MDM2 upregulation induces mitophagy deficiency via Mic60 ubiquitination in fetal microglial inflammation and consequently neuronal DNA damage caused by exposure to ZnO-NPs during pregnancy.
MDM2 upregulation induces mitophagy deficiency via Mic60 ubiquitination in fetal microglial inflammation and consequently neuronal DNA damage caused by exposure to ZnO-NPs during pregnancy.
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DOI：
10.1016/j.jhazmat.2023.131750
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发表时间：
2023-06
影响因子：
13.6
通讯作者：
Yanli Zhang;Yulin Zhang;Ye Lei;Junrong Wu;Yiyuan Kang;Shuo-li Zheng;L. Shao
中科院分区：
文献类型：
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作者：
Yanli Zhang;Yulin Zhang;Ye Lei;Junrong Wu;Yiyuan Kang;Shuo-li Zheng;L. Shao
在怀孕期间，人体很容易受到外界刺激。氧化锌纳米颗粒（ZnO-NPs）广泛应用于日常生活中，它们通过环境或生物医学暴露进入人体，具有潜在的风险。尽管越来越多的研究证明了ZnO-NP的毒性作用，但很少有研究表明产前暴露于ZnO-NP对胎儿脑组织发育的影响。本文系统研究了zno - np致胎儿脑损伤及其机制。通过体内和体外实验，我们发现ZnO-NPs可以穿过未发育的血单键脑屏障进入胎儿脑组织，并被小胶质细胞内吞。ZnO-NP暴露损害线粒体功能，通过下调Mic60诱导自噬体过度积累，从而诱导小胶质细胞炎症。从机制上讲，ZnO-NPs通过激活MDM2增加Mic60泛素化，导致线粒体稳态失衡。通过MDM2沉默抑制Mic60泛素化可显著减轻zno - np诱导的线粒体损伤，从而防止自噬体过度积累，减轻zno - np介导的炎症和神经元DNA损伤。我们的研究结果表明，ZnO-NPs可能会破坏线粒体稳态，导致胎儿的自噬通量异常、小胶质细胞炎症和继发性神经元损伤。我们希望本研究提供的信息能够提高对产前ZnO-NP暴露对胎儿脑组织发育影响的认识，并引起对孕妇日常使用和治疗性暴露ZnO-NP的更多关注。
During pregnancy, the human body is quite vulnerable to external stimuli. Zinc oxide nanoparticles (ZnO-NPs) are widely used in daily life, and they enter the human body via environmental or biomedical exposure, thus having potential risks. Although accumulating studies have demonstrated the toxic effects of ZnO-NPs, few studies have addressed the effect of prenatal ZnO-NP exposure on fetal brain tissue development. Here, we systematically studied ZnO-NP-induced fetal brain damage and the underlying mechanism. Using in vivo and in vitro assays, we found that ZnO-NPs could cross the underdeveloped bloodsingle bondbrain barrier and enter fetal brain tissue, where they could be endocytosed by microglia. ZnO-NP exposure impaired mitochondrial function and induced autophagosome overaccumulation by downregulation of Mic60, thus inducing microglial inflammation. Mechanistically, ZnO-NPs increased Mic60 ubiquitination by activating MDM2, resulting in imbalanced mitochondrial homeostasis. Inhibition of Mic60 ubiquitination by MDM2 silencing significantly attenuated the mitochondrial damage induced by ZnO-NPs, thereby preventing autophagosome overaccumulation and reducing ZnO-NP-mediated inflammation and neuronal DNA damage. Our results demonstrate that ZnO-NPs are likely to disrupt mitochondrial homeostasis, inducing abnormal autophagic flux and microglial inflammation and secondary neuronal damage in the fetus. We hope the information provided in our study will improve the understanding of the effects of prenatal ZnO-NP exposure on fetal brain tissue development and draw more attention to the daily use of and therapeutic exposure to ZnO-NPs among pregnant women.