Methylmercury is known to have devastating effects on the mammalian nervous system. In order to characterize the dose dependence of methylmercury-induced neurotoxicity, we first studied neurite outgrowth from rat dorsal root ganglia explants. In this model, methylmercury inhibited neurite outgrowth with a TD50 of approximately 0.5 μM. We then used this relationship to optimize dosing for subsequent transcriptional profiling analyses in two independent neuronal model systems: dissociated sensory neurons and PC12 cells. As seen in previous studies, the expression of a number of genes associated with oxidative stress was altered following a 6 h challenge with 1 μM methylmercury. When PC12 cells were subjected to a longer exposure (24 h), a relative increase was noted in the representation of genes associated with cell cycling and apoptosis. To confirm the presence of apoptosis in cultured neurons, we then applied TUNEL staining and bis-benzimide staining techniques to primary cultures of dissociated sensory neurons. After 24 h, 1 μM methylmercury increased both DNA end-labeling (P < 0.01) and nuclear fragmentation (P < 0.02). The latter effect appeared to be dose-dependent.
- Oxidative stress
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