Life cycle benzophenone 1 exposure induces anxiety- and depression-like behaviors in zebrafish via endoplasmic reticulum stress-mediated dopaminergic system dysfunction

Environmental exposure to benzophenones (BPs) has emerged as a potential risk factor for the comorbidity of anxiety and depression. Among them, BP1 has attracted increasing attention due to its potential neurotoxic effects. However, whether and how long-term exposure to BP1 induces anxiety- and depression-like behaviors remains unclear. To investigate the adverse effects of BP1 on mental health, zebrafish were exposed to environmentally relevant concentrations of BP1 (0 to 1 μM) from 0 to 180 days post-fertilization (dpf). Chemical analysis confirmed significant accumulation of BP1 in zebrafish brain tissue, indicating effective internal exposure of the nervous system. We then showed that exposure to BP1 increased scototaxis and bottom-dwelling behaviors while reducing exploratory activity in adult zebrafish, suggesting that BP1 exposure can cause anxiety- and depression-like behaviors. Moreover, histopathological analysis revealed that BP1 exposure induced morphological damage in the zebrafish midbrain, characterized by neuronal degeneration, interstitial vacuolation, and loss of Nissl bodies. Transcriptomic analysis revealed that life cycle BP1 exposure activated endoplasmic reticulum (ER) stress signaling and downregulated dopamine receptor drd4a . Furthermore, BP1 exposure suppressed the proliferation of dopaminergic neurons and decreased dopamine levels in the zebrafish brain. At the translational level, BP1 exposure significantly increased GRP78 and ATF4B protein levels and decreased EIF2α phosphorylation level, indicating activation of chronic ER stress. Concomitantly, the protein levels of TH and DRD4 were reduced. To further validate these findings, parallel experiments in PC12 cells demonstrated that BP1 exposure similarly dysregulated GRP78, ATF4B, p-EIF2α, TH, and DRD4. Importantly, pharmacological inhibition of ER stress with 4-phenylbutyric acid (4-PBA) effectively rescued the BP1-induced downregulation of TH and DRD4 in vitro. Taken together, these findings provide crucial evidence elucidating the underlying mechanism by which BP1 exposure induces anxiety- and depression-like behaviors in aquatic organisms, offering novel insights into its neurotoxic effects. • Chronic BP1 exposure induces anxiety- and depression-like behaviors in zebrafish. • BP1 disrupts dopaminergic signaling to mediate neurobehavioral toxicity. • ER stress–mediated disruption of DA signaling is a key mechanism underlying BP1-induced anxiety- and depression-like behaviors.