<p>Zinc Oxide Nanoparticles Induce Ferroptotic Neuronal Cell Death in vitro and in vivo</p>

Abstract

Purpose Zinc oxide nanoparticles (ZnONPs) are one of the most important nanomaterials that are widely used in the food, cosmetic and medical industries. Humans are often exposed to ZnONPs via inhalation, and they may reach the brain where neurotoxic effects could occur via systemic distribution. However, the mechanisms underlying how ZnONPs produce neurotoxic effects in the brain remain unclear. In this study, we aimed to investigate the novel mechanism involved in ZnONPs-induced neurotoxicity. Methods and Results We demonstrated for the first time that pulmonary exposure to ZnONPs by intratracheal instillation could trigger ferroptosis, a new form of cell death, in the neuronal cells of mouse cerebral cortex. A similar phenomenon was also observed in cultured neuron-like PC-12 cell line. By using a specific inhibitor of ferroptosis ferrostatin-1 (Fer-1), our results showed that inhibition of ferroptosis by Fer-1 could significantly alleviate the ZnONPs-induced neuronal cell death both in vivo and in vitro. Mechanistic investigation revealed that ZnONPs selectively activated the JNK pathway and thus resulted in the ferroptotic phenotypes, JNK inhibitor SP600125 could reverse lipid peroxidation upregulation and ferroptotic cell death induced by ZnONPs in PC-12 cells. Conclusion Taken together, this study not only demonstrates that pulmonary exposure of ZnONPs can induce JNK-involved ferroptotic cell death in mouse cortex and PC-12 cells, but also provides a clue that inhibition of ferroptosis by specific agents or drugs may serve as a feasible approach for reducing the untreatable neurotoxicity induced by ZnONPs.

Behavioural alterations induced by chronic exposure to 10 nm silicon dioxide nanoparticles

“…The failure to do so indicates an error in the reference memory while the working memory is assessed when the mouse made an entry to each arm a single time. Re‐entry into the arms with no food reward would be considered as working memory error [ 43 ].…”

Bioinformatics Analysis Identifies Potential Ferroptosis Key Genes in the Pathogenesis of Intracerebral Hemorrhage

“…A previous study on ICH suggested that the JNK pathway could be initiated, with upregulation of pJNK (Hibi et al, 1993;Pei et al, 2016). Other studies indicated that JNK is involved in ferroptotic cell death in mouse cortex and PC-12 cells (Qin et al, 2020). TNFAIP3, an important anti-inflammatory factor, can repress the expression of inflammatory NF-κB signaling and promote cell survival (Catrysse et al, 2014).…”

Nickel oxide nanoparticles induce apoptosis and ferroptosis in airway epithelial cells via ATF3

“…Zinc oxide nanoparticles (ZnONPs) interfere with iron homeostasis and ROS production, ultimately leading to ferroptosis 30 . The ferroptosis induced by ZnONPs is JNK and p53 dependent, as JNK, inhibitor and p53 siRNA abrogate this effect 30,31 . Besides, other nanomaterials such as Al 2 O 3 , Fe 3 O 4 , and TiO 2 also cause intracellular Fe 2+ elevation in HUVECs 30 .…”