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Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications
Susanne Jahreis1, Saskia Trump2, Mario Bauer3
1Department 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.
Insights
Maternal exposure to butyl benzyl phthalate (BBP) increases asthma risk in children. This effect is mediated by epigenetic changes, specifically DNA hypermethylation, impacting T-helper 2 cell differentiation and allergic airway inflammation.
Area of Science:
- Environmental Health
- Immunology
- Epigenetics
Background:
- Increasing prevalence of allergic diseases linked to prenatal and early postnatal environmental exposures.
- Inconsistent findings and lack of mechanistic data regarding plasticizer (phthalate) effects on childhood allergies.
Purpose of the Study:
- Investigate maternal phthalate exposure's impact on asthma development across generations.
- Elucidate underlying mechanisms, including epigenetic alterations.
Main Methods:
- Analysis of phthalate metabolites in a mother-child cohort (LINA).
- Correlation of exposure with childhood asthma development.
- Utilized a murine transgenerational asthma model to identify pathways.
Main Results:
- Maternal mono-n-butyl phthalate (BBP metabolite) linked to increased childhood asthma risk.
- BBP exposure caused persistent airway inflammation in offspring (up to F2 generation) in a murine model.
- DNA hypermethylation in CD4+ T cells mediated BBP's effect; demethylation treatment reduced inflammation.
Conclusions:
- Maternal BBP exposure elevates allergic airway inflammation risk in offspring.
- Epigenetic modifications, specifically DNA hypermethylation, play a key role.
- BBP alters gene expression in T H 2 differentiation pathways, increasing asthma susceptibility.
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.
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