Dose-inverted neurotoxicity: La₂O₃ nanoparticles cause redox dysregulation at low concentrations but excitotoxic catastrophe at high doses

Abstract

This study investigated the effects of lanthanum oxide nanoparticles (La₂O₃ NPs) on cognitive and motor functions in female mice. We used behavioral tests, biochemical analysis, and tissue examination. Our findings indicate that neurotoxicity is dose-dependent, with distinct mechanisms at play. Low doses (60 mg/kg) caused severe oxidative stress, increasing a key damage marker (MDA) by 40–80 times and depleting antioxidants (glutathione) in the blood. These doses also led to the accumulation of pro-oxidant metals (Fe, Mn, Cu, Ti) and a reduction in brain calcium levels, as determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). At moderate doses, mice exhibited hyperactive movement but normal muscle strength, indicating a brain-specific effect. In contrast, high doses (300 mg/kg) triggered a different pattern of damage. This included a harmful calcium-potassium imbalance, disruption of key brain health signals (BDNF pathway), and widespread neuronal death. These changes are associated with significant cognitive deficits in avoidance learning and a complete lack of response to warning stimuli. Histopathological analysis revealed that neurotoxicity primarily affected motor coordination pathways, with degeneration observed in the cerebellum and medulla. We propose that La₂O₃ NPs release La³ ⁺ ions, which disrupt cellular calcium balance and produce harmful reactive oxygen species (ROS). This leads to two toxicity phases: at low doses, metal ions drive ROS generation, while at high doses, nanoparticle aggregation causes a catastrophic failure of ion regulation in neurons. These findings have important implications for understanding nanomaterial-induced neurodegeneration and creating protective strategies against La₂O₃ exposure.