Cu disrupts the olfacto-retinal centrifugal pathway and mediates reduced feeding-related behavior in zebrafish (Danio rerio).

Cu is an environmental trace metal, but excess Cu is known to disrupt chemosensory functions. However, the chronic effects on the olfacto-retinal centrifugal (ORC) pathway and feeding-related behavior of Cu in fish remain largely uncharacterized. Zebrafish (Danio rerio, six-month-old) were exposed to environmentally relevant concentrations of Cu (i.e., 1.6, 5.6, 16, and 35 μg L^-1; Cont, Cu-L, Cu-M, and Cu-H) over a 30-day period. Behavioral, neurochemical, and transcriptional biomarkers were measured to evaluate toxic effects of Cu. The results demonstrated that Cu significantly accumulated in olfactory tissues, eyes, and brains. Cu induced divergent olfactory and visual impairments in female and male fish. It markedly impaired olfactory signal transduction and processing (e.g., gnal; ∼56% decrease), while visual function was more severely impaired in females (e.g., a 48% decrease in velocity during visually guided behavior). Correlation analysis further showed that Cu induced coordinated changes between olfactory tissue and eyes. Meanwhile, such olfactory and visual impairments, together with altered neurotransmitter levels and disruptive appetite regulation (e.g., ∼1.2-fold increases in the orexigenic neuropeptide Y (NPY) and the anorexigenic pro-opiomelanocortin (POMC)), may collectively contribute to the 6.0-17% decline in feeding-related behavior. Our findings suggest that Cu-induced feeding suppression may involve disrupted ORC pathway and sex-dependent appetite regulation, providing critical insights into the ecological risks of Cu contamination.