氧化应激因子FOXO在大气细颗粒物致肺遗传损伤中的作用及机制

Atmospheric pollution is a serious social problem in China, particularly in the Beijing-Tianjin-Hebei Region. Clarification of the health impact of key air pollutants and the underlying mechanisms is essential for policy-making and development of specific intervention strategies. In the evaluation report of IARC, atmospheric particles are carcinogenic to humans (group 1). However, the carcinogenic mechanism is not known very clearly. In the present project, the airborne fine particulate matter （PM 2.5） samples will be collected from Beijing and Shijiazhuang city and detected the ingredients, respectively. At meantime, the mouse and cell line will be used to establish the PM2.5 exposure models. In our previous study, we found the mechanism of damages induced by particles was regulated by FOXO. Based on these results, the cell colony and flow cytometry sorting were used to evaluate the ability of cell transformation and gene mutation. The gene recombination、kinase activity analysis、ChIP、qRT-PCR, Western blot was used to test the genotoxicity and the mechanism through FOXO signal induced by PM2.5. The present project will look for the sensitive biomarkers and early health effect indexes induced by PM2.5 particles before the advent of respiratory diseases and genetic damages end point by combination of field and laboratory research. The regulation of FOXO will be studied to explore the mechanism of genotoxicity induced by PM2.5.

大气污染是我国面临的重要社会问题，特别是在京津冀地区尤为严重。阐明大气污染对健康的作用机制是制定有针对性的防治策略和研发有效防治手段的关键。IARC的研究报告将大气细颗粒物确定为人类I类致癌物，但其作用机制仍为阐明。本项目采集污染典型地区北京市和石家庄市大气细颗粒物（PM2.5）样品，对其组分进行分析，同时建立动式吸入染毒的小鼠模型、气-液染毒细胞模型，以课题组前期发现的颗粒物诱导的损伤与氧化应激因子FOXO信号有关的研究结果为切入点，采用基因克隆、ChIP、流式细胞分选等技术，探讨大气细颗粒物致DNA损伤、基因突变等遗传毒性，寻找大气细颗粒物在致呼吸系统疾病和遗传损伤终点出现之前的早期健康效应指标，阐明FOXO介导的信号途径在大气细颗粒物遗传毒性中的作用机制。

大气污染是我国面临的重要社会问题，特别是在京津冀地区尤为严重。阐明大气污染对健康的作用机制是制定有针对性的防治策略和研发有效防治手段的关键。IARC的研究报告将大气细颗粒物确定为人类I类致癌物，但其作用机制仍为阐明。本项目采集污染典型地区石家庄市大气细颗粒物（PM2.5）样品，对采集的颗粒物的物理化学特性进行了表征，通过扫描电子显微镜和透射电子显微镜观察大气细颗粒物呈不规则形状，分散性较好，粒径在50-100nm之间，其聚集态500-600nm。对其组分进行分析，结果表明组分呈现季节分布差异。建立动式吸入染毒的小鼠模型、细胞染毒模型，探讨大气细颗粒的毒性效应及可能机制。结果表明，大气细颗粒物可引起系统炎症和肺部炎症，可引起小鼠抑郁样表现，心脏肥大和纤维化，增加动脉粥样硬化的发病风险，引起雄性小鼠生殖能力下降，体外受精成功率下降。其毒性作用机制与大气细颗粒物诱导的氧化应激、炎症反应有关：（1）PP2A介导的炎性小体信号通路在PM2.5诱导的肺组织纤维化中发挥作用；（2）PM2.5诱导小鼠血清中与肺癌通路发生有关的miRNAs失调；（3）PM2.5诱导的小鼠肺组织发生上皮间质转化；（4）PI3K/AKT/FoxO信号通路在PM2.5诱导心肌肥厚中发挥作用；（5）巨噬细胞活化后炎症因子浸润在PM2.5暴露致小鼠心肌纤维化中发挥作用；（6）Nrf2介导的NLRP3小体激活在PM2.5致抑郁中发挥重要作用；（7）PM2.5暴露对睾丸组织NALP3炎症小体及miR-183/96/182靶向FOXO1通路的影响。.该项目为寻找大气细颗粒物在致人群呼吸系统、心血管系统、神经系统、生殖系统疾病的早期健康效应指标，发现大气细颗粒物致肺及肺外组织损伤中的作用机制，为制定相应的环境卫生标准提供科学依据，为预防大气颗粒物引起的疾病寻找治疗靶点。