D007073:Immunoglobulin E; D007371:Interferon-gamma
keywords: FOXP3; IFN-γ; T regulatory cells; Treg function; epigenetics; polycyclic aromatic hydrocarbons; total IgE