Nasal Instillation of Complex Metal Oxide Particles Induces Brain Metal Accumulation and Neurobehavioral Toxicity in...

The rapid expansion of complex metal oxide particles (CMOPs) in energy technologies raises emerging health concerns, yet their neuropsychiatric impacts remain unclear. Using intranasal exposure to lithium iron phosphate (LFP) and nickel-cobalt-manganese oxide (NCM) at dose levels selected with reference to reported ambient and occupational monitoring scenarios (0.8 and 8 mg/kg/day, n = 8 per group), we show that short-term CMOP exposure induces distinct neurobehavioral alterations in mice, characterized by changes in cognitive performance, risk assessment, and stress-related coping behavior. These changes co-occurred with dose-dependent brain accumulation of Li, Ni, Mn, and Co. Unexpectedly, low-dose exposure yielded 5-17-fold higher brain bioaccumulation factors than high-dose exposure, indicating disproportionate brain retention at lower exposure levels. Neurotransmitter profiling showed alterations consistent with perturbation of catecholamine metabolism, the tryptophan-kynurenine pathway, and the glutamate-glutamine cycle. At the molecular level, brain metal burden was associated with changes in barrier-related, neuroimmune, and synaptic signaling markers prioritized in relation to behavioral outcomes. Collectively, the findings indicate that short-term CMOP exposure can co-occur with brain metal bioaccumulation and neurobehavioral dysfunction, supporting the need for future inhalation-based and chronic studies to better define toxicokinetics, exposure relevance, and long-term health implications.