Developmental exposure to environmental levels of cadmium induces neurotoxicity and activates microglia in zebrafish larvae: From the perspectives of neurobehavior and neuroimaging

Cadmium (Cd) is a worldwide environmental pollutant that postures serious threats to humans and ecosystems. Over the years, its adverse effects on the central nervous system (CNS) have been concerned, whereas the underlying cellular/molecular mechanisms remain unclear. In this study, taking advantages of zebrafish model in high-throughput imaging and behavioral tests, we have explored the potential developmental neurotoxicity of Cd at environmentally relevant levels, from the perspectives of neurobehavior and neuroimaging. Briefly, Cd2+ exposure resulted in a general impairment of zebrafish early development. Zebrafish neurobehavioral patterns including locomotion and reactivity to environmental signals were significantly perturbed upon Cd2+ exposure. Importantly, a combination of in vivo two-photon neuroimaging, flow cytometry and gene expression analyses revealed notable neurodevelopmental disorders as well as neuroimmune responses induced by Cd2+ exposure. Both cell-cycle arrest and apoptosis contributed jointly to a significant decrease of neuronal density in zebrafish larvae exposed to Cd2+. The dramatic morphological alterations of microglia from multi-branched to amoeboid, the microgliosis, as well as the modulation of gene expression profiles demonstrated a strong activation of microglia and neuroinflammation triggered by environmental levels of Cd2+. Together, our study points to the developmental toxicity of Cd in inducing CNS impairment and neuroinflammation thereby providing visualized etiological evidence of this heavy metal induced neurodevelopmental disorders. It's tempting to speculate that this research model might represent a promising tool not only for understanding the molecular mechanisms of Cd-induced neurotoxicity, but also for developing pharmacotherapies to mitigate the neurological damage resulting from exposure to Cd, and other neurotoxicants.