Mitochondrial Impairment Associated With Dopaminergic Neurotoxicity Following Exposure to Manganese and Methylmercury in <i>Caenorhabditis elegans</i>

Methylmercury (MeHg) and manganese (Mn) are environmental contaminants widely distributed in the Earth's crust and are associated with neurotoxicity, particularly affecting dopaminergic function. While both metals are known to share common toxicity pathways, such as mitochondrial dysfunction and dopaminergic neurodegeneration, limited research has explored the combined effects of MeHg and Mn exposure. Using Caenorhabditis elegans (C. elegans) as a model, we assessed the effects of acute co-exposure to MeHg and Mn on survival, dopaminergic neuron integrity, behavior analysis and mitochondrial function via high-resolution respirometry. Our results show that co-exposure reduced worm survival and body size and caused dopaminergic neuron disruptions, impaired locomotion, reduced basal slowing response (BSR), and increased swimming-induced paralysis (SWIP). Mitochondrial dysfunction was also evident, with Mn-induced impairment of mitochondrial respiration, while co-exposure led to possible compensatory increases in several mitochondrial activities, including OXPHOS CI and citrate synthase activity. The differential sensitivity of these endpoints to the metal combination underscores the importance of evaluating co-exposure scenarios to capture a more comprehensive view of the potential neurotoxic risks associated with environmental contaminants upon real-life exposure scenarios. These findings highlight the need to assess combined exposures, particularly in environments with complex contamination profiles, as the neurotoxic risks may exceed those observed with individual toxicants.