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

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 blood-brain 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.

Automated summary

During pregnancy, the human body is vulnerable to external stimuli, including zinc oxide nanoparticles (ZnO-NPs). This study investigates the effects of prenatal ZnO-NP exposure on fetal brain tissue development. The findings suggest that ZnO-NPs can cross the blood-brain barrier and enter fetal brain tissue, causing mitochondrial damage, autophagosome overaccumulation, microglial inflammation, and neuronal damage. These findings highlight the importance of understanding the effects of prenatal ZnO-NP exposure on fetal brain development and raising awareness of the use of ZnO-NPs among pregnant women.