Abstract：
Emerging studies implicate fine particulate matter (PM2.5) and its organic components (OCs) as urgent hazard factors for lung cancer progression in nonsmokers. Establishing the adverse outcome pathway (AOP)-directed nontargeted identification method, this study aimed to explore whether PM2.5 exposure in coal-burning areas promoted lung tumor metastasis and how we identify its effective OCs to support traceability and control of regional PM2.5 pollution. First, we used a nude mouse model of lung cancer for PM2.5 exposure and found that the exposure significantly promoted the hematogenous metastases of A549-Luc cells in lung tissues and the adverse outcomes (AOs), with key events (KEs) including the changed expression of epithelial-mesenchymal transition (EMT) markers, such as suppression of E-cad and increased expression of Fib. Subsequently, using AOs and KEs as adverse outcome directors, we identified a total of 35 candidate chemicals based on the in vitro model and nontargeted analysis. Among them, tributyl phosphate (C12H27O4P), 2-bromotetradecane (C14H29Br), and methyl decanoate (C11H22O2) made greater contributions to the AOs. Finally, we clarified the interactions between these OCs and EMT-activating transcription factors (EMT-ATFs) as the molecular initiation event (MIE) to support the feasibility of the above identification strategy. The present study updates a new framework for identifying tumor metastasis-promoting OCs in PM2.5 and provides solid data for screening out chemicals that need priority control in polluted areas posing higher lung cancer risk.
摘要：
新兴研究暗示细颗粒物（PM2.5）及其有机成分（OCs）是非吸烟者肺癌进展的紧急危险因素。建立不良结局通路(AOP)导向的非靶向鉴定方法,本研究旨在探讨燃煤地区的PM2.5暴露是否促进肺肿瘤转移，以及我们如何识别其有效的OCs以支持区域PM2.5污染的可追溯性和控制。首先,我们使用裸鼠肺癌模型进行PM2.5暴露，发现暴露显著促进肺组织中A549-Luc细胞的血源性转移和不良结局（AOs），关键事件（KE）包括上皮-间质转化（EMT）标志物表达的变化，如抑制E-cad和增加Fib的表达。随后，使用AOs和KEs作为不利结果总监，我们根据体外模型和非靶向分析确定了总共35种候选化学品.其中,磷酸三丁酯(C12H27O4P),2-溴十八烷(C14H29Br),癸酸甲酯（C11H22O2）对AOs的贡献更大。最后,我们阐明了这些OCs与EMT激活转录因子(EMT-ATFs)之间的相互作用作为分子起始事件(MIE),以支持上述鉴定策略的可行性.本研究更新了一个新的框架，用于识别PM2.5中促进肿瘤转移的OCs，并提供了可靠的数据，用于筛查在污染地区需要优先控制的化学物质，从而导致更高的肺癌风险。
