Zhang Yangchun, Liu Ziqi, He Qianmei, Wu Fei, Xiao Yongmei, Chen Wen, Jin Yuan, Yu Dianke, Wang Qing
Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China.
Front Genet. 2021 Jul 23;12:696892. doi: 10.3389/fgene.2021.696892. eCollection 2021.
Although it is recognized that cadmium (Cd) causes renal tubular dysfunction, the mechanism of Cd-induced nephrotoxicity is not yet fully understood. Mode of action (MOA) is a developing tool for chemical risk assessment. To establish the mechanistic MOA of Cd-induced renal tubular dysfunction, the Comparative Toxicogenomics Database (CTD) was used to obtain genomics data of Cd-induced nephrotoxicity, and Ingenuity Pathway Analysis (IPA) software was applied for bioinformatics analysis. Based on the perturbed toxicity pathways during the process of Cd-induced nephrotoxicity, we established the MOA of Cd-induced renal tubular dysfunction and assessed its confidence with the tailored Bradford Hill criteria. Bioinformatics analysis showed that oxidative stress, DNA damage, cell cycle arrest, and cell death were the probable key events (KEs). Assessment of the overall MOA of Cd-induced renal tubular dysfunction indicated a moderate confidence, and there are still some evidence gaps to be filled by rational experimental designs.
尽管人们认识到镉（Cd）会导致肾小管功能障碍，但Cd诱导肾毒性的机制尚未完全明确。作用模式（MOA）是一种用于化学风险评估的新兴工具。为了建立Cd诱导肾小管功能障碍的机制性MOA，利用比较毒理基因组学数据库（CTD）获取Cd诱导肾毒性的基因组学数据，并应用 Ingenuity 通路分析（IPA）软件进行生物信息学分析。基于Cd诱导肾毒性过程中受干扰的毒性通路，我们建立了Cd诱导肾小管功能障碍的MOA，并根据定制的布拉德福德·希尔标准评估其可信度。生物信息学分析表明，氧化应激、DNA损伤、细胞周期停滞和细胞死亡是可能的关键事件（KEs）。对Cd诱导肾小管功能障碍的整体MOA评估显示可信度为中等，仍存在一些证据空白，需要通过合理的实验设计来填补。
