Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity.
Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity.
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DOI：
10.1016/j.toxlet.2015.02.004
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发表时间：
2015-04-02
影响因子：
3.5
通讯作者：
Jiang, Mizu
中科院分区：
文献类型：
--
作者：
Yang, Xia;Shao, Huali;Liu, Weirong;Gu, Weizhong;Shu, Xiaoli;Mo, Yiqun;Chen, Xuejun;Zhang, Qunwei;Jiang, Mizu
纳米氧化锌广泛应用于防晒霜、服装、医药和电子设备等领域。然而，人类接触的潜在风险和对健康的不利影响还没有得到很好的了解。以往的研究表明，暴露于纳米氧化锌可通过氧化应激引起肝脏损伤和肝细胞凋亡，但纳米氧化锌致肝毒性的分子机制尚不清楚。内质网对氧化应激非常敏感，在氧化应激诱导的损伤中也起着至关重要的作用。以往的研究表明，内质网应激参与了许多化学性肝损伤的发生。我们推测，暴露于纳米氧化锌会引起氧化应激和内质网应激，而氧化应激和内质网应激参与了纳米氧化锌诱导的肝损伤。为了验证我们的假设，小鼠每天给小鼠灌胃200 mg/kg或400 mg/kg的纳米氧化锌，为期90天，并采集血液和肝组织进行研究。结果表明，暴露于纳米氧化锌可引起肝损伤，表现为肝细胞局灶性坏死、中央静脉充血性扩张，丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)水平显著升高。暴露于纳米氧化锌也会导致肝脏组织中谷胱甘肽(GSH)的耗竭。此外，我们的电子显微镜结果显示，经纳米氧化锌处理的小鼠肝组织出现内质网肿胀和核糖体脱颗粒。纳米氧化锌处理组小鼠内质网应激相关基因(GRP78、grp94、PDI-3、XBP-1)的mRNA表达水平也上调。纳米氧化锌使依赖于核糖核酸的蛋白激酶样ER激酶(PERK)和真核细胞起始因子2α(eIF2α)的磷酸化增加。最后，我们发现，暴露于纳米氧化锌导致内质网应激相关的凋亡蛋白水平增加，如caspase-3、caspase-9、caspase-12、JNK和CHOP/GADD153的磷酸化，以及促凋亡基因(CHOP和Bax)的上调。这些结果提示氧化应激和内质网应激诱导的细胞凋亡参与了纳米氧化锌诱导的小鼠肝毒性。
Zinc oxide nanoparticles (Nano-ZnO) are widely used in sunscreens, clothes, medicine and electronic devices. However, the potential risks of human exposure and the potential for adverse health impacts are not well understood. Previous studies have demonstrated that exposure to Nano-ZnO caused liver damage and hepatocyte apoptosis through oxidative stress, but the molecular mechanisms that are involved in Nano-ZnO-induced hepatotoxicity are still unclear. Endoplasmic reticulum (ER) is sensitive to oxidative stress, and also plays a crucial role in oxidative stress-induced damage. Previous studies showed that ER stress was involved in many chemical-induced liver injuries. We hypothesized that exposure to Nano-ZnO caused oxidative stress and ER stress that were involved in Nano-ZnO-induced liver injury. To test our hypothesis, mice were gavaged with 200 mg/kg or 400 mg/kg of Nano-ZnO once a day for a period of 90 days, and blood and liver tissues were obtained for study. Our results showed that exposure to Nano-ZnO caused liver injury that was reflected by focal hepatocellular necrosis, congestive dilation of central veins, and significantly increased alanine transaminase (ALT) and aspartate transaminase (AST) levels. Exposure to Nano-ZnO also caused depletion of glutathione (GSH) the liver tissues. In addition, our electron microscope results showed that ER swelling and ribosomal degranulation were observed in the liver tissues from mice treated with Nano-ZnO. The mRNA expression levels of ER stress-associated genes (grp78, grp94, pdi-3, xbp-1) were also up-regulated in Nano-ZnO-treated mice. Nano-ZnO caused increased phosphorylation of RNA-dependent protein kinase-like ER kinase (PERK) and eukaryotic initiation factor 2α (eIF2α). Finally, we found that exposure to Nano-ZnO caused increased ER stress-associated apoptotic protein levels, such as caspase-3, caspase-9, caspase-12, phosphorylation of JNK, and CHOP/GADD153, and up-regulation of pro-apoptotic genes (chop and bax). These results suggest that oxidative stress and ER stress-induced apoptosis are involved in Nano-ZnO-induced hepatotoxicity in mice.
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影响因子：
6.6
作者：
Rasmussen JW;Martinez E;Louka P;Wingett DG
通讯作者：
Wingett DG
氧化锌纳米颗粒的药代动力学，组织分布和排泄。
影响因子：
8
作者：
Baek M;Chung HE;Yu J;Lee JA;Kim TH;Oh JM;Lee WJ;Paek SM;Lee JK;Jeong J;Choy JH;Choi SJ
通讯作者：
Choi SJ
影响因子：
7.8
作者：
Hitomi, Junichi;Katayama, Taiichi;Eguchi, Yutaka;Kudo, Takashi;Taniguchi, Manabu;Koyama, Yoshihisa;Manabe, Takayuki;Yamagishi, Satoru;Bando, Yoshio;Imaizumi, Kazunori;Tsujimoto, Yoshihide;Tohyama, Masaya
通讯作者：
Tohyama, Masaya
DOI：
10.1016/j.nano.2010.10.001
发表时间：
2011-04-01
影响因子：
5.4
作者：
Premanathan, Mariappan;Karthikeyan, Krishnamoorthy;Manivannan, Govindasamy
通讯作者：
Manivannan, Govindasamy
影响因子：
25.7
作者：
Malhi, Harmeet;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.