焦炉逸散物主要成分与基因组遗传变异的交互作用对机体早期健康效应影响的前瞻性队列研究

The coke-oven emissions, produced during the coking process, contains large amount of chemical pollutants, including polycyclic aromatic hydrocarbons (PAHs) and heavy metals. Long-termly exposed to high levels of PAHs and heavy metals can cause a series of health damage effects, leading to the development of many chronic diseases like cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer. Our research group had set up an occupational cohort of 1628 workers from a coke-oven plant in 2010, and completed the first follow-up study of this population in 2014. Based on the previous research work, we aim to investigate the interaction effect and potential mechanism of PAHs and metals with genome-wide variations on the early health damage of the coke-oven workers in the present research project. We will detect the internal exposure levels of PAHs and metals by using GC-MS and ICP-MS systems, and measure the levels of several early health effect biomarkers, including metabolic disorder, lung function decline, oxidative stress, DNA damage, and telomere length shorten, both in the baseline and follow-up stage of this prospective occupational cohort. The genomic variations of all participants in this cohort is going to be genotyped by using Illumina Global Screening Array (GSA). We will evaluate the dose-response relationships between PAHs and metals exposure levels and change of early health effect, reveal the interaction effects of PAHs and metals with genetic variations on the early health effects among the coke-oven workers, and further explore the underline mechanisms in the followed molecular biological studies. The results of this project will help uncover the biological mechanisms of the occupational related diseases, and provide important clues to establish appropriate scheme of early occupational health surveillance for the coke-oven workers.

炼焦作业产生的焦炉逸散物中含有大量的多环芳烃（PAHs）和重金属等化学污染物，长期吸入可造成一系列健康损伤效应，最后引起多种疾病（如心血管疾病、呼吸系统疾病、肺癌等）的发生。本课题组于2010年建立了1628例焦炉工职业人群队列，并在2014年进行了随访。本项目拟在前期研究工作的基础上，将前瞻性队列研究和分子生物学研究相结合，通过检测队列人群基线和随访后焦炉逸散物主要成分（PAHs、金属）内暴露水平和多种早期健康标志物水平（如代谢紊乱、肺功能下降、氧化应激、DNA损伤、端粒长度缩短），采用GSA芯片对基因组遗传变异进行分型，建立焦炉逸散物主要成分单独和复合暴露与机体早期健康效应动态变化的剂量-效应关系，发现与焦炉逸散物主要成分在影响工人早期健康效应水平上具有交互作用的遗传位点，并阐明其生物学机制。本研究将为职业相关疾病发生机制的进一步阐明、疾病早期预警和职业健康监护体系的制订提供科学依据。

本课题主要探讨了焦炉逸散物主要成分（如多环芳烃、金属）与基因组遗传变异的交互作用对机体早期健康效应（如DNA损伤、端粒缩短、肺功能改变）的影响。研究发现，多环芳烃中萘和芘暴露可促进外周血白细胞端粒缩短，且与TERT-CLPTM1L区域遗传变异具有交互效应；萘和芘造成的氧化性DNA损伤在其致端粒缩短效应中介导约1/3~1/2的总效应；较高浓度的血浆锰对白细胞端粒长度具有潜在的保护作用。发现金属钛可以降低机体染色体损伤水平，血浆miR-24-3p和miR-28-5p可以介导该效应的1/5~1/4。发现RARB基因遗传变异与多环芳烃暴露水平在影响FEV1/FVC降低上具有交互作用，多环芳烃高暴露可通过促进RARB基因甲基化从而降低其表达和维护正常肺容量的作用。发现重金属铊、铅、砷暴露促进肺功能下降，铊和砷暴露与吸烟可能通过共同增加机体炎症反应加重肺功能损伤；铅与氧化应激通路的关键基因NQO1遗传变异在影响FEV1降低程度上存在显著的交互作用。在肺癌巢式病例对照研究中，高水平血浆锌能降低端粒缩短程度和肺癌的发生风险，提示适当提高人体血锌水平可能对肺癌预防提供新方向。发现多环芳烃、金属锑和钼暴露水平和男性外周血白细胞中mLOY程度的剂量-效应关系，并进一步发现1-羟基萘、金属锑和钼可能通过共同的DNA氧化损伤过程发挥联合效应。本课题还发现苯并[a]芘暴露引起关键基因DNA甲基化在其致肺癌发生过程中的作用。上述研究结果在呼吸医学（AJRCCM）和环境健康领域国际权威期刊（JHM、EI、EP、ER）以通讯作者发表SCI论文13篇（其中IF>10分4篇、IF 5~10分9篇，累计影响因子127.289），为焦炉逸散物主要成分致机体早期健康损伤和肺癌发生过程中的量效关系、及其与遗传变异的交互作用提供了新的流行病学证据，为焦炉工职业相关疾病的防控提供了新的研究证据和探索方向。