垃圾焚烧厂细颗粒物暴露引发机体氧化-还原稳态失衡的分子机制及毒理效应研究

飞灰颗粒物毒性机制极其复杂，大量实验表明细颗粒物具有引发氧化应激的共性，而自由基的产生以及氧化还原稳态失衡在其诱发的病变中起了关键作用，但相关机理未知，尚待深入研究。Nrf2/ARE是人体一条重要的抗氧化应激、解毒的信号通路，此通路的失控和呼吸道等多种疾病紧密相关。本课题组在前期工作中发现焚烧厂飞灰组分可异常激活Nrf2，造成Nrf2/ARE信号通路长时间持续处于激活状态，诱发细胞氧化还原稳态失衡,因此提出Nrf2信号通路异常与细颗粒物毒理效应相关的假说。本项目拟利用野生型/Nrf2敲除小鼠、细胞系和报告基因细胞株，结合分析化学、基因组学、表观遗传学、分子细胞生物学、毒理学等研究方法和手段，开展中国垃圾焚烧厂细颗粒物短时期和长时期暴露诱发小鼠肺损伤模型研究；探讨氧化还原稳态失衡在肺损伤、炎症、DNA损伤和呼吸系统功能异常中的作用及可能机理。本研究将为探索大气细颗粒物毒性机理提供理论依据。

Municipal solid wastes incineration (MSWI) fly ashes, which are of properties of large surface area and the presence of metals and organics, have the potential to produce oxidative stress. Particulate matter from MSWI may also exert genotoxic effects, depending on their composition. The nuclear factor erythroid-2 related factor 2 （NRF2) is a pivotal activator of genes encoding cytoprotective and detoxifying enzymes that protect against oxidative and eletrophilic stress. However, persistent over-expression of NRF2 has been recently found in lung cancers, attributed to tumor development. MSWI fly ashes contain highly toxic PCDD/Fs and carcinogenic heavy metals, which are harmful to the environment and human beings. Although a volume of work has been published regarding to their toxic effects, the underlying mechanism are poorly characterized. In our preliminary study, we discovered that exposure to particulate matter (PM) from MSWI induced consistent Nrf2 activation in vitro. In our study, we used well characterized, size-fractionated fly ashes from specific MSW incinerator plants in China as a model for real-world ambient particulate matter. In this proposal, we are planning to investigate the pathogenesis of disorders in association with particle exposure. In addition, the de-regulation of Nrf2/ARE signalling pathway in vitro and in vivo, induced by PM, will also be investigated. Furthermore, our study would provide understanding on the underlying molecular mechanisms of oxidative stress induced by PM.