Cyclosporin A-induced embryopathy in embryo culture is mediated through inhibition of the arachidonic acid pathway.
Embryos from Swiss Webster mice were grown in culture for 24 hr starting at Day 8.5 of gestation to study the effects of cyclosporin A (CsA) on the developing embryo. The embryos exposed to concentrations of CsA from 0.1 microgram/ml to 10.0 micrograms/ml developed a significant increase in the incidence of malformations from 28.6% to 78.6%, as compared with the 6.8% incidence of malformations in the control embryos. These malformations included defects in the neural tubes, head folds, and facial arches. In addition, inhibition of embryonic growth in CsA-exposed embryos was shown by a lower somite number, crown-rump length, and protein content than those of the control embryos. Supplementation of the culture medium with arachidonic acid or prostaglandin E2 decreased the incidence of CsA-induced malformations by 50% to 70% and prevented the CsA-induced inhibition of growth. We conclude that CsA causes abnormal embryonic development in mouse embryo culture and that the mechanism of CsA-induced embryopathy involves inhibition of the arachidonic acid pathway.
Uhing
M R
MR
Division of Neonatology, University of Illinois College of Medicine, Chicago 60612.
Goldman
A S
AS
Goto
M P
MP
D000014:Abnormalities, Drug-Induced; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D046508:Culture Techniques; D016572:Cyclosporine / Q000633:toxicity*; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000502:physiology; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D006257:Head / Q000002:abnormalities / Q000196:embryology; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced; D011506:Proteins / Q000378:metabolism; D012044:Regression Analysis
D011506:Proteins; D016718:Arachidonic Acid; D016572:Cyclosporine; D015232:Dinoprostone