Zhao Hu, Yan Yi, Gao Yanyan, Wang Jiafu, Li Sheng
Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), College of Life Sciences/Institute of Agro-Bioengineering, Guizhou University, Guiyang 550025, China.
Toxics. 2024 Jun 22;12(7):452. doi: 10.3390/toxics12070452.
Organophosphorus compounds (OPs) are widely used and have the potential to be harmful environmental toxicants to humans. Long non-coding RNA (lncRNA) plays a crucial regulatory role in cytotoxicity. This study aimed to investigate the effects of OPs on the expression of lncRNAs in cells. The effects of the industrial OPs TNPP and TCPP on both CYTOR and cellular viability were examined in the following human renal cell lines: HEK293T and HK-2. Both TCPP and TNPP downregulated CYTOR expression, increased reactive oxygen species levels, and induced apoptosis; the upregulated expression of CYTOR resulted in a reduction in apoptosis. The results of the luciferase reporter assay and the knock-down assay indicate that CEBPA binds to the upstream promoter region of CYTOR and regulates its transcription. Furthermore, TCPP and TNPP were found to downregulate the phosphorylation of ERK in the signaling pathway that is upstream of CEBPA. These results indicate that TCPP and TNPP can decrease the level of CEBPA by reducing ERK phosphorylation; this leads to a decrease in CYTOR expression, which further promotes cellular reactive oxygen species and apoptosis. Therefore, the ERK/CEBPA/CYTOR axis is one of the pathways by which organophosphates produce cytotoxicity, leading to renal cell injury. This study presents evidence for both the abnormal expression of lncRNA that is caused by organophosphates and the regulatory function of lncRNA regarding downstream cellular viability.
有机磷化合物（OPs）被广泛使用，有可能成为对人类有害的环境毒物。长链非编码RNA（lncRNA）在细胞毒性中起关键调节作用。本研究旨在探讨OPs对细胞中lncRNAs表达的影响。在以下人类肾细胞系中检测了工业OPs磷酸三（2-氯丙基）酯（TNPP）和磷酸三（1,3-二氯丙基）酯（TCPP）对CYTOR及细胞活力的影响：人胚肾细胞系293T（HEK293T）和人近端肾小管上皮细胞系（HK-2）。TCPP和TNPP均下调CYTOR表达、增加活性氧水平并诱导细胞凋亡；CYTOR表达上调导致细胞凋亡减少。荧光素酶报告基因检测和敲低实验结果表明，CCAAT增强子结合蛋白α（CEBPA）与CYTOR的上游启动子区域结合并调节其转录。此外，发现TCPP和TNPP下调CEBPA上游信号通路中细胞外信号调节激酶（ERK）的磷酸化。这些结果表明，TCPP和TNPP可通过降低ERK磷酸化来降低CEBPA水平；这导致CYTOR表达下降，进而进一步促进细胞活性氧生成和细胞凋亡。因此，ERK/CEBPA/CYTOR轴是有机磷酸酯产生细胞毒性导致肾细胞损伤的途径之一。本研究为有机磷酸酯引起的lncRNA异常表达以及lncRNA对下游细胞活力的调节功能提供了证据。
