ABSTRACT
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While human exposure to mercury occurs via inorganic and organic forms, clinically relevant studies of mercury neurotoxicity follow exposure to the alkyl (methyl) mercury derivatives (MeHg). The following chapter by Professor L. Chang discusses the clinical features of human and experimental neuropathology associated with mercury exposure. In this discussion, experimental studies elucidating the pathogenesis of organic mercurial neurotoxicity will be summarized. Despite numerous studies devoted to the identification of a single locus for the toxicity, it is now believed that a multifactorial pathogenesis accounts for the end-stage neuronal injury. Although many toxic effects of MeHg have been identified in neuron systems, the role of astrocytes in mediating and/or modulating neuronal toxicity has assumed importance. Recent reviews have examined differing aspects of methyl mercury toxicity.1-4
Methyl mercury toxicity commonly results following ingestion. The bulk of gastrointestinal MeHg undergoes fecal excretion with a minor component undergoing demethylation or absorption. Once absorbed, MeHg may enter red cells and be covalently bound to glutathione and protein cysteine groups.5 The preferential sensitivity and toxicity of MeHg for dorsal root ganglion cells is related to the lack of an efficient blood-nerve barrier, in marked contrast to the role played by blood-brain barrier mechanisms. Mechanisms underlying the uptake or efflux of MeHg in brain appear dependent upon binding to high-affinity -SH groups on specific translocator molecules. Brain uptake follows binding of MeHg to L-cysteine and translocation at the neutral amino acid carrier site.6 Similarly, in vitro studies using astrocyte cultures have provided evidence for a similar role
of -SH-containing molecules in the efflux of MeHg which also appears specific for the MeHgcysteine conjugate.4 Glutathione plays a major role in the modulation of MeHg toxicity: firstly, as a major cellular antioxidant mitigating the lipoperoxidative injury induced by MeHg; secondly, in participating in the stress protein response following low-dose MeHg exposure, and thirdly, conjugation with MeHg providing an accelerated efflux from glia and renal epitheliurn7 (Fujiyarna et al., personal communication).
