Neurotoxicity of chronic nano-neodymium oxide exposure in zebrafish: Behavioral and molecular insights

Rare earth elements (REEs) are crucial in modern technology and essential for the transition to a low-carbon economy. Despite the rising global demand for nano-neodymium oxide (NPs-Nd₂O₃), a rare earth nanoparticle, comprehensive studies on its neurotoxic effects are limited. This study aims to elucidate the chronic neurotoxic effects of NPs-Nd₂O₃ and explore their molecular mechanisms. Our findings show that NPs-Nd₂O₃ accumulation in zebrafish brains impairs embryonic neural development, acute exposure to 120 h post-fertilization (hpf) - 7 days post-fertilization (dpf), causing behavioral alterations such as reduced movement distance, average velocity, and increased manic frequency and thigmotaxis. Chronic exposure to NPs-Nd₂O₃ until 42 dpf exhibited similar anxiety-like behavioral abnormalities. Histopathological analysis revealed developmental delays in brain formation, significant tectal ventricle (TeV) and midbrain ventricle atrophy, deterioration of the periventricular gray zone (PGZ), and decreased Nissl body density in exposed larvae. Continued exposure to 100 dpf resulted in further reductions in brain width, length, and area, and decreased Nissl body density. RNA-Seq analysis identified the retinol metabolic pathway as a critical target of NPs-Nd₂O₃ exposure, with validation confirming differential gene expression related to this pathway. Disrupted retinol metabolism may underlie NPs-Nd₂O₃-induced neurotoxicity, exacerbated by reduced dopaminergic neurons. Additionally, cellular experiments showed that NPs-Nd₂O₃ inhibit neurite growth. This study advances our understanding of NPs-Nd₂O₃ toxicity mechanisms and provides a framework for investigating the neurotoxic effects of similar compounds.