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

描述(申请人提供)：暴露在与交通相关的空气污染中与儿童哮喘加重有关。有症状的青少年往往会患上持续性疾病。我们哥伦比亚儿童环境健康中心(CCCEH)出生队列的团队使用纵向方法，在了解出生前和出生后暴露于空气污染对儿童不利的呼吸道健康后果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)，这可能与这种暴露相关。尽管关于短期接触黑碳(BC)/柴油和富金属颗粒物与DNA甲基化变化之间的关系的研究越来越多，但以前的研究缺乏对个人接触的准确评估和对儿童早期接触的影响的考虑。他们也没有将可能对基因转录产生持续影响的DNA甲基化变化与儿童的重要临床结果进行比较。颊粘膜细胞可作为呼吸道细胞的前哨群，以非侵袭性方式进入。我们假设，接触BC、镍(Ni)和钒(V)与促炎性哮喘基因(白介素4、干扰素-3、诱导型一氧化氮合酶)口腔DNA甲基化的变化有关，并且这种甲基化变化与CCCEH队列中城市青少年中更严重的呼吸道炎症和阻塞有关。其目的是a)在控制了包括哮喘在内的多个协变量后，确定最近暴露于BC、Ni、V是否与儿童中几个哮喘基因口腔DNA甲基化改变有关，以及b)确定哮喘基因甲基化是否与哮喘儿童中更严重的呼吸道炎症(呼出的一氧化氮部分、呼出的冷凝液pH值)和气流阻塞(两次评估，间隔5天)有关。居住在曼哈顿北部和南布朗克斯的100名哮喘儿童和80名非哮喘儿童将从CCCEH队列中招募。这些儿童生活在曼哈顿北部和南布朗克斯，与交通相关的空气污染与哮喘和其他疾病有关。血色素水平将通过个人监测在24小时内测量，重复5天和6个月后。金属将在5天内通过住宅监测进行测量，6个月后重复测量。分析将控制血清学、产前、以前(5-6岁、9-10岁)和当前环境烟草烟雾(ETS)暴露、以前(5-6岁、9-10岁)PAH和BC暴露、过去6个月和12个月BC暴露、早期住宅室内过敏原水平、性别、年龄、青春期早期(通过制革阶段)、种族。如果建议的目标得以实现，我们将识别出可能导致临床相关表观遗传事件的成分污染物。更好地了解环境中的BC、镍和钒在市中心哮喘恶化中的作用将刺激有针对性的干预措施，以减少年龄较大的儿童的疾病。

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.