Mechanisms of methylmercury toxicity in cultured neonatal rat cortical astrocytes

Methylmercury is a highly neurotoxic, environmentally ubiquitous chemical that exerts its toxic effects by largely unknown mechanisms. Mercurials localize almost exclusively within astrocytes suggesting astrocytic dysfunction may mediate neuronal toxicity. These studies were designed to examine the effects of methylmercury on astrocytic functions essential for neuronal survival.; The initial study examined the effects of methylmercury on the uptake of cystine, a precursor for the antioxidant glutathione, in cultured astrocytes and neurons. This study revealed that cystine is transported in astrocytes and neurons by multiple mechanisms not previously described in these cell types. Methylmercury selectively decreased astrocytic cystine uptake, but had no effect on neuronal cystine uptake. The methylmercury-mediated decrease in cystine was due to inhibition of a glutamate transporter that also carries cystine. Inhibition of cystine uptake in astrocytes decreases glutathione levels increasing astrocytic vulnerability to other potentially toxic effects of methylmercury; The second study explored possible mechanisms mediating methylmercury-induced inhibition of a glutamate transporter. Catalase, a H₂O₂ metabolizing enzyme, completely reversed the inhibitory effects of methylmercury on glutamate transport. The inhibitory effects of methylmercury on glutamate transport are possibly due to H₂O₂-mediated inhibition of Na+/K+-ATPase activity dissipating intracellular/extracellular Na+ gradients, the driving force for glutamate transport.; Finally, the ability of methylmercury, and inorganic mercury, the result of in vivo methylmercury metabolism, to inhibit the astrocytic enzyme glutamine synthetase was studied in primary cultures of cortical astrocytes. Inorganic mercury, but not methylmercury, inhibited the activity of glutamine synthetase, an enzyme that coverts potentially toxic glutamate and ammonia to non-toxic glutamine. Glutamine produced by astrocytes is used by neurons for GABA and glutamate synthesis as part of the glutamate-glutamine cycle, thus inhibition of glutamine synthetase activity by mercury will lead to altered neurotransmission. The well-described delay in neurotoxicity following methylmercury exposure may in part be related to the differential effects of methylmercury, and its metabolic product, inorganic mercury.; These studies suggest methylmercury inhibits glutamate transport via overproduction of H₂O₂. This inhibits not only glutamate, but also cystine transport which will lead to decreased intracellular glutathione levels, rendering cells more vulnerable of the toxic effects of methylmercury.