Modulation of acrylonitrile-induced embryotoxicity in vitro by glutathione depletion.
The effects of glutathione (GSH) depletion on the embryotoxicity of acrylonitrile were assessed in vitro using the rat whole-embryo culture system. Day 10 rat embryos were cultured in rat serum medium for 6 h in the presence of 250 microM L-buthionine-S,R-sulfoximine (BSO), a specific inhibitor of GSH synthesis, to deplete GSH in both embryo and visceral yolk sac. Following pretreatment, conceptuses were cultured for an additional 21 h in the presence of 152, 228, or 304 microM acrylonitrile. At the end of the culture period, conceptuses were assessed for survival, growth and development, malformations, and the protein and glutathione content of embryos and yolk sacs were assayed. Acrylonitrile alone produced concentration-related and statistically significant decreases in yolk sac diameter, crown-rump length, head length and number of somite pairs, as well as in embryonic and yolk sac proteins. The chemical also caused dysmorphogenesis of the brain and of the caudal extremity, and a concentration-related and statistically significant increase in GSH content in the yolk sac. Pretreatment with BSO significantly enhanced the embryotoxic effects of acrylonitrile. The conceptuses displayed further decreases in functional yolk sac circulation, yolk sac diameter, crown-rump and head length, when compared to either acrylonitrile or BSO alone. The incidence of caudal malformations and the severity of brain malformations produced by acrylonitrile were also increased. Marked decreases in embryonic and yolk sac GSH contents were observed after exposure to BSO alone or in combination with acrylonitrile.(ABSTRACT TRUNCATED AT 250 WORDS)
Institut National de Recherche et de Sécurité, Vandoeuvre, France.
A M
AM
Saillenfait
J P
JP
Payan
I
I
Langonné
D
D
Beydon
M C
MC
Grandclaude
J P
JP
Sabaté
J
J
de Ceaurriz
D000014:Abnormalities, Drug-Induced / Q000196:embryology* / Q000378:metabolism; D000181:Acrylonitrile / Q000633:toxicity*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D004357:Drug Synergism; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000473:pathology; D005260:Female; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D008855:Microscopy, Electron, Scanning; D011506:Proteins / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015017:Yolk Sac / Q000187:drug effects
D000963:Antimetabolites; D011506:Proteins; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D000181:Acrylonitrile