职业暴露柴油机尾气致全甲基化组改变及与呼吸功能损伤的机制研究

Diesel exhaust emission (DEE) is a ubiquitous health hazard in many occupational settings. International society has paid a lot of attention to the cancer risk of DEE exposure, however, minimal attention has been paid to the lung function impairment caused by chronic exposure to DEE and its underlying molecular mechanisms. Based on already established unique occupational cohorts exposed to pure DEE and their biospecimen banks, we propose to employ a research strategy that combines the methylome-wide association approach and ex vivo functional validation approach to identify the epigenetic mechanisms and biomarkers of early lung function impairment in DEE exposed populations which may eventually direct the screening of intervention approaches. First, we will explore the methylome changes in nasal epithelial cells in chronic DEE-exposed populations compared to non-DEE controls. Second, we will define the methylome pattern in nasal epithelial cells and assess its relationship with the phenotype of small airway injury and its biomarkers. Finally, we will use air liquid culture combined with DEE aerosol delivery approach to study the epigenetic—environment interaction on COPD associated phenotypes such as goblet cell metaplasia and mucociliary function. The findings of this study will contribute to the establishment of the occupational exposure limit, conduction of health monitoring, addition of new items on the list of occupational diseases and their diagnosis criteria in DEE-exposed occupational populations, which can eventually be used to better serve the occupational and general populations.

柴油机尾气（DEE）暴露是生产环境中普遍存在的职业危害。国际上对DEE的致癌性较为关注，而对其导致的早期肺功能损伤及其分子机制认识不足。基于已建立的单纯暴露于DEE的职业队列及其生物学样本库，采用人群甲基化组学关联研究和离体功能验证相结合的研究策略，阐明DEE暴露致早期肺功能损伤的表观遗传学机制，发现表观遗传生物标志物，指导未来有效干预措施筛选。首先在人群关联研究中解析慢性DEE暴露导致的上呼吸道上皮细胞（鼻粘膜细胞）中甲基化组学的改变；继之定义暴露个体上呼吸道上皮中的常见甲基化模式，并分析其与小气道损伤间的关系；后使用离体气液界面培养结合DEE气溶胶染毒技术分析二者对鼻黏膜上皮细胞离体分化和粘液纤毛功能的表观遗传—环境交互作用。该研究有助于针对职业DEE暴露人群现场制定防护卫生标准，开展健康监护、丰富新增职业病名单和职业病的诊断及早期干预，更好的保护就业人员健康。

柴油机尾气(DEE)暴露是生产环境中普遍存在的职业危害。国际上对DEE的致癌性较为关注，而对其导致的早期肺功能损伤及其分子机制认识不足。 本项目基于已建立的炭黑和柴油机试车工人队列的基础上，开展了随访研究，收集了血、尿、痰液和口鼻粘膜等生物学材料，并使用高分辨率CT对67名在岗和54名退休炭黑包装工，以及99名对照工人行肺部CT扫描，分析第六级和第九级小气道的管壁和内径尺寸以及肺气肿指数；测定了在岗炭黑包装工人体内与致癌明确相关的，反应基因组不稳定性的外周血淋巴细胞的双核细胞微核，及其与痰液巨噬细胞痰颗粒含量间的剂量反应关系；柴油机试车工人离体动脉内皮细胞活化实验；多组学关联分析，完成从300例研究对象的鼻粘膜细胞刷中提取DNA，并开展了EPIC甲基化芯片测试和外周血DNA的全基因组芯片的测试。基于痰液菌群的16S DNA测序工作也已经完成。该研究有助于针对职业DEE暴露 人群现场制定防护卫生标准，开展健康监护、丰富新增职业病名单和职业病的诊断及早期干预 ，更好的保护就业人员健康。