Yttrium Oxide Nanoparticles Affect Both Cognitive and Memory Function by Disrupting Copper Output in Neuronal Cells in a Rat Model

Background: The cerebral cortex is the foundation of cognitive function, and an imbalance in copper homeostasis in the cerebral cortex may cause cognitive and memory dysfunction. Metal exposure may disrupt copper (Cu) homeostasis in cells, leading to cognitive impairment. Yttrium oxide nanoparticles (Y 2 O 3 NPs) are widely used in the biomedical field and have potential neurotoxicity. However, the influence of Y 2 O 3 NPs on cognitive memory function in the brain is currently unclear. Methods: The effects of Y 2 O 3 NPs on cognitive and memory function were evaluated by rat behavioural experiments after intraperitoneal injection in a rat model. Subsequently, histological analysis was conducted on the cerebral cortex, and the Cu content and expression levels of cuproptosis-related proteins were detected both in vitro and in vivo. Finally, the copper output protein Cu transporting alpha polypeptide (ATP7A) was screened and detected at the mRNA and protein levels. Plasmid transfection experiments further confirmed that Y 2 O 3 NPs mediate disordered Cu output through ATP7A. Results: Y 2 O 3 NP exposure induced cognitive and memory dysfunction in rats. This effect was related to the disruption of copper homeostasis in neuronal cells caused by Y 2 O 3 NPs, which induced cuproptosis. Further research revealed that Y 2 O 3 NPs downregulate ATP7A expression, thus disrupting copper output and inducing cuproptosis. Conclusion: Y 2 O 3 NPs induce cognitive and memory dysfunction by mediating the disruption of copper output in neuronal cells, revealing the toxicity of Y 2 O 3 NPs to neurons. These findings contribute to their safe application in the biomedical field. Keywords: Yttrium oxide nanoparticles, neurotoxicity, neuronal cells, copper homeostasis, cuproptosis