title: Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications.
abstract: Prenatal and early postnatal exposures to environmental factors are considered responsible for the increasing prevalence of allergic diseases. Although there is some evidence for allergy-promoting effects in children because of exposure to plasticizers, such as phthalates, findings of previous studies are inconsistent and lack mechanistic information.
  
  
  
  We investigated the effect of maternal phthalate exposure on asthma development in subsequent generations and their underlying mechanisms, including epigenetic alterations.
  
  
  
  Phthalate metabolites were measured within the prospective mother-child cohort Lifestyle and Environmental Factors and Their Influence on Newborns Allergy Risk (LINA) and correlated with asthma development in the children. A murine transgenerational asthma model was used to identify involved pathways.
  
  
  
  In LINA maternal urinary concentrations of mono-n-butyl phthalate, a metabolite of butyl benzyl phthalate (BBP), were associated with an increased asthma risk in the children. Using a murine transgenerational asthma model, we demonstrate a direct effect of BBP on asthma severity in the offspring with a persistently increased airway inflammation up to the F2 generation. This disease-promoting effect was mediated by BBP-induced global DNA hypermethylation in CD4+T cells of the offspring because treatment with a DNA-demethylating agent alleviated exacerbation of allergic airway inflammation. Thirteen transcriptionally downregulated genes linked to promoter or enhancer hypermethylation were identified. Among these, the GATA-3 repressor zinc finger protein 1 (Zfpm1) emerged as a potential mediator of the enhanced susceptibility for TH2-driven allergic asthma.
  
  
  
  These data provide strong evidence that maternal BBP exposure increases the risk for allergic airway inflammation in the offspring by modulating the expression of genes involved in TH2 differentiation through epigenetic alterations.
authors.affiliation: Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany; Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany; Infections in Hematology/Oncology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Jahreis
authors.affiliation: Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany; Institute of Pharmacy and Molecular Biotechnology, and Bioquant Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Trump
authors.affiliation: Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bauer
authors.affiliation: Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany.
authors.forename: Loreen
authors.initials: L
authors.lastname: Thürmann
authors.affiliation: Department Molecular Systems Biology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Feltens
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Cell Biology, Harvard Medical School, Boston.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Grützmann
authors.affiliation: Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Röder
authors.affiliation: Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Averbeck
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Institute of Clinical Immunology, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sack
authors.affiliation: Municipal Hospital "St Georg" Children's Hospital, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Borte
authors.affiliation: Young Investigators Group Bioinformatics and Transcriptomics, Department Molecular Systems Biology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany.
authors.forename: Virginie
authors.initials: V
authors.lastname: Dubourg
authors.affiliation: Department of Ecological Chemistry, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany; Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Freiberg, Germany.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Schüürmann
authors.affiliation: Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Simon
authors.affiliation: Department Molecular Systems Biology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany; Institute of Biochemistry, Faculty of Bioscience, Pharmacy and Psychology, University of Leipzig, Leipzig, Germany; Department of Chemistry and Bioscience, University of Aalborg, Aalborg, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: von Bergen
authors.affiliation: Young Investigators Group Bioinformatics and Transcriptomics, Department Molecular Systems Biology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hackermüller
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pharmacy and Molecular Biotechnology, and Bioquant Center, University of Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.affiliation: Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Lehmann
authors.affiliation: Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany; Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany. Electronic address: tobias.polte@ufz.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Polte
mesh_terms: D000328:Adult; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D002648:Child; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000276:immunology; D005260:Female; D005858:Germany; D006801:Humans; D007231:Infant, Newborn; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D009687:Nuclear Proteins / Q000276:immunology; D010795:Phthalic Acids / Q000633:toxicity*; D011247:Pregnancy; D011446:Prospective Studies; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D014157:Transcription Factors / Q000276:immunology
chemical_list: D009687:Nuclear Proteins; D010795:Phthalic Acids; D014157:Transcription Factors; C107310:Zfpm1 protein, mouse; C032279:phthalic acid
keywords: Airway inflammation; T cells; asthma; epigenetics; phthalates