Combined Copper and Zinc Exposure Exacerbates Neurotoxicity in C. Elegans

Cordeiro LM, Soares MV, da Silva AF, Dos Santos LV, de Souza LI, da Silveira TL, Baptista FBO, de Oliveira GV, Pappis C, Dressler VL, Arantes LP, Zheng F, Soares FAA. Toxicity of copper and zinc alone and in combination in Caenorhabditis elegans model of Huntington’s disease and protective effects of rutin. Neurotoxicology 2023;97:120-132. doi: 10.1016/j.neuro.2023.06.005.

Background: Exposure to mixtures of metals such as copper (Cu) and zinc (Zn) can affect neuronal health and contribute to neurodegenerative disorders. The nematode Caenorhabditis elegans is a well-established model organism for studying metal-induced neurotoxicity and Huntington’s disease (HD)-like symptoms because of its conserved molecular pathways and available transgenic strains expressing polyglutamine (polyQ) expansions.

Hypothesis: This study hypothesized that combined exposure to Cu and Zn would induce greater neurotoxic effects in C. elegans than either metal alone, promoting neurodegeneration and polyQ aggregation, and that the flavonoid rutin could mitigate these effects.

Methods: The authors exposed wild-type and HD-model C. elegans strains to Cu, Zn or their combination and assessed morphology, locomotion, neuronal function and aggregation. Behavioral and locomotion parameters were recorded and analyzed using WormLab. Additional assays included octanol and touch responses, dye-filling to assess neuronal integrity, and inductively coupled plasma mass spectrometry for metal quantification.

Results: Combined Cu and Zn exposure significantly reduced survival, body length, width and locomotor performance compared to controls. Developmental delay occurred in all strains exposed to the metal mixture. The combination increased latency in octanol response, impaired touch sensitivity and enhanced muscle polyQ aggregation and neurodegeneration. Rutin treatment reduced aggregation and neuronal loss, and metal analyses revealed altered Fe and Zn accumulation after co-exposure.

Conclusions: The study demonstrated that low-level combined Cu and Zn exposure causes neurotoxic effects and worsens HD-like phenotypes in C. elegans, while rutin exerts neuroprotective, metal-chelating and antioxidant effects.