Endoplasmic Reticulum Stress Induced by Zinc Oxide Nanoparticles Is an Earlier Biomarker for Nanotoxicological Evaluation
Endoplasmic Reticulum Stress Induced by Zinc Oxide Nanoparticles Is an Earlier Biomarker for Nanotoxicological Evaluation
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氧化锌纳米颗粒诱导的内质网应激是纳米毒理学评估的早期生物标志物
DOI：
10.1021/nn406184r
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发表时间：
2014-03-01
期刊：
影响因子：
17.1
通讯作者：
Chen, Chunying
中科院分区：
文献类型：
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作者：
Chen, Rui;Huo, Lingling;Chen, Chunying
氧化锌纳米颗粒（ZnO NPs）已广泛应用于化妆品和防晒霜、高级纺织品、自充电和电子设备;其制造和使用的每个阶段的人体暴露和健康影响的可能性引起了极大的关注。除了肺损伤，纳米颗粒暴露也与心血管疾病发病率的增加密切相关;然而，它们的毒性潜力在很大程度上仍不清楚。在此，我们研究了细胞反应和内质网（ER）应激诱导的ZnO纳米粒子在人脐静脉内皮细胞（HUVECs）相比，锌离子和CeO 2纳米粒子。我们发现溶解的锌离子是HUVECs细胞毒性的最重要因素。更重要的是，非细胞毒性浓度的ZnO NPs，而不是CeO 2 NPs，可以诱导显著的细胞ER应激反应，在mRNA水平上剪接的xbp-1，chop和caspase-12的表达更高，在蛋白水平上相关的ER标记蛋白包括BiP，Chop，GADD 34，p-PERK，p-eIF 2 α和切割的Caspase-12。此外，内质网应激被广泛激活后，处理与ZnO纳米粒子，而84个标记基因中的6个显着增加。内质网应激反应是检测ZnO纳米颗粒对内质网稳态破坏的敏感指标。此外，较高剂量的ZnO纳米颗粒（240 μ M）迅速呈现ER应激反应诱导凋亡之前。这些结果表明，ZnO纳米颗粒激活ER应激反应途径，ER应激反应可能被用作纳米毒理学研究的早期和敏感的终点。
Zinc oxide nanoparticles (ZnO NPs) have been widely used in cosmetics and sunscreens, advanced textiles, self-charging and electronic devices; the potential for human exposure and the health impact at each stage of their manufacture and use are attracting great concerns. In addition to pulmonary damage, nanoparticle exposure is also strongly correlated with the increase in incidences of cardiovascular diseases; however, their toxic potential remains largely unclear. Herein, we investigated the cellular responses and endoplasmatic reticulum (ER) stress induced by ZnO NPs in human umbilical vein endothelial cells (HUVECs) in comparison with the Zn2+ ions and CeO2 NPs. We found that the dissolved zinc ion was the most significant factor for cytotoxicity in HUVECs. More importantly, ZnO NPs at noncytotoxic concentration, but not CeO2 NPs, can induce significant cellular ER stress response with higher expression of spliced xbp-1, chop, and caspase-12 at the mRNA level, and associated ER marker proteins including BiP, Chop, GADD34, p-PERK, p-eIF2 alpha, and cleaved Caspase-12 at the protein levels. Moreover, ER stress was widely activated after treatment with ZnO NPs, while six of 84 marker genes significantly increased. ER stress response is a sensitive marker for checking the interruption of ER homeostasis by ZnO NPs. Furthermore, higher dosage of ZnO NPs (240 mu M) quickly rendered ER stress response before inducing apoptosis. These results demonstrate that ZnO NPs activate ER stress-responsive pathway and the ER stress response might be used as an earlier and sensitive end point for nanotoxicological study.