The foetal toxicity of the methyl isocyanate metabolites trimethylamine (TMA) and S-(N-methylcarbamoyl)glutathione (SMG) was studied in mice. Administration of TMA but not SMG during pregnancy decreased foetal weight and selectively inhibited the postnatal growth of male offspring. Both TMA and SMG were teratogenic to mouse embryos in culture. TMA caused a dorsal-rostral split in the head and SMG produced distortion and separation of somites; both agents decreased the growth of embryos. The inhibition of embryonic growth by TMA could not be antagonized by antioxidants or growth factors. The embryotoxic effects of SMG could be antagonized by glutathione (GSH). TMA inhibited the incorporation of $ sp3$H-thymidine, $ sp3$H-uridine and $ sp3$H-leucine into their respective macromolecules; SMG inhibited the incorporation of $ sp3$H-thymidine. Uptake by the yolk sac placenta and incorporation into embryonic proteins of $ sp3$H-leucine-labelled proteins but not of free $ sp3$H-leucine was inhibited by TMA at concentrations which did not inhibit lysosomal degradation of proteins. SMG inhibited the uptake and incorporation of both free $ sp3$H-leucine and $ sp3$H-leucine-labelled proteins. The inhibition of receptor-mediated uptake by SMG could be antagonized by GSH. The data suggest that TMA, and SMG produce embryotoxicity mainly by an inhibition of uptake mechanisms of the yolk sac placenta.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.41276 |
| Date | January 1993 |
| Creators | Guest, Ian |
| Contributors | Varma, D. R. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology & Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001351488, proquestno: NN91817, Theses scanned by UMI/ProQuest. |
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