Histone modifications and respiratory effects of traffic particle exposure

描述(申请人提供)：空气污染是一个主要的公共卫生问题，每年造成约80万人死亡。暴露在空气颗粒物(PM)中已被证明会降低肺功能，增加呼吸道疾病的发病率。吸入PM可上调血液中的全身炎症反应，在PM相关的肺功能降低和呼吸系统疾病中起重要作用。高PM暴露受试者的血白细胞基因表达谱显示，血液中的全身性炎症反应是由广泛的基因表达变化介导的。这一观察结果为开发与基因表达调控相关的新生物标志物提供了巨大的机会。组蛋白是一种核球状蛋白，可以通过添加甲基、乙酰基和其他化学基团进行共价修饰，这些基团可以被某些炎症介质诱导，从而影响染色质结构和基因表达。暴露在环境污染物中已被证明在体外诱导组蛋白修饰。我们最近观察到，在高度PM暴露人群的血白细胞中，有两种这样的修饰增加，即H3K4二甲基化和H3K9乙酰化。我们假设环境PM暴露可能引起血中白细胞组蛋白的改变，以响应PM诱导的全身炎症。这种组蛋白修饰可能会使血白细胞基因表达向促进进一步全身炎症反应的方向发展，进而对肺功能产生不利影响。我们打算使用我们最近在北京完成的北京卡车司机空气污染研究(BTDAS)的数据和生物谱来验证这些假设，北京是世界上污染最严重的城市之一。 招募了60名卡车司机(高暴露组)和60名室内工人(低暴露组)。我们使用个人空气监测仪和尿液生物标志物来测量PM2.5、其有毒金属和交通废气在两个独立工作日的暴露情况，每隔1-2周。我们收集了下班后的血样和肺功能数据，并测定了炎症标志物。我们建议进行一项辅助研究，以研究个人PM2.5及其金属成分是否与先前实验研究中发现的含有PM的金属诱导的组蛋白修饰有关；以及PM相关的组蛋白修饰是否与血浆炎症介质和/或肺功能有关。我们将在意大利米兰的交通事故暴露警察和参照者身上复制我们的BTDAS研究结果。 PM2.5水平是欧洲/北美大城市的典型水平。在暴露程度相对较低和不同种族的人群中进行复制将允许测试泛化能力。这项拟议的研究具有很高的时间和成本效益，并首次检验组蛋白修饰在空气污染相关肺功能降低中的作用。我们的研究结果将为进一步研究组蛋白修饰在PM相关肺功能降低中的作用提供新的研究领域。如果我们观察到假设的关联，我们将寻求资金，在美国等暴露水平较低的人群中进行大规模研究，以扩大这一研究路线。

DESCRIPTION (provided by applicant): Air pollution is a major public health concern, accounting for ~800,000 annual deaths. Exposure to air particulate matter (PM) has been shown to reduce lung function and increase respiratory disease rates. Inhaled PM can up-regulate systemic inflammatory responses in blood, which play important roles in PM- related lung function reduction and respiratory diseases. Blood leukocyte gene expression profiling in highly PM-exposed subjects has revealed that systemic inflammatory responses in blood are mediated by extensive gene expression shifts. This observation provides a tremendous opportunity to develop new biomarkers that are related to gene expression regulation. Histones are nuclear globular proteins that can be covalently modified by the addition of methyl, acetyl, and other chemical groups, which are inducible by certain inflammatory mediators, thus influencing chromatin structure and gene expression. Exposure to environmental pollutants has been shown to induce histone modifications in vitro. We recently observed increases in two of such modifications, i.e., H3K4 dimethylation and H3K9 acetylation, in blood leukocytes from a highly PM- exposed population. We hypothesize that ambient PM exposure may cause blood leukocyte histone modifications in response to PM-induced systemic inflammation. Such histone modifications may shift blood leukocyte gene expression toward profiles promoting further systemic inflammatory responses that, in turn, adversely affect lung function. We propose to test these hypotheses using data and biospecimens from our recently completed Beijing Truck Driver Air Pollution Study (BTDAS) in Beijing, China, one of the most polluted cities in the world. Sixty truck drivers (high exposure) and 60 indoor workers (low exposure) were recruited. We used personal air monitors and urine biomarkers to measure exposure to PM2.5, its toxic metals, and traffic exhausts on two independent work days with 1-2 week intervals. We collected after-work blood samples and lung function data, and measured inflammation markers. We propose to conduct an ancillary study to examine whether personal PM2.5 and its metal components are associated with histone modifications found to be induced by PM-contained metals in previous experimental studies; and whether PM-related histone modifications are associated with plasma inflammatory mediators) and/or lung function. We will replicate our findings from BTDAS in traffic-exposed police officers and referents in Milan, Italy, with PM2.5 levels typical of large cities in Europe/North America. Replication in a population with relatively lower exposure and different ethnicity will permit to test generalizability. The proposed study is highly time- and cost-effective and the first to examine the role of histone modifications in air pollution-related lung function reduction. Our results will offer a new researh area for future investigations on the role of histone modifications in PM-related lung function reduction. If we observed the hypothesized associations, we will seek funding to expand this line of research in large-scale studies in populations with lower exposure such as the US populations.