Synergistic neurotoxicity of polystyrene nanoplastics and cadmium co-exposure: oxidative stress, mitochondrial dysfunction, and ATF5-mediated mitochondrial unfolded protein response in C. elegans and PC12 cells

Abstract

Environmental co-contamination with microplastics and heavy metals such as cadmium (Cd) poses emerging health risks, yet their synergistic neurotoxic effects remain poorly understood. This study investigated the synergistic neurotoxic effects of polystyrene nanoplastics (PS-NPs) and Cd co-exposure, focusing on mitochondrial dysfunction and the mitochondrial unfolded protein response (UPR ^mt ) in Caenorhabditis elegans (C. elegans) and PC12 cells. Results demonstrated that coexposure to PS-NPs and Cd significantly increased Cd accumulation and oxidative stress relative to single toxicant treatments, producing greater impairment of learning-associated behavior and dopaminergic, glutamatergic and GABAergic neuronal integrity in C. elegans. In PC12 cells, co-exposure exacerbated mitochondrial membrane depolarization, ATP depletion, disrupted mitochondrial dynamics, and neuronal synaptic damage. Notably, it robustly activated the UPR^mt pathway, mediated by the transcription factor activating transcription factor 5 (ATF5) (and its homolog atfs-1 in C. elegans).In PC12 cells, the antioxidant N-acetylcysteine (NAC) pretreatment mitigated these effects, while ATF5 knockdown attenuated UPR^mt activation and synaptic damage, indicating the critical role of the ATF5-UPR^mt axis. These findings reveal that PS-NPs and Cd act synergistically to induce neurotoxicity via oxidative stress, mitochondrial dysfunction, and ATF5-mediated UPR^mt activation. This highlights the need to consider combined pollutant exposures in environmental risk assessment and to provide mechanistic insights into nanoplastic-metal co-toxicity.