MoS2 Nanosheets at Low Doses Induced Cardiotoxicity in Developing Zebrafish via Ferroptosis: Influence of Lateral Size and Surface Modification

Abstract

The widespread applications of molybdenum disulfide (MoS₂) nanosheets inevitably result in their release into aquatic environments, necessitating an exploration of their potential toxic effects on aquatic organisms. This study analyzes the cardiac responses of zebrafish larvae exposed to MoS₂, with a focus on the influence of size and surface modifications. At higher concentrations (1 and 5 mg/L), MoS₂ nanosheets hampered larval growth without influencing cardiomyogenesis. At lower doses (0.5–100 μg/L), small-sized MoS₂ (ssMoS₂, 187.2 nm) significantly impaired cardiac development, as proved by morphology abnormality, decreased heartbeat, stroke volume, and cardiac output, whereas these undesirable changes were not observed in the cysteine-modified form. Large-sized nanosheets (1.638 μm) did not localize to the heart, barely showing a cardiac disorder. Transcriptomics, biochemical analysis, and computational simulation validated that ssMoS₂ aggravated Fe²⁺ overload through excessive ferritinophagy and ferroportin-1 inhibition, accompanied by down-regulation of glutathione peroxidase 4 and activation of PUFAs esterification, leading to ferroptosis. Significant associations between ferroptosis signals and cardiac indices, along with the ferrostatin-1 inhibition test, confirmed the ferroptosis-mediated cardiotoxicity of ssMoS₂. Our study provides a key understanding of molecular events underlying MoS₂-induced cardiotoxicity and highlights the importance of size and surface characteristics, which are significant for risk assessment and the safe design of nanoproducts.