Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications - 28/02/18
Abstract |
Background |
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.
Objective |
We investigated the effect of maternal phthalate exposure on asthma development in subsequent generations and their underlying mechanisms, including epigenetic alterations.
Methods |
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.
Results |
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.
Conclusion |
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.
Le texte complet de cet article est disponible en PDF.Key words : Airway inflammation, asthma, phthalates, epigenetics, T cells
Abbreviations used : AHR, Aza, BBP, DEG, DMR, Fads1, Fanca, Foxp3, LINA, MBzP, MnBP, OVA, WGBS, Zfpm1
Plan
Supported by the Helmholtz Association grant VG-NG-337, the LIFE–Leipzig Research Center for Civilization Diseases (LIFE-007-D7), and the Helmholtz Initiative for Personalized Medicine (iMed). M.v.B. was funded by the DFG SFB 1052. |
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Disclosure of potential conflict of interest: C. Plass and M. Borte have received consultancy fees from BioMedX. T. Bauer was supported by the Federal Ministry of Education and Research (BMBF)-funded eMED network PANC–STRAT. U. Sack has personally received travel expenses from Phadia GmbH, Freiburg, Germany, for other works. J. Hackermüller's institution received grant VH-NG738 from the Initiative and Networking Fund of the Helmholtz Association for this work and has patents from Fraunhofer Society for other works and his institution has received travel expenses from the European Centre for Ecotoxicology and Toxicology of Chemicals for other works. R. Eils' institution received a grant from the BMBF for this work and other works, received consultancy fees from Qiagen, and received fees for expert testimony from Steinbeis GmbH & Co KG, and he has personally received consultancy fees from Merck Darmstadt. S. Trump received e:Med funding from the BMBF and was supported by iMed from the Helmholtz Association. T. Polte's institute has received grants VG-NG-337 from Helmholtz Association, LIFE-007-D7 from LIFE–Leipzig Research Center for Civilization Diseases, and support from iMed from Helmholtz Association for this work. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 141 - N° 2
P. 741-753 - février 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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