Chronic Dietary PhIP Exposure Disrupts Brain Homeostasis in Adult Zebrafish through Dose-Dependent Proteostatic and Clock-Associated Remodeling.

Heterocyclic aromatic amines formed during high-temperature cooking are persistent dietary contaminants, and 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) has emerged as a potential neurotoxicant beyond its established carcinogenicity. Adult zebrafish were fed PhIP for 90 days at 0.006, 0.4, and 7.2 mg/kg body weight/day. Chronic exposure impaired locomotion and induced brain injury, oxidative imbalance, and glial reactivity. Transcriptomic analyses revealed dose-dependent remodeling, with low exposures primarily engaging endoplasmic reticulum proteostasis, intermediate dosages enriching oxidative phosphorylation- and proteasome-related pathways, and high exposure associated with clock-related regulation. Proteasome-related enrichment increased progressively with dose (ρ = 0.842). Molecular validation supported a shift from adaptive unfolded protein response signaling toward unresolved cellular stress, accompanied by depletion of melatonin, dopamine, serotonin, and GABA. These findings indicate that chronic dietary PhIP disrupts brain homeostasis through progressive proteostatic and clock-associated dysregulation, supporting consideration of long-term neurological effects in food safety evaluation.