Mechanisms Mediating Mancozeb-Induced Toxicity in SH-SY5Y Cells: Mitochondrial Complex II Impairment, Oxidative Stress and Genotoxicity

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and associated with both genetic and environmental factors. Among environmental agents, the fungicide mancozeb (MZ) has gained attention due to its potential to induce neuronal damage. However, the mechanisms underlying its neurotoxicity are not completely understood. This study aimed to investigate the mechanisms of MZ-induced toxicity in SH-SY5Y neuroblastoma cells, focusing on oxidative stress and mitochondrial dysfunction pathways. MZ reduced SH-SY5Y cell viability in a concentration- and time-dependent manner, inducing cell death at concentrations of 15 μM or higher. Exposure to low MZ concentrations (6 μM) for short periods significantly increased general reactive oxygen species (ROS), including superoxide production, as well as lipid peroxidation. In addition, 6 μM MZ decreased nonprotein thiol (NPSH) levels relative to the corresponding vehicle control at 3 h, whereas NPSH levels were increased relative to the corresponding vehicle control at 12 h. Pretreatment with the antioxidant ascorbic acid fully prevented MZ-induced cytotoxicity at 10 μM, supporting the involvement of oxidative stress in the toxic response. MZ also induced mitochondrial membrane potential (MMP) loss and reduced complex II activity, while complex I and citrate synthase activities remained unchanged. These events were paralleled by an increased rate of DNA strand breaks in MZ-exposed cells, supporting a role for oxidative stress and mitochondrial dysfunction in its genotoxic effects in neuroblastoma cells. In summary, MZ exposure impaired mitochondrial complex II activity and induced oxidative stress as well as genotoxicity in SH-SY5Y cells. These findings reveal that MZ exposure disrupts mitochondrial complex II and induces oxidative stress, mechanisms central to PD pathology, underscoring the potential neurotoxic risk posed by this fungicide.