**Abstract**

Silver nanoparticles (AgNPs) are one of the most highly commercialized nanoparticles, having been used extensively as an antimicrobial agent in cosmetics, textiles, foods, and the treatment of diseases. However, the impact of AgNPs on human mental health has not yet been well characterized. Using the human pluripotent stem cell (hPSC) neuronal differentiation cellular model to assess AgNPs neurotoxicity has several benefits. First, hPSCs neuronal differentiation process can faithfully recapitulate stages of neural development from neuronal progenitors to mature neurons which can provide an excellent platform for neurodevelopment and neurodegeneration toxicity testing. Furthermore, it can limit the amount of animal use for toxicity studies. With this cellular model, we examined citrate-coated AgNPs (AgSCs) and Polyvinylpyrrolidone-coated (AgSP) mediated neurotoxicity. Our results suggested that AgNP induced neurotoxicity exhibited a coating and dose-dependent manner. AgSC had high neurotoxicity compared with AgSP. AgSC significantly up-graduated Metallothionein (1F, 1E, 2A) proteins, a metal-binding protein that plays an essential role in metal homeostasis, heavy metal detoxification, and cellular anti-oxidative defense. Transcriptome analysis indicated that AgSC inhibited neurogenesis and axon guidance, promoted gliogenesis and neuronal apoptosis through oxidative stress. Supplementation with ascorbic acid can act as an antioxidant to attenuate AgNP-mediated neurotoxicity.

**Keywords:** silver nanoparticles (AgNP), human pluripotent stem cell-derived neuronal network, transcriptome analysis, oxidative stress, neurogenesis and gliogenesis, neurodegeneration
