6-OHBDE-47 诱导 HepG2 细胞 CYP1A1、XRCC2、HSPA1A、EGR1 基因转录组改变并触发细胞凋亡。
6-OHBDE-47 induces transcriptomic alterations of CYP1A1, XRCC2, HSPA1A, EGR1 genes and trigger apoptosis in HepG2 cells.
机构信息
Zoology Department, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; A.R. Al-Jeraisy Chair for DNA Research, Zoology Department, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
Zoology Department, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; A.R. Al-Jeraisy Chair for DNA Research, Zoology Department, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
出版信息
Toxicology. 2018 May 1;400-401:40-47. doi: 10.1016/j.tox.2018.03.007. Epub 2018 Mar 27.
In this study, HepG2 cells were exposed to 6-hydroxy- 2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE-47) for 3 and 6 days for monitoring cytotoxic effects and alterations in its transcriptomic profile. MTT assay showed that cells exposed to 6-OH-BDE-47 (50 nM) exhibited 48.5% and 53.7% decline in cell survival after 3 and 6 days. Neutral red uptake (NRU) assay also demonstrated 47.1% and 56% reduction in cell survival at 50 nM, indicating lysosomal toxicity. The flow cytometric data confirmed an increase in intracellular reactive oxygen species (ROS) and mitochondrial dysfunction (ΔΨm). In comet assay, HepG2 cells exposed to 6-OH-BDE-47 (50 nM) showed 7.6-fold greater DNA damage. Cell cycle data revealed G/M arrest at 10 and 25 nM after 3 days of exposure, while 50 nM induced mild apoptotic effect. The intensity of apoptosis increased after 6 days of exposure with 21.5%, 47% and 99.1% of cells recorded in subG1 apoptotic phase vis-à- vis the control showed 14.5% background apoptotic cells. Transcriptome analysis of 6-OH-BDE-47 (25 nM, 3 days) treated cells revealed cross talk between vital pathways. Especially, the genes involved in oxidative or metabolic stress, heat shock, growth arrest and senescence were differentially up- and down regulated to orchestrate the cellular toxicity and triggering apoptosis in HepG2 cells.
在这项研究中，HepG2 细胞分别暴露于 6-羟基-2,2',4,4'-四溴二苯醚（6-OH-BDE-47）50 nM 中 3 天和 6 天，以监测细胞毒性作用及其转录组谱的变化。MTT 试验显示，暴露于 6-OH-BDE-47（50 nM）的细胞在 3 天和 6 天后的细胞存活率分别下降了 48.5%和 53.7%。中性红摄取（NRU）试验也表明，在 50 nM 时，细胞存活率降低了 47.1%和 56%，表明溶酶体毒性。流式细胞术数据证实细胞内活性氧（ROS）和线粒体功能障碍（ΔΨm）增加。在彗星试验中，暴露于 6-OH-BDE-47（50 nM）的 HepG2 细胞的 DNA 损伤增加了 7.6 倍。细胞周期数据显示，在暴露于 3 天后，10 nM 和 25 nM 时出现 G2/M 期阻滞，而 50 nM 则诱导轻度凋亡作用。在暴露于 6 天后，细胞凋亡的强度增加，在亚 G1 凋亡期有 21.5%、47%和 99.1%的细胞，而对照细胞只有 14.5%的背景凋亡细胞。6-OH-BDE-47（25 nM，3 天）处理细胞的转录组分析显示，重要途径之间存在串扰。特别是，参与氧化或代谢应激、热休克、生长阻滞和衰老的基因上调或下调，以协调 HepG2 细胞的细胞毒性和触发细胞凋亡。
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