Acute Cu exposure induces neurotoxicity via DAF-16/FoxO and SKN-1/Nrf2 pathway.

Copper (Cu) pollution has raised global environmental concern due to its persistence and toxicity. Numerous studies have shown that the imbalance of Cu metabolism is closely related the neurodegenerative diseases. Previous study exposited that excessive Cu participating in neurotoxic mechanism through oxidative stress, protein misfolding, mitochondrial malfunction, autophagy dysregulation, and apoptosis. However, the mechanism of neurotoxicity of Cu is still inconclusive. In this study, Caenorhabditis elegans was used to investigate the acute Cu exposure on the nervous system and the possible mechanism. Initially, 0.01-10 mg/L Cu exposure inhibited locomotion behavior, and that 1-10 mg/L decreased the sensory behavior in C. elegans. Subsequently, dopaminergic, glutamatergic, GABAergic and cholinergic neurons were destroyed, as well as the decreased expression of neurotransmitters after Cu exposure. Pearson's correlation analysis showed that locomotion behaviors were positively correlated with the health of the dopaminergic, glutamatergic, GABAergic and cholinergic neurons. In addition, Cu exposure promoted the formation of oxidative stress. Study showed Cu significantly promoted nuclear localization of SKN-1, but inhibited that of DAF-16 in C. elegans. Further evidence showed skn-1 mutants and daf-16 mutants were more sensitiveness to Cu-induced behavioral defect. Meanwhile, the regulatory effects of SKN-1 and DAF-16 on downstream genes were blocked in skn-1 mutants and daf-16 mutants. Cu regulated the expression of downstream genes sod-3, ctl-1, gcs-1 and gst-4 through transcription factors SKN-1 and DAF-16, in response to Cu-induced neurotoxicity. Thus, the present study contributes to the understanding of the potential neurotoxicity of acute exposure to Cu in C. elegans.