Neurodevelopmental and behavioural effects of arsenic in zebrafish (Danio rerio)

The current study was designed to investigate the molecular mechanisms by which arsenic causes neurobehavioural impairments in larval zebrafish following early developmental exposure to environmentally relevant concentrations. Zebrafish embryos were exposed to arsenic [0 (control), 5, 10, 50, and 100 µg/L as arsenite] from 1-120 hpf (hours-post-fertilization) and raised in clean water until 30-dpf (days-post-fertilization) to assess long-term effects. Arsenic-induced ROS, apoptosis, and lipid peroxidation were measured at 5-dpf. In addition, gene expression analysis and immunostaining (24-hpf and 5-dpf) were performed to examine how embryonic arsenic exposure affects neurogenesis and development of neural signalling pathways, including dopaminergic, serotonergic, and cholinergic pathways. Furthermore, arsenic-induced behavioural alterations in zebrafish larvae were evaluated by assessing photomotor response (5-dpf), thigmotaxis (15-dpf), social preference (21-dpf), and novel object recognition capacity (30-dpf). Embryonic arsenic exposure resulted in a dose-dependent increase in ROS production, abundance of apoptotic cells, and lipid peroxidation. Moreover, arsenic exposure significantly reduced hypothalamic neurogenesis and the expression of diencephalic dopaminergic neurons and peripheral motor neurons. Arsenic exposure also caused dysregulation of genes associated with neurogenesis, and dopaminergic, serotonergic and cholinergic signalling, and antioxidant response. Behavioural analysis revealed arsenic exposure impaired photomotor reflexes and locomotion at 5-dpf, heightened anxiety response at 15-dpf, and compromised cognitive function at 30-dpf. Interestingly, pretreatment with an antioxidant, N-acetyl-l-cysteine (NAC), ameliorated arsenic-induced ROS production and behavioural impairments (photomotor response and thigmotaxis). Overall, our study demonstrated that embryonic arsenic exposure causes behavioural deficits in larval zebrafish by inducing oxidative stress, leading to the disruption of neurogenesis and neural signalling pathways.