王晓晴^1,3,
刘佳琳¹,
李斐^1,,,
曹天贵¹,
吴惠丰^1,2,
孟祥敬^1,3,
吉成龙^1,2
1. 中国科学院海岸带环境过程与生态修复重点实验室, 中国科学院烟台海岸带研究所, 山东省海岸带环境过程重点实验室, 烟台 264003;
2. 青岛海洋科学与技术国家实验室, 海洋渔业科学与食物产出过程功能实验室, 青岛 266237;
3. 中国科学院大学, 北京 100049

作者简介: 王晓晴(1994-),女,硕士研究生,研究方向为生态毒理学,E-mail:xqwang@yic.ac.cn.

通讯作者: 李斐,fli@yic.ac.cn ;

基金项目: 国家自然科学基金项目(41530642,21677173)；中国科学院青年创新促进会项目(2017255,2015169)


中图分类号: X171.5

The Mechanisms on Apoptosis of Human Embryonic Kidney Cells 293 (HEK293) Induced by Triphenyl Phosphate (TPP) and Tris(2-chloroisopropyl) Phosphate (TCPP)

Wang Xiaoqing^1,3,
Liu Jialin¹,
Li Fei^1,,,
Cao Tiangui¹,
Wu Huifeng^1,2,
Meng Xiangjing^1,3,
Ji Chenglong^1,2
1. CAS Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences;Shandong Key Laboratory of Coastal Environmental Processes, Yantai 264003, China;
2. Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China;
3. University of Chinese Academy of Sciences, Beijing 100049, China

Corresponding author: Li Fei,fli@yic.ac.cn ;

CLC number: X171.5

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摘要:磷系阻燃剂对人体的潜在毒性作用引起了国内外研究者的广泛关注。肾脏是机体重要的排毒器官，若肾脏细胞受损，可能影响肾脏功能的正常发挥。本研究以人胚肾细胞HEK293为研究对象，结合传统毒理学实验，筛选出磷酸三苯酯(TPP)及磷酸三(2-氯异丙基)酯(TCPP)诱导人胚肾细胞HEK293凋亡的关键靶标基因p53。在此基础上采用分子对接模拟和光谱法分析发现，TPP和TCPP分别以嵌插方式和沟槽方式结合p53-DNA，改变基因片段的框架结构，启动分子起始事件，通过影响相关基因(Bax、Hrk、Bcl-2和Bad)的表达量，导致线粒体途径释放cyt c，最终激活Caspase 7实现细胞凋亡。研究结果阐明了此类污染物诱导凋亡的作用机制，为毒害化学品的污染防控提供理论依据。
关键词: 有机磷酸酯阻燃剂/
磷酸三(2-氯异丙基)酯(TCPP)/
磷酸三苯酯(TPP)/
肾细胞/
细胞凋亡

Abstract:Phosphorus flame retardants, the substitutes for brominated flame retardants, have been widely used in plastics, rubber and other materials. The potential toxic effects of organophosphate flame retardants (OPFRs) on the human body have also attracted widespread attentions from researchers home and abroad. The kidney is a crucial organ for the body eliminating toxicants. The damage of kidney cells may disrupt the normal function of the kidney. In this study, triphenyl phosphate (TPP) and tris(2-chloroisopropyl) phosphate (TCPP) were tested to investigate the mechanisms of apoptosis for human embryonic kidney cell 293 (HEK293). The key target gene p53 was screened by traditional toxicology experiments. Molecular docking and spectroscopic methods showed that TPP and TCPP could inert into the p53-DNA with intercalation and groove bindings. By disrupting the double helix structure of p53 gene fragments and activating molecular initiation events, the expression of related genes (Bax, Hrk, Bcl-2 and Bad) were affected, leading to the release of cytochrome c (cyt c) by mitochondrial pathway. Release of cyt c ultimately activate Caspase 7 to achieve cell apoptosis. This study provided basic data to research the toxic mechanism of phosphorus flame retardants.
Key words:organophosphate flame retardant/
tris(2-chloroisopropyl) phosphate (TCPP)/
triphenyl phosphate (TPP)/
kidney cell/
apoptosis.