Mechanisms of Methylmercury Cytotoxicity in Astrocytes
نویسنده
چکیده
The objective of this review is to address the mechanisms of methylmercury (MeHg)-induced neuronal toxicity. Astrocytes play a key role in MeHginduced excitotoxicity as manifested in the following terms: [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 nontoxic concentrations of MeHg and glutamate leads to the typical appearance of neuronal lesions associated with excitotoxic stimulation. [5] MeHg induces swelling of astrocytes. Studies in our laboratory have addressed the osmoregulatory effects of MeHg, characterizing ion, electrolyte, and non-electrolyte transport changes in response to MeHg. The results are consistent with dysregulation of excitatory amino acid homeostasis and indicate that a glutamate-mediated excitotoxic mechanism is involved. Furthermore, these studies establish an important role for metallothioneins (MTs) in ameliorating the acute effects of MeHg on astrocyte function. The review will address the effects of MeHg on astrocytic swelling and ion fluxes, followed by a synopsis on the role of MTs in protecting these cells from MeHg-induced injury. Environmental Pathways to Human Exposure to Methylmercury As evidenced by tragic poisonings in Japan and Iraq, MeHg is a potent neurotoxin. In the 1950s, a chemical plant in Minamata Bay (Japan) discharged mercury into the Bay as part of waste sludge. Within the Bay’s sediment, inorganic mercury was methylated to MeHg, and as a result fish and shellfish became contaminated. Because the primary dietary source of proteins in the local population was largely derived from fish consumption, a MeHg epidemic erupted shortly thereafter (53, 54). Approximately a decade later, a second epidemic occurred in Iraq. Following a major drought in 1971, the local government opted to switch from its customary order of wheat to a more resilient variety. An order was placed with the Mexican government. Unfortunately, however, a single letter typographical error was made in the labeling of the fungicide the wheat was to be treated with. Consequently, instead of treatment with a relatively harmless mercury containing fungicide, the wheat was treated with the poisonous MeHg. To compound matters, the wheat had arrived in Iraq past the planting season. Being unaware of the significance of the packaging labeling (skull and crossbones poison designation) and the pink dye additive that was added to warn them of the poisonous nature of the wheat, the farmers proceeded to use the wheat for their customary baking of Pita bread. Within weeks of the wheat consumption, the effects of MeHg intoxication were widespread and devastating, leading to mass poisoning epidemic with approximately 450-deaths (15). Considerable attention in the scientific and health policy fora continues to focus on the question of whether MeHg intake from a diet high in fish is associated with aberrant CNS function. A number of studies (27, 36) suggest that fetal exposure at levels attained by mothers eating fish regularly during pregnancy are associated with neurological as well as cardiovascular effects in their offspring (27, 28, 43, 51). Notably, this outcome has not been replicated in children exposed to MeHg in the Republic of the Seychelles (22, 23, 44). Methylmercury (MeHg) and Astrocytic Volume Astrocytes occupy ~25% of the CNS volume. The “foot” processes of astrocytes are closely associated with synapses, nodes of Ranvier, axonal tracts, and capillaries. Astrocytic functions include neurotrophic factor secretion, control of extracellular pH, inactivation of glutamate, as well as uptake and metabolism of neurotransmitters (35; 37; Aschner and Kimelberg, 1996). Although not the only cell type to be adversely affected by MeHg (13), astrocytes play a key role in MeHg-induced excitotoxicity. [1] After chronic in vivo exposure in human and non-human primates, MeHg preferentially accumulates in astrocytes [and to some degree in microglia; likely due to phagocytosis of damaged cells (19, 20, 25, 45, 57). [2] MeHg potently and specifically inhibits glutamate uptake in astrocytes (1), resulting in excessive concentrations of excitatory amino acids (EAAs) in the extracellular fluid (ECF). Other transport systems are 2-5 fold less sensitive to inhibition by MeHg (16). The effect of MeHg (CH3Hg+) and Hg2+ on glutamate uptake is not mimicked by other divalent cations (6, 17, 42). [3] In the absence of glutamate, neurons are unaffected by acute exposure to mercury, suggesting that neuronal dysfunction is secondary to disturbances in astrocytes (17). [4] Co-application of nontoxic concentrations of MeHg and glutamate leads to the typical appearance of neuronal lesions associated with excitotoxic stimulation (39). [5] In human and non-human primates chronic in vivo exposure to MeHg is associated with swelling of astrocytes (19, 20, 45, 57). Swollen astrocytes undergo regulatory volume decrease (RVD) and reestablish volume by releasing intracellular ions and EAAs, such as glutamate and aspartate (32, 46), leading to neuronal injury according to the excitotoxic hypothesis (21). Possible Mechanisms of Methylmercury Cytotoxicity * For correspondence. Tel: 336-716-8530. Fax: 336-716-8501. 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