The protein co-chaperone STI-1 impacts motor function in C. elegans upon developmental methylmercury exposure

Methylmercury (MeHg) exposure poses a significant neurotoxic health risk, especially in early development. While acute MeHg exposure is associated with persistent neurotoxicity, it remains unclear whether and how low-level developmental MeHg exposures during juvenile stages contribute to long-term declines in brain function, particularly later in life during aging. To address this question, we utilized the genetically tractable nematode model C. elegans, exposing worms at the early larval stage to 10 nM or 50 nM MeHg for 24 h. Motor function was then assessed across various adult stages to evaluate long-term effects of early-life exposure. We hypothesized that the motor function of aged worms would be impaired following developmental MeHg exposure. In a human stem-cell neuronal model of MeHg neurotoxicity, we found changes in the expression of the human homolog of STI-1. We further hypothesized that the protein STI-1, a protein co-cochaperone in the protein quality control pathway, modifies the age-dependent neurobehavioral effects of early MeHg exposure. In the two motor functions, namely crawling on a solid surface and swimming in liquid, aged worms' moving speed was significantly reduced by prior MeHg exposure at larval stages. In the sti-1 KO animals, the moving speed across all adult stages was significantly decreased; however, the moving speed during swimming was increased by MeHg exposure in the sti-1 KO young adults. MeHg exposure also increased exploratory behavior wild-type animals, while the sti-1 KO animals showed a severe defect in this behavior. The deletion of sti-1 also caused an abnormal response of mitochondria to the uncoupler carbonyl cyanide p-trifluoro-methoxyphenyl hydrazone (FCCP) and elevated reactive oxygen species (ROS) production upon MeHg exposure. In the stem-cell neuronal model, we also found alterations in mitochondrial energetic gene pathways consistent with the worm findings. Together, these novel findings establish that developmental MeHg exposure leads to a decline in motor function in aged worms. Moreover, mitochondrial dysfunction associated with sti-1 KO accelerates the onset of motor impairment, suggesting a synergistic effect between genetic susceptibility and early-life toxicant exposure.