Methylmercury (MeHg) poisonings are amongst the best documented chemical poisoning disasters in history. Because methylation of inorganic mercury species to MeHg by microorganisms is known to take place in waterways, resulting in its accumulation in the food chain, any source of environmental mercury represents a potential source for MeHg poisoning. Anthropogenic sources culminating in the acidification of freshwater streams and lakes in North America, and the impoundment of water for large hydroelectric schemes have led to increased MeHg concentrations in fish, posing increasingly greater risks to human populations. The case for significant toxicity of MeHg to the central nervous system (CNS) is strongly supported by both in vivo and in vitro studies. While astrocytes preferentially accumulate MeHg, only recently have their responses been considered in the etiology of MeHg-induced neuronal toxicity. The primary working hypothesis of this proposal postulates that a direct toxic effect of MeHg on astrocytes leads to astrocytic swelling and release of excitatory amino acids (EAAs), which in turn results in neuronal impairment, injury and death by an excitotoxic mechanism. The initial experimental approach will examine the mechanisms and consequences of MeHg-induced astrocytic swelling with an electrical impedance method which can measure changes in astrocytic volume in a dynamic, real time manner, combined with continuous, on-line measurements of the release of endogenous amino acids (glutamate, aspartate and taurine) in a well- characterized in vitro model of neonatal rat primary astrocyte cultures. In correlative in vivo microdialysis studies in rats, the effects of MeHg on the extracellular concentrations of glutamate, aspartate and taurine will be determined by directly perfusing MeHg into the CNS via the microdialysis probe. Finally, in order to resolve the troubling problem of linking astrocytic accumulation of MeHg to neuronal toxicity, studies will be performed to determine the role of metallothioneins (MTs; MT-I and MT- II) in the preferential accumulation of MeHg in astrocytes. MeHg-induced MT mRNA expression will be studied by in situ hybridization, and correlated with the regional inducibility of MTs by MeHg in GFAP-positive cells by means of autometallography and immunocytochemistry. A correlation between the spatio-temporal distribution of MTs and MeHg staining in GFAP(+) cells with N-methyl-D-aspartate (NMDA) receptor density would provide further support for the excitotoxic hypothesis of MeHg-induced neuronal toxicity. The overall aim of the laboratory continues to be to elucidate the mechanisms of MeHg neurotoxicity and the potentially deleterious effects of astrocytic swelling and EAA release in its etiology, gaining further knowledge on inhibitor sensitivity and potential therapeutic modalities.
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