Transgenerational Susceptibility to Asthma from Air Pollution Exposure

空气污染暴露对哮喘的跨代易感性

• 批准号: 8728858
• 负责人: LESTER KOBZIK
• 金额: $ 27.98万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728858
• 关键词: Adoptive Transfer; Adult; Aerosols; Air; Air Pollution; Allergens; Allergic inflammation; Animal Model; Asthma; Bioinformatics; Breeding; Cell Lineage; Chemicals; Childhood Asthma; DNA; DNA Methylation; DNA mapping; Dendritic Cells; Diesel Exhaust; Disease; Dose; Environmental Exposure; Environmental Health; Epigenetic Process; Exposure to; Fetus; Foundations; Future; Gene Expression Profile; Generations; Genomic DNA; Genomics; Histology; Hypersensitivity; Inbred BALB C Mice; Investigation; Laboratories; Lead; Learning; Link; Maps; Measures; Mediator of activation protein; Methylation; Modeling; Molecular; Mothers; Mus; Outcome; Ovalbumin; Ovum; Particulate; Paternal Exposure; Pattern; Phenotype; Predisposition; Pregnancy; Protocols documentation; Public Policy; Resolution; Risk; Risk Factors; Scientist; Solutions; Testing; Time; Time Study; Toxic Environmental Substances; Validation; Work; airway hyperresponsiveness; allergic airway inflammation; allergic response; bisulfite; cell type; cytokine; disorder risk; eosinophil; epigenome; epigenomics; expectation; methylome; mouse model; neonate; offspring; particle; pollutant; pregnant; public health relevance; pup; pyrosequencing; response; transmission process

DESCRIPTION (provided by applicant): The Problem: We know that parental asthma is a major risk factor for asthma in children (maternal > paternal), and that exposures to chemicals and pollutants during pregnancy can increase risk of future disease. In contrast, it remains unknown whether pregnancy exposures of the developing fetus can cause true transgenerational effects---i.e. increased asthma susceptibility in the F3 offspring (progeny of the F1 fetus and its F2 ova). The Solution: Our laboratory has already established a robust model of maternal transmission of asthma susceptibility. A single exposure of normal pregnant mice to diesel exhaust particles (DEP) causes enhanced allergic responses and an asthma-like phenotype in F1 offspring, linked to epigenetic changes in offspring dendritic cells (DCs.) this groundwork provides a robust platform to test whether transgenerational inheritance of asthma susceptibility will follow pregnancy-exposure to a prototypical environmental toxin. Aim 1 will investigate transgenerational transmission of asthma susceptibility to F2 and F3 offspring after a single pregnancy exposure to diesel exhaust particles (DEP) of F0 mother mice. For all 3 generations, we will measure allergic airway inflammation (BAL eosinophils, cytokines, histology) and airway hyperresponsiveness (AHR) after an intentionally sub-optimal allergen (ovalbumin) sensitization and aerosol challenge protocol that has minimal effects in normal pups. Dose and timing studies will follow initial trials using parameters already shown to have F1 effects. Aim 2 will map DNA methylome changes in 'susceptible' DCs from F1, F2 and F3 generations. This aim builds on prior work showing a distinct methylome in F1 DCs of asthma-susceptible pups born to DEP-exposed mothers. We will track the methylome changes that accompany persistence (or disappearance) of asthma susceptibility from F1 to F2 and F3 progeny of DEP-exposed mother mice. To do this, we will use reduced-representation bisulfite sequencing (RRBS) to quantify and map DNA methylation changes in splenic DCs, with additional validation of selected targets by pyrosequencing. Bioinformatic analysis will identify patterns and magnitude of methylation changes seen in every generation, and allow direct correlation to the phenotype observed in littermates (susceptibility and magnitude of allergic inflammation, AHR). Significance: The project will determine if transgenerational inheritance of asthma susceptibility occurs, and lays the foundation for better mechanistic analysis of persistence or resolution of pregnancy exposure effects.

描述（申请人提供）：问题：我们知道父母哮喘是儿童哮喘的主要危险因素（母亲>父亲），怀孕期间暴露于化学品和污染物会增加未来疾病的风险。相反，尚不清楚发育中胎儿的妊娠暴露是否会导致真正的跨代效应-即F3后代（F1胎儿及其F2卵子的后代）的哮喘易感性增加。解决方案：我们的实验室已经建立了一个强大的哮喘易感性母体传播模型。正常妊娠小鼠单次暴露于柴油机排气颗粒（DEP）导致F1后代的过敏反应增强和哮喘样表型，与后代树突状细胞（DC）的表观遗传变化有关。这一基础工作提供了一个强有力的平台，以测试哮喘易感性的跨代遗传是否会在妊娠暴露于典型的环境毒素之后发生。目的1研究柴油机尾气颗粒物（DEP）对F0代母鼠哮喘易感性的影响。对于所有3代，我们将在对正常幼仔影响最小的故意次优过敏原（卵清蛋白）致敏和气雾剂激发方案后测量过敏性气道炎症（BAL嗜酸性粒细胞、细胞因子、组织学）和气道高反应性（AHR）。剂量和时间研究将遵循初始试验，使用已显示具有F1效应的参数。目的2将绘制来自F1、F2和F3代的“易感”DC中的DNA甲基化组变化。这一目标建立在先前的工作基础上，这些工作表明暴露于DEP的母亲所生的哮喘易感幼崽的F1 DC中存在独特的甲基化组。我们将跟踪从暴露于DEP的母鼠的F1到F2和F3后代的哮喘易感性的持续（或消失）伴随的甲基化组变化。为此，我们将使用简化代表性亚硫酸氢盐测序（RRBS）来量化和绘制脾DC中的DNA甲基化变化，并通过焦磷酸测序对选定的靶点进行额外验证。生物信息学分析将鉴定在每一代中观察到的甲基化变化的模式和幅度，并允许与同窝仔中观察到的表型直接相关（过敏性炎症的易感性和幅度，AHR）。重要性：该项目将确定哮喘易感性是否会发生跨代遗传，并为更好地分析妊娠暴露效应的持续性或解决方案奠定基础。