Histone modifications and respiratory effects of traffic particle exposure

描述（由申请人提供）：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。暴露于空气颗粒物（PM）已被证明会降低肺功能并增加呼吸道疾病的发病率。吸入PM可上调全身血液炎症反应，在PM相关的肺功能降低和呼吸系统疾病中发挥重要作用。高pm暴露受试者的血液白细胞基因表达谱显示，血液中的全身炎症反应是由广泛的基因表达变化介导的。这一发现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，可被某些炎症介质诱导，从而影响染色质结构和基因表达。暴露于环境污染物已被证明可以诱导组蛋白修饰。我们最近观察到两种这样的修饰，即H3K4二甲基化和H3K9乙酰化，在高PM暴露人群的血液白细胞中增加。我们假设环境PM暴露可能导致血液白细胞组蛋白改变，以响应PM诱导的全身性炎症。这种组蛋白修饰可能会将血液白细胞基因表达转向促进进一步全身炎症反应的谱，从而对肺功能产生不利影响。我们建议使用我们最近在中国北京（世界上污染最严重的城市之一）完成的北京卡车司机空气污染研究（BTDAS）中的数据和生物标本来检验这些假设。

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. PUBLIC HEALTH RELEVANCE: Air pollution is a well known contributor to reduced lung function and respiratory diseases. This study is designed to identify novel mechanisms, i.e., histone modifications that regulate gene expression, for air pollution-related lung function reduction. Analysis of biospecimens and data from a highly air pollution- exposed population in Beijing, China, will have the potential to identify mechanisms that may not be detectable in low-exposed populations, such as US populations, and provide the groundwork to develop important novel preventive strategies to curb pollution-related respiratory diseases.