基于联合组学技术的铬酸盐职业接触致呼吸系统损伤及修复机制研究

Respiratory diseases are common diseases that seriously endanger the health of residents. Environmental and occupational pollutants are common causes of respiratory diseases. Although chromate is an important strategic material in China's economic development, it is one of the typical occupational and environmental pollutants. Our previous study found that long-term exposure to low level of chromate can also induce respiratory diseases such as chromium-induced rhinopathy and decreased pulmonary function. This project intends to combine methods of occupational chromate exposure cohort study and animal experiments so that we can dynamically monitor the impact of pulmonary function in the workers as well as lung tissue pathology and changes of pulmonary progenitor cell proliferation and ultrastructure and immunoinflammatory in the experimental animals during the chromate exposure or after terminating the exposure based on different levels of molecule, in vitro, in vivo, human population and others. This project will apply integrated proteomics and metabonomics data to provide a multi-level view of changes in the specific protein/metabolic profile related to respiratory system injury and repair induced by chromate exposure and to use bioinformatics and statistical models to build a comprehensive signaling pathways and to identify early key biological events of respiratory system injury and repair, offering important scientific evidences for recognizing the cause of respiratory damage and monitoring the health status of people at risk of environmental exposure.

呼吸系统疾病是严重危害居民健康的常见疾病，环境和职业污染物暴露是其常见病因。铬酸盐虽是我国经济发展重要的战略物质，但却属于典型的职业和环境污染物。我们前期研究发现，长期接触低水平铬酸盐亦可诱发铬鼻病和肺功能下降等呼吸系统损伤。本项目拟采用铬酸盐职业接触人群队列研究及动物实验相结合的方法，从分子、细胞、整体动物及人群等不同水平，动态观察铬酸盐接触和脱离接触对肺功能影响、实验动物肺组织病理、肺内祖/干细胞增殖、超微结构和免疫炎症变化，集成蛋白组学和代谢组学数据，多层次、全景式研究铬酸盐接触所致呼吸系统损伤与修复相关的特异性蛋白/代谢谱的变化规律，利用生物信息学和统计学模型综合构建损伤和修复相关信号通路及调节网络，识别呼吸系统损伤的早期关键生物学事件，探讨铬酸盐致呼吸系统损伤和修复机制及影响因素，为环境有害因素致呼吸系统损伤的病因识别及暴露人群健康监护提供重要科学依据。

呼吸系统是铬酸盐职业接触最主要的靶器官，铬酸盐所致肺癌属于法定的职业肿瘤。铬酸盐所致呼吸系统损伤和早期致癌机制尚未完全阐明，本项目通过职业人群流行病学调查、实验动物及体外细胞相结合的方法，发现铬酸盐职业暴露可引起人群肺功能下降，内暴露评价指标全血铬水平与肺功能相关指标呈显著负相关。铬酸盐暴露人群代谢组学和体外人支气管上皮细胞转录组及其共表达网络分析显示，铬酸盐职业暴露人群所致差异代谢物主要富集在精氨酸、脯氨酸代谢物通路以及甘油磷脂类代谢通路；铬酸盐所致体外支气管上皮细胞损伤与DNA复制、染色质组装和DNA修复等细胞周期调控通路相关。关键驱动因素分析显示ARD3，SND1和lnc-DHX32 -2:1在细胞周期G2/M、G1/S和M期中作用较为突出。实验小鼠长期暴露于低浓度铬酸盐气溶胶，仍可出现血细胞铬累积、系统炎症、肺组织细胞损伤及肺纤维化，肺功能下降等。脱离铬酸盐暴露2周，动物肺组织损伤及呼吸功能有一定改善，联合代谢组、转录组、表观遗传组分析表明，铬酸盐暴露13周可诱导小鼠肺组织转录组和转录后调控，影响肺组织的免疫应答和代谢，并导致氧化磷酸化、脂质代谢及谷胱甘肽等紊乱。实验小鼠停止铬酸盐暴露2周后，铬酸盐诱导的差异基因和代谢物大部分可恢复到对照水平，NOD样受体信号通路和花生四烯酸代谢通路可能参与损伤修复，差异miRNA和mRNA显著减少，且氧化磷酸化和谷胱甘肽代谢通路被显著抑制，炎性相关代谢产物增多。停止染毒后，响应外源性刺激的小鼠肺组织miRNA和mRNA表达增强，参与损伤修复。铬酸盐暴露-差异蛋白/代谢分子-呼吸系统损伤/修复网络模型提示，脂质代谢、氨基酸代谢、能量代谢和核苷酸代谢通路紊乱可能与铬酸盐毒作用有关，miRNA调控相应基因表达改变，进而引起脂质代谢和氨基酸代谢紊乱，加剧呼吸系统损伤。该项目研究发现，丰富、完善了铬酸盐所致呼吸系统损伤和修复机制，为相关环境有害因素致呼吸系统损害的病因识别、早期健康危害评价及干预提供了研究证据。项目共培养博士4名和硕士3名，发表论文13篇。