Methylglyoxal exposure at dietary-relevant concentrations induces cognitive deficits through dopaminergic damage system and metabolic perturbation in zebrafish larvae.

Abstract

This study investigated the effects of MGO exposure at dietary-relevant concentrations on cognitive function and the underlying mechanisms using zebrafish larvae. Behavioral assessments demonstrated that MGO induced dose-dependent cognitive impairment, with the medium and high dose groups showing a remarkable reduction in spatial memory and locomotor activity. Mechanistic investigations revealed that MGO triggered substantial oxidative stress, evidenced by suppressed antioxidant enzyme activities (SOD and CAT decreased by approximately 30% and 28%, respectively, in the high-dose group) and elevated lipid peroxidation (MDA increased by 3.5-fold). These changes were accompanied by dopaminergic system impairment, including neurotransmitter depletion (dopamine levels reduced to 0.27±0.01 μg/g prot in high dose group) and neuronal degeneration (neuronal density decreased by 39%). Metabolomics analysis identified 37 differential metabolites across all groups, with significant enrichment in glycerophospholipid metabolism pathways. Our findings establish a comprehensive mechanistic pathway linking MGO exposure to cognitive deficits through oxidative stress-mediated dopaminergic damage and metabolic dysregulation, suggesting potential neurotoxic risks of dietary carbonyl compounds and underscoring the need for further mechanistic and translational studies. This study provides a preliminary toxicological basis for food safety evaluation, while acknowledging that validation in higher vertebrate systems is essential for human risk assessment.