In vitro neurotoxicity of methyl iodide.
Methyl iodide (MeI) and two other commonly used monohalomethanes, methyl bromide and methyl chloride, are potent human neurotoxicants. In the present study neural cell cultures were used to investigate MeI neurotoxicity in vitro. In primary, dispersed mixed (neurons and glia) neural cultures from mouse embryos, MeI produced severe morphological alterations and leakage of lactate dehydrogenase into the medium (LC(50), 5-6 mm). These effects showed steep concentration-response curves. Both glial and neuronal cells from both the cerebral cortex and the cerebellum were affected. The dual cyclooxygenase-lipoxygenase inhibitor, 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW755C) protected against monohalomethane toxicity (EC(50) 100 mum). All of these observations reflected those previously reported to occur in vivo after exposure to other monohalomethanes. They indicated that MeI shared similar mechanisms of toxicity with other monohalomethanes and supported the validity of the in vitro model to study these mechanisms. Another lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), was also effective in protecting neural cultures against the effects of MeI (EC(50) 3 mum). The use of BW755C/NDGA and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) as specific inhibitors of MeI and glutamate neurotoxicity, respectively, demonstrated that MeI toxicity is not mediated by glutamate, a potential by-product of glutathione-mediated metabolism of MeI. When BW755C and NDGA were compared with other modifiers of arachidonic acid metabolism for their protection against MeI toxicity, their mechanisms of action appeared to be unrelated to inhibition of the oxygenases. Their mechanism of action could be related to their antioxidant effect. Results from this work show the value of primary neural cultures to demonstrate and study monohalomethane neurotoxicity.
Davenport
C J
CJ
Chemical Industry Institute of Toxicology, 6 Davis Drive, PO Box 12137, Research Triangle Park, NC 27709, USA.
Bonnefoi
M S
MS
Williams
D A
DA
Morgan
K T
KT