Oxidative mechanisms underlying methyl mercury neurotoxicity.

Cerebellar granule cells from 5-12-day-old rats can be incubated in suspension at 37 degrees C for up to 3 hr with minimal decline in viability. Methyl mercury was found to produce time- and concentration-dependent cell killing with greater than 85% cell death after 3 hr exposure to a concentration of 20 microM. Previously characterized inhibition of protein and RNA synthesis as well as known methyl mercury-induced defects in cellular ATP production have been shown to be incapable of causing this degree of cell death. Here we report that methyl mercury induced a concentration-dependent increase in membrane lipoperoxidation and a rapid decline in reduced glutathione in this cerebellar neuronal preparation. Hydrogen peroxide at 5 mM was found to closely reproduce each of the cytotoxic effects manifested by methyl mercury suggesting that oxidizing conditions produced by methyl mercury may account for the observed cell death. Methyl mercury-induced lipoperoxidation was not the cause of cell death since malonaldehyde production could be blocked by alpha-tocopherol or EDTA without appreciable protecting against cell death. Significant protection from methyl mercury-induced cell death was observed, with EGTA, deferoxamine and KCN. We propose that oxidative events contribute to the toxic mechanism of action of methyl mercury in isolated cerebellar granule neurons.