M. Aschner, Astrocytic swelling, phospholipase A(2), glutathione and glutamate: Interactions in methylmercury-induced neurotoxicity, CELL MOL B, 46(4), 2000, pp. 843-854
Methylmercury (MeHg) is a significant environmental contaminant that will c
ontinue to pose great risk to human health. Considerable attention in the s
cientific 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 attain
ed by mothers eating fish regularly during pregnancy are associated with ne
urological deficits in their offspring. Astrocytes play a key role in MeHg-
induced excitotoxicity as evidence by the following points: 1) MeHg prefere
ntially accumulates in astrocytes; 2) MeHg potently and specifically inhibi
ts glutamate uptake in astrocytes; 3) Neuronal dysfunction is secondary to
disturbances in astrocytes; 4) Co-application of non-toxic concentrations o
f MeHg and glutamate leads to the typical appearance of neuronal lesions as
sociated with excitotoxic stimulation, and 5) MeHg induces swelling of astr
ocytes. These observations are fully consistent with MeHg-induced dysregula
tion of excitatory amino acid homeostasis, and indicate that a glutamate-me
diated excitotoxic mechanism is involved. The manuscript will outline a num
ber of critical target sites for MeHg-induced neurotoxicity. It will addres
s the interrelationship between the activation of cytosolic phospholipase A
(2) (cPLA(2)) and the ensuing hydrolysis and release of arachidonic acid (A
A) as potential mediators for glutamate release upon exposure to MeHg, and
determine the relationship between cytosolic cPLA2 activation, regulatory v
olume decrease (RVD), and glutamate release. In addition, the effect of MeH
g on glutathione (GSH) homeostasis will be discussed with particular emphas
is on its effects on cystine and cysteine uptake, precursors of GSH synthes
is.