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.
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.
J Allergy Clin Immunol. 2018 Feb;141(2):741-753. doi: 10.1016/j.jaci.2017.03.017. Epub 2017 Apr 6.
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 T2-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 T2 differentiation through epigenetic alterations.
产前和产后早期接触环境因素被认为是导致过敏疾病患病率上升的原因。尽管有一些证据表明塑化剂（如邻苯二甲酸酯）暴露会促进儿童过敏，但之前研究的结果并不一致，且缺乏机制信息。
我们研究了母体邻苯二甲酸酯暴露对后代哮喘发展的影响及其潜在机制，包括表观遗传改变。
前瞻性母子队列“生活方式和环境因素及其对新生儿过敏风险的影响（LINA）”中测量了邻苯二甲酸酯代谢物，并将其与儿童的哮喘发展相关联。使用一种鼠类跨代哮喘模型来鉴定涉及的途径。
在 LINA 中，母体尿液中单正丁基邻苯二甲酸酯（BBP 的代谢物）浓度与儿童哮喘风险增加相关。使用鼠类跨代哮喘模型，我们证明了 BBP 对后代哮喘严重程度的直接影响，后代的气道炎症持续增加，直至 F2 代。这种促进疾病的作用是由 BBP 诱导的后代 CD4 T 细胞中的全基因组 DNA 超甲基化介导的，因为用 DNA 去甲基化剂治疗可缓解过敏气道炎症的加重。鉴定出 13 个与启动子或增强子超甲基化相关的转录下调基因。其中，GATA-3 抑制锌指蛋白 1（Zfpm1）作为增强 T2 驱动的过敏性哮喘易感性的潜在介质出现。
这些数据提供了有力的证据，表明母体 BBP 暴露通过调节涉及 T2 分化的基因的表达，通过表观遗传改变增加后代发生过敏气道炎症的风险。
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