Toxicity of the methyl isocyanate metabolite S-(N-methylcarbamoyl)GSH on mouse embryos in culture.
Methyl isocyanate, the chemical involved in the 1984 accident at Bhopal, India, forms a labile conjugate, S-(N-methylcarbamoyl)GSH (SMG), by way of a reversible reaction with GSH. We studied the toxicity of SMG on mouse embryos explanted on day 8 of gestation and cultured in rat serum for 42 hr. SMG caused concentration-dependent decreases in growth and development over the range 0.1-2 mM, without causing significant mortality. At a concentration of 2 mM, SMG completely arrested embryo development, but heartbeat was absent in only one of nine embryos at 42 hr. At a concentration of 0.25 mM, SMG reduced embryo size to 75% and protein content to 63% of the control; 18% of embryos failed to rotate. At this concentration (0.25 mM), which was selected for all other studies, spinal kinks and somite pair distortion in the region of the forelimb were evident in 38% of embryos; no other abnormalities were noted. DNA content of and thymidine incorporation by embryos and yolk sacs was reduced by SMG, although this was more pronounced in the yolk sac than in embryos. At subtoxic concentrations, the L-cysteine precursor (-)-2-oxo-4-thiazolidine-carboxylic acid did not, but GSH did, inhibit embryotoxicity of SMG. It is concluded that SMG exerts embryotoxic and dysmorphogenic effects and may contribute to systemic toxicity of methyl isocyanate.
Guest
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Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Baillie
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Varma
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D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D046508:Culture Techniques; D003485:Cyanates / Q000378:metabolism*; D004247:DNA / Q000187:drug effects; D004527:Egg Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000187:drug effects*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000633:toxicity; D017953:Isocyanates; D051379:Mice; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D015017:Yolk Sac / Q000378:metabolism
D003485:Cyanates; D004527:Egg Proteins; D017953:Isocyanates; D013438:Sulfhydryl Compounds; C053323:S-(N-methylcarbamoyl)glutathione; D004247:DNA; C008461:methyl isocyanate; D005978:Glutathione; D013936:Thymidine