Embryonic Arsenic Exposure Triggers Long-Term Behavioral Impairment with Metabolite Alterations in Zebrafish

Arsenic trioxide (As₂O₃) is a ubiquitous heavy metal in the environment. Exposure to this toxin at low concentrations is unremarkable in developing organisms. Nevertheless, understanding the underlying mechanism of its long-term adverse effects remains a challenge. In this study, embryos were initially exposed to As₂O₃ from gastrulation to hatching under semi-static conditions. Results showed dose-dependent increased mortality, with exposure to 30-40 µM As₂O₃ significantly reducing tail-coiling and heart rate at early larval stages. Surviving larvae after 30 µM As₂O₃ exposure showed deficits in motor behavior without impairment of anxiety-like responses at 6 dpf and a slight impairment in color preference behavior at 11 dpf, which was later evident in adulthood. As₂O₃ also altered locomotor function, with a loss of directional and color preference in adult zebrafish, which correlated with changes in transcriptional regulation of adsl, shank3a, and tsc1b genes. During these processes, As₂O₃ mainly induced metabolic changes in lipids, particularly arachidonic acid, docosahexaenoic acid, prostaglandin, and sphinganine-1-phosphate in the post-hatching period of zebrafish. Overall, this study provides new insight into the potential mechanism of arsenic toxicity leading to long-term learning impairment in zebrafish and may benefit future risk assessments of other environmental toxins of concern.