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急性发作有关。有症状的青少年往往会发展为持续性疾病。使用纵向方法，我们在哥伦比亚儿童环境健康中心（CCCEH）出生队列的研究小组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科学进展。此外，我们在理解表观遗传变化方面取得了重要进展（例如，DNA甲基化），可能与此类暴露相关。尽管越来越多的研究短期暴露于黑碳（BC）/柴油和富含金属的颗粒物和DNA甲基化的变化之间的关联，以前的研究缺乏对个人暴露的准确评估和对儿童早期暴露影响的考虑。他们也没有比较DNA甲基化的变化，这些变化可能导致对基因转录的持续影响，并对儿童产生重要的临床结果。颊粘膜细胞可用作代表气道中细胞的哨兵群体，并且可非侵入性地接近。我们假设暴露于BC、镍（Ni）和钒（V）与促炎性哮喘基因（白细胞介素-4、干扰素-3、诱导型一氧化氮合酶）的颊DNA甲基化变化相关，并且这种甲基化变化与CCCEH队列中城市青少年的气道炎症和阻塞相关。目的是a）在控制包括哮喘在内的多个协变量后，确定近期暴露于BC、Ni、V是否与儿童中几种哮喘基因的颊部DNA甲基化改变相关，和B）确定哮喘基因的甲基化是否与更严重的气道炎症相关（呼出气一氧化氮分数，呼出气冷凝液pH值）和气流阻塞（均评估两次，间隔5天）。将从CCCEH队列中招募100名哮喘和80名非哮喘9 - 13岁儿童，这些儿童来自非裔美国人和多米尼加种族，居住在北方曼哈顿和南布朗克斯，这些地区暴露于交通相关的空气污染与哮喘和其他疾病有关。将在24小时内通过个人监测测量BC水平，间隔5天，6个月后重复。金属将在5天内通过住宅监测进行测量，6个月后重复。分析将控制血清反应性、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）PAH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（通过坦纳阶段）、种族。如果实现了拟议的目标，我们将确定可能导致临床相关表观遗传事件的污染物成分。更深入地了解环境BC，镍和钒在内城哮喘急性发作中的作用将刺激重点干预，以减少年龄较大儿童的疾病。

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.