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Title (Primary) Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications
Author Jahreis, S.; Trump, S.; Bauer, M.; Bauer, T.; Thürmann, L.; Feltens, R.; Wang, Q.; Gu, L.; Grützmann, K.; Röder, S.; Averbeck, M.; Weichenhan, D.; Plass, C.; Sack, U.; Borte, M.; Dubourg, V.; Schüürmann, G.; Simon, J.C.; von Bergen, M.; Hackermüller, J.; Eils, R.; Lehmann, I.; Polte, T.;
Journal Journal of Allergy and Clinical Immunology
Year 2018
Department OEC; IMMU; METABOX; STUDIEN; MOLSYB;
Volume 141
Issue 2
Language englisch;
POF III (all) F11; T42;
Supplements https://www.jacionline.org/cms/attachment/2118980974/2087558731/mmc3.xls
https://www.jacionline.org/cms/attachment/2118980974/2087558732/mmc2.xlsx
https://www.jacionline.org/cms/attachment/2118980974/2087558733/mmc4.xlsx
https://www.jacionline.org/cms/attachment/2118980974/2087558734/mmc1.docx
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Keywords airway inflammation, asthma, phthalates, epigenetics, T cells
UFZ wide themes RU3;
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 due to exposure to plasticizers like phthalates, findings of previous studies are inconsistent and lack mechanistic information.

Objective

We investigated the effect of maternal phthalate exposure on asthma development in the subsequent generations and their underlying mechanisms including epigenetic alterations.

Methods

Phthalate metabolites were measured within the prospective mother-child cohort LINA and correlated with asthma development in the children. A murine trans-generational 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 trans-generational 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 a BBP-induced global DNA hypermethylation in CD4+ T cells of the offspring as treatment with a DNA demethylating agent alleviated exacerbation of allergic airway inflammation. 13 transcriptionally down-regulated genes linked to promoter or enhancer hypermethylation were identified. Among these, the GATA-3 repressor 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 via epigenetic alterations.

ID 18496
Persistent UFZ Identifier https://www.ufz.de/index.php?en=20939&ufzPublicationIdentifier=18496
Jahreis, S., Trump, S., Bauer, M., Bauer, T., Thürmann, L., Feltens, R., Wang, Q., Gu, L., Grützmann, K., Röder, S., Averbeck, M., Weichenhan, D., Plass, C., Sack, U., Borte, M., Dubourg, V., Schüürmann, G., Simon, J.C., von Bergen, M., Hackermüller, J., Eils, R., Lehmann, I., Polte, T. (2018):
Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications
J. Allergy Clin. Immunol. 141 (2), 741 - 753