6PPD-Q alters zebrafish neurobehavior by inducing neuroinflammation and inhibiting ERK1/2-CREB-BDNF pathway

6PPD-quinone (6PPD-Q) is the main oxidation product of the tire antioxidant 6PPD, and has received increasing attention due to its widespread presence and toxic effects. However, the neurotoxic effects of 6PPD-Q and its potential mechanisms in adult zebrafish remain insufficiently understood. In this study, zebrafish were exposed to environmental concentrations of 6PPD-Q (5, 10, and 20 μg/L) for 21 days. Behavior, brain histopathology, 5-HT and DA levels, and the expression of their related genes were measured. By network toxicology, molecular docking and brain RNA-seq of 6PPD-Q, the possible molecular mechanisms underlying the neurotoxic effects of 6PPD-Q were investigated and the expression of identified pathway or molecules was determined. 6PPD-Q caused neurobehavioral changes and damaged the brain in zebrafish. The levels of 5-HT and DA in brain were reduced, and their related genes expression was downregulated. Network toxicology and RNA-seq identified 5 potential core molecules targeted by 6PPD-Q and these molecules were significantly enriched in MAPK pathway. 6PPD-Q significantly increased the protein levels of TLR4, TRAF6, and p-p38, as well as the mRNA expression of il-6, il-1β and tnf-α, while decreasing the expression level of il-10. Meanwhile, 6PPD-Q significantly reduced the protein levels of MEK1/2, p-ERK1/2, p-CREB, and BDNF. These findings suggest that 6PPD-Q alters neurobehavior in zebrafish, accompanied by monoamine neurotransmitter disruption, activation of inflammatory signaling and suppression of MEK1/2-ERK1/2-CREB-BDNF pathway, providing new insights into 6PPD-Q neurotoxicity and its mechanism.