Nickel oxide nanoparticles induce developmental neurotoxicity in zebrafish by triggering both apoptosis and ferroptosis

Nickel oxide nanoparticles (NiO-NPs) with unique characteristics have been widely utilized in numerous manufacturing processes, which have inevitably led to environmental pollution and health hazards. Previous studies have shown that nanoparticles may enter the central nervous system (CNS) and trigger off various adverse effects, however, the NiO-NPs induced neurotoxic effects as well as the underlying mechanisms remain unclear yet. In the present study, by taking advantage of the zebrafish model system for genetic analyses, in vivo neuroimaging, and neurobehavioral studies, we have investigated how early-life exposure to environmental levels of NiO-NPs (0, 5, 20, 50, 100 mg L −1 ) affects embryonic development, neurobehavior and neurodevelopment of zebrafish larvae. Our results reveal that the observed neurobehavioral and neurodevelopmental disorders induced by environmental NiO-NPs exposure are closely related to ROS-mediated apoptosis and iron-mediated ferroptosis, the two main forms of programmed cell death which have been strongly implicated in many types of CNS injuries and diseases. Furthermore, pharmacological interventions of apoptosis and ferroptosis pathways via N -acetylcysteine (NAC) and deferoxamine (DFO) respectively, have strongly implicated apoptosis and ferroptosis in these NiO-NPs induced neurotoxic effects. Thus, this study elucidates the potential cellular and molecular mechanisms underlying NiO-NPs induced neurotoxicity, with implications for our understandings as well as pharmacotherapies of the physiologically damaging effects of other environmental nano-pollutants. NiO-NPs exert toxic effects on zebrafish neurobehavior and neurodevelopment through activation of apoptosis and ferroptosis.