Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu 210009, China.
Ecotoxicol Environ Saf. 2024 Sep 15;283:116809. doi: 10.1016/j.ecoenv.2024.116809. Epub 2024 Jul 30.
Environmental pollutants are considered as a cause of tumorigenesis, but approaches to assess their risk of causing tumors remain insufficient. As an alternative approach, the adverse outcome pathway (AOP) framework is used to assess the risk of tumors caused by environmental pollutants. Arsenic is a pollutant associated with lung cancer, but early assessment of lung cancer risk is lacking. Therefore, we applied the AOP framework to arsenic-induced lung cancer. A systematic review revealed increased risks of lung cancer following exposure to a range of arsenic concentrations in drinking water (OR = 1.83, 95 % CI = 1.46-2.30). We obtained, from public databases, genes related to risk of arsenic-induced lung cancer. Then, Cox and LASSO regressions were used to screen target genes from the risk genes. Subsequently, target genes, phenotypes, and pathways were used to construct the computational AOP network, which was determined by Cytoscape to have 156 edges and 45 nodes. Further, target genes, phenotypes, and pathways were used as molecular initiating events and key events to construct the AOP framework depending on upstream and downstream relationships. In the AOP framework, by Weight of Evidence, arsenic exposure increased levels of EGFR, activated the PI3K/AKT pathway, regulated cell proliferation by promoting the G1/S phase transition, and caused generation of lung cancers. External validation was achieved through arsenite-induced, malignant transformed human bronchial epithelial (HBE) cells. Overall, these results, by integration into existing data to construct an AOP framework, provide insights into the assessment of lung cancer risk for arsenic exposure. Special attention needs to be focused on populations with low-dose arsenic exposure.
环境污染物被认为是肿瘤发生的原因之一，但评估其致癌风险的方法仍然不足。作为一种替代方法，有害结局路径（AOP）框架被用于评估环境污染物引起肿瘤的风险。砷是一种与肺癌相关的污染物，但早期评估肺癌风险的方法还很缺乏。因此，我们应用 AOP 框架来评估砷诱导的肺癌。系统评价显示，饮用水中接触一系列砷浓度会增加患肺癌的风险（OR = 1.83，95%CI = 1.46-2.30）。我们从公共数据库中获取了与砷诱导的肺癌风险相关的基因。然后，使用 Cox 和 LASSO 回归从风险基因中筛选出靶基因。随后，将靶基因、表型和途径用于构建计算 AOP 网络，该网络由 Cytoscape 确定，有 156 条边和 45 个节点。此外，将靶基因、表型和途径用作分子起始事件和关键事件，根据上下游关系构建 AOP 框架。在 AOP 框架中，通过证据权重，砷暴露会增加 EGFR 水平，激活 PI3K/AKT 通路，通过促进 G1/S 期转化来调节细胞增殖，并导致肺癌的发生。通过亚砷酸盐诱导的恶性转化人支气管上皮（HBE）细胞进行了外部验证。总的来说，这些结果通过整合现有数据构建 AOP 框架，为评估砷暴露引起的肺癌风险提供了新的认识。需要特别关注低剂量砷暴露的人群。
