ZnO-NPs Neurotoxicity to <i>Caenorhabditis elegans</i>: Disorders of Fatty Acid Synthesis and Glutathione Metabolism

Zinc oxide nanoparticles (ZnO-NPs) are a widely used class of engineered nanomaterials, but their increasing environmental release raises concerns as potential neurotoxic contaminants. Although ZnO-NPs are known to induce cognitive deficits and motor dysfunction in organisms, their underlying molecular mechanisms remain unclear. This study systematically investigated ZnO-NPs-induced neurotoxicity in <i>Caenorhabditis elegans</i>, revealing significant perturbations in lipid homeostasis, concomitant with impaired foraging behavior, learning and memory deficits, and chemotaxis dysfunction, along with neuronal damage. Transcriptomic profiling identified critical enrichment of differentially expressed genes in lipid metabolism and glutathione-mediated detoxification pathways with concurrent dysregulation of oxidative stress-responsive and neurodevelopment-related gene networks. Notably, ZnO-NPs exposure triggered remarkable upregulation of the <i>fat-5</i> gene, which encodes a key enzyme in palmitoleic acid (PA) biosynthesis. The impact of ZnO-NPs on lipid metabolic dysregulation was attenuated in the <i>fat-5</i> knockout strain, and exogenous PA administration phenocopied the toxicological profile of nanoparticles. Importantly, combined intervention with oleic acid and glutathione effectively ameliorated disordered lipid metabolism, attenuated reactive oxygen species accumulation, and restored neuronal integrity. Our findings delineate a novel mechanistic paradigm wherein ZnO-NPs exert neurotoxicity through lipid remodeling-mediated oxidative damage, proposing a promising therapeutic strategy involving dietary supplementation with unsaturated fatty acids and antioxidants to mitigate nanomaterial-induced toxicity.