Brain metabolomics reveals metabolic alterations associated with chronic polystyrene microplastic-induced neurotoxicity in Drosophila melanogaster

Microplastic (MP) pollution is a widespread global environmental problem and poses growing risks to food safety and human health. Increasing evidence indicates that MPs accumulate in human biological tissues, including the brain. However, the brain-specific metabolic alterations associated with chronic MPs exposure remain poorly understood. Here, we investigated the neurotoxic effects of chronic dietary exposure to polystyrene microplastics (PS-MPs; 10 and 50 ppm) in Drosophila melanogaster using an integrated metabolomic, biochemical, histological, and behavioral approach. Chronic dietary exposure to PS-MPs is linked to behavioral impairments, including decreased locomotor activity, impaired climbing, altered feeding, and reduced circadian amplitude, at the two tested concentrations. Untargeted brain metabolomics revealed widespread alterations in amino acid, nitrogen, kynurenine, polyamine, and central carbon metabolism, including reduced putrescine, elevated spermidine and spermine, and perturbations in glycolytic and tricarboxylic acid (TCA) cycle intermediates. Biochemical analyses demonstrated elevated oxidative stress and impaired antioxidant defenses, including reduced catalase (↓46%) and superoxide dismutase (↓40%) activity, and evidence of mitochondrial impairment (increased mitochondrial ROS, loss of membrane potential, reduced electron transport, altered NAD/NADH balance, and diminished metabolic viability). Histological examination revealed increased brain tissue damage and decreased neuronal viability. Moreover, PS-MPs exposure was associated with alterations in dopaminergic markers, including reduced tyrosine hydroxylase and dopamine levels, together with decreased γ-aminobutyric acid (GABA), indicating broader neurotransmitter alterations. These findings show that chronic PS-MPs exposure is associated with widespread brain metabolic perturbations, mitochondrial dysfunction, and dopaminergic impairment, highlighting associations between chronic PS-MPs exposure, brain metabolic alterations, and neurotoxic outcomes.