Black carbon exposure, DNA methylation, airway inflammation in pediatric asthma

描述（由申请人提供）：暴露于交通相关的空气污染与儿童哮喘恶化有关。有症状的青少年容易发展成持续性疾病。我们哥伦比亚儿童环境健康中心（CCCEH）的研究小组采用纵向研究方法，在了解产前和产后暴露于空气污染对儿童呼吸系统健康的不良影响方面取得了重大的科学进展。此外，我们在理解表观遗传变化方面也取得了重要进展。DNA甲基化)可能与这种暴露有关。尽管越来越多的研究表明，短期暴露于黑碳(BC)/柴油和富含金属的颗粒物与DNA甲基化变化之间存在关联，但之前的研究缺乏对个人暴露的准确评估，也没有考虑到幼儿暴露的影响。他们也没有将可能导致基因转录持续影响的DNA甲基化变化与儿童重要的临床结果进行比较。口腔粘膜细胞可以作为呼吸道细胞的前哨群代表，并且可以无创地进入。我们假设暴露于BC、镍（Ni）和钒(V)与促炎哮喘基因（白细胞介素-4、干扰素-3、诱导型一氧化氮合酶）的颊DNA甲基化变化有关，并且这种甲基化变化与CCCEH队列中城市青少年更大的气道炎症和阻塞有关。目的是：a)在控制包括哮喘在内的多个共变量后，确定近期暴露于BC， Ni， V是否与儿童中几种哮喘基因的口腔DNA甲基化改变有关；b)确定哮喘基因甲基化是否与哮喘儿童中更严重的气道炎症（分数呼出一氧化氮，呼出冷凝水pH）和气流阻塞（两次评估，间隔5天）有关。来自曼哈顿北部和南布朗克斯地区的100名患有哮喘和80名非哮喘的9至13岁非裔美国人和多米尼加裔儿童将从CCCEH队列中招募，这些地区与交通相关的空气污染暴露与哮喘和其他疾病有关。BC水平将在24小时内由个人监测测量，间隔5天，6个月后重复。金属将在5天内由居民监测测量，6个月后重复。分析将控制血清学、产前、既往（5-6岁、9-10岁）和当前环境烟草烟雾（ETS）暴露、既往（5-6岁、9-10岁）多环芳烃和BC暴露、过去6个月和12个月的BC暴露、早期住宅室内过敏原水平、性别、年龄、青春期早期（通过坦纳期）、种族。如果提出的目标得以实现，我们将确定可能驱动临床相关表观遗传事件的成分污染物。更好地了解环境BC、镍和钒在市中心哮喘加重中的作用，将刺激有针对性的干预，以减少大龄儿童的疾病。

DESCRIPTION (provided by applicant): Exposure to traffic-related air pollution is associated with asthma exacerbations among children. Symptomatic adolescents tend to develop persistent disease. Using a longitudinal approach, our group at the Columbia Center for Children's Environmental Health (CCCEH) birth cohort has made major scientific advances in the understanding of adverse respiratory health consequences for children following prenatal and postnatal exposure to air pollution. Moreover, we have made important strides in the understanding of epigenetic changes (eg. DNA methylation) that may occur in association with such exposures. Despite increasing research on the associations between short-term exposure to black carbon(BC)/diesel and metal rich particulate matter and changes in DNA methylation, previous studies have lacked accurate assessment of personal exposure and consideration of the effects of early childhood exposure. Nor have they compared changes in DNA methylation that could lead to sustained effects on gene transcription with important clinical outcomes in children. Buccal mucosal cells may be used as a sentinel population representative of cells in the airways and accessed noninvasively. We hypothesize that exposure to BC, nickel (Ni), and vanadium (V) is associated with changes in buccal DNA methylation of proinflammatory asthma genes (interleukin-4, interferon-3, inducible nitric oxide synthases), and that such methylation changes are associated with greater airway inflammation and obstruction among urban adolescents in the CCCEH cohort. The aims are to a) Determine whether recent exposure to BC, Ni, V is associated with altered buccal DNA methylation of several asthma genes among children after controlling for multiple covariates including asthma, and b) Determine whether methylation of asthma genes is associated with greater airway inflammation (fractional exhaled nitric oxide, exhaled breath condensate pH) and airflow obstruction (both assessed twice; 5 days apart) among asthmatic children. 100 asthmatic and 80 nonasthmatic 9 to 13 year old children of African-American and Dominican ethnicity and living in Northern Manhattan and the South Bronx, areas where exposure to traffic- related air pollution has been implicated in asthma and other diseases, will be recruited from the CCCEH cohort. BC levels will be measured by personal monitoring over a 24 hour period repeated 5 days apart and 6 months later. Metals will be measured by residential monitoring over 5 days, repeated 6 months later. Analyses will control for seroatopy, prenatal, previous (age 5-6 years, 9-10 years) and current environmental tobacco smoke (ETS) exposure, and previous (age 5-6, 9-10 years) PAH and BC exposure, BC exposure over the last 6 and 12 months, early residential indoor allergen levels, sex, age, early puberty (via Tanner stage), ethnicity. If the proposed aims are achieved, we will have identified constituent pollutants that may drive clinically-relevant epigenetic events. A greater understanding of the role of ambient BC, nickel and vanadium in inner city asthma exacerbations will stimulate focused intervention to reduce disease among older children.