Mechanistic insights into glufosinate-ammonium (GLA)-Induced brain injury revealed by LC-MS/MS-based metabolomics

AIMS: This study aimed to elucidate the biochemical and metabolic mechanisms underlying glufosinate-ammonium-induced neurotoxicity, with a focus on brain metabolic disturbances. METHODS: Male Sprague-Dawley rats were administered glufosinate-ammonium by intragastric gavage, with saline-treated animals serving as controls. Neuropathological changes and cognitive performance were assessed at 2 and 6 days post-exposure. Oxidative stress and energy metabolism were evaluated by measuring plasma antioxidant indices, and brain levels of superoxide dismutase (SOD), glutathione (GSH/GSSG), total antioxidant capacity (T-AOC), and adenosine triphosphate (ATP). In addition, untargeted LC-MS/MS-based metabolomics of brain tissue was conducted to characterize exposure-related metabolic perturbations. RESULTS: Histopathological examination revealed marked brain injury on day 2 post-exposure, characterized by neuronal necrosis, apoptosis, and severe mitochondrial disruption. Although pathological severity was attenuated by day 6, residual cellular damage remained evident. Behavioral testing revealed significant impairments in spatial learning and memory in the glufosinate-ammonium-exposed group. Biochemical analyses revealed disrupted oxidative stress and energy metabolism, reflected by altered levels of superoxide dismutase (SOD), glutathione (GSH/GSSG), total antioxidant capacity (T-AOC), and adenosine triphosphate (ATP) in brain tissue. Metabolomic analysis revealed pronounced alterations in brain metabolic profiles, involving pathways related to oxidative stress, energy metabolism, and amino acid metabolism. Early-stage disturbances were dominated by alterations in glutamate and tricarboxylic acid (TCA) cycle-related metabolites, whereas later-stage changes primarily involved taurine and hypotaurine metabolism. CONCLUSION: Following glufosinate-ammonium exposure, rats exhibited neurological dysfunction and cognitive impairment, accompanied by metabolic disturbances in brain tissue, particularly in oxidative stress, energy metabolism, and amino acid metabolism. These findings provide mechanistic insight into glufosinate-ammonium-induced neurotoxicity and highlight the critical role of metabolic dysregulation.