Astrocytic swelling, phospholipase A2, glutathione and glutamate: interactions in methylmercury-induced neurotoxicity.
Methylmercury (MeHg) is a significant environmental contaminant that will continue to pose great risk to human health. Considerable attention in the scientific and health policy fora is focused on the question of whether MeHg intake from a diet high in fish is associated with aberrant CNS function. A number of recent studies (McKeown-Eyssen et al., 1983; Kjellstrom et al., 1989; Grandjean et al., 1997) suggest that fetal exposure at levels attained by mothers eating fish regularly during pregnancy are associated with neurological deficits in their offspring. Astrocytes play a key role in MeHg-induced excitotoxicity as evidence by the following points: 1) MeHg preferentially accumulates in astrocytes; 2) MeHg potently and specifically inhibits glutamate uptake in astrocytes; 3) Neuronal dysfunction is secondary to disturbances in astrocytes; 4) Co-application of non-toxic concentrations of MeHg and glutamate leads to the typical appearance of neuronal lesions associated with excitotoxic stimulation, and 5) MeHg induces swelling of astrocytes. These observations are fully consistent with MeHg-induced dysregulation of excitatory amino acid homeostasis, and indicate that a glutamate-mediated excitotoxic mechanism is involved. The manuscript will outline a number of critical target sites for MeHg-induced neurotoxicity. It will address the interrelationship between the activation of cytosolic phospholipase A2 (cPLA2) and the ensuing hydrolysis and release of arachidonic acid (AA) as potential mediators for glutamate release upon exposure to MeHg, and determine the relationship between cytosolic cPLA2 activation, regulatory volume decrease (RVD), and glutamate release. In addition, the effect of MeHg on glutathione (GSH) homeostasis will be discussed, with particular emphasis on its effects on cystine and cysteine uptake, precursors of GSH synthesis.
Aschner
M
M
Department of Physiology and Pharmacology, and Interdisciplinary Program in Neuroscience, Wake Forest University School of Medicine of Wake Forest University, Winston-Salem 27157-1083, USA. maschner@wfubmc.edu
D000818:Animals; D016718:Arachidonic Acid / Q000096:biosynthesis; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008767:Methylmercury Compounds / Q000633:toxicity*; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2
D008767:Methylmercury Compounds; D016718:Arachidonic Acid; D018698:Glutamic Acid; D010741:Phospholipases A; D054467:Phospholipases A2; D005978:Glutathione