Embryotoxicity of carbamazepine in rat postimplantation embryo culture after in vitro exposure via three different routes.
Postimplantation rat embryo culture is used widely for studies of embryotoxic effects on the isolated embryo after in vitro exposure to xenobiotic compounds. In this study, the relevance of three routes of exposure of the embryo in vitro was evaluated using the embryotoxic anticonvulsant carbamazepine. Embryotoxic effects were assessed, and analyses in conceptus tissues were done to reveal uptake and metabolism of the compound. Exposure via the culture medium resulted in neural tube defects and general retardation of growth and development. After injections into the amniotic or exocoelomic space, local membrane adhesions were found. Intra-amniotic exposure caused adhesions of the amniotic membrane with the embryonic neural plate, resulting in trapping of the membrane in the closing neural tube, as well as in open neural tube defects occurring in various areas of the neural tube. Only after exposure via the culture medium were amounts of carbamazepine detectable in the embryonic tissue, correlating with the systemic effects found. It is concluded that uptake from the culture medium via the yolk sac circulation is the relevant exposure route to be used for embryotoxicity effect assessment.
Piersma
A H
AH
Health Effects Research Laboratory, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Verhoef
A
A
Opperhuizen
A
A
Klaassen
R
R
van Eijkeren
J
J
Olling
M
M
D000650:Amnion / Q000187:drug effects / Q000473:pathology; D000653:Amniotic Fluid; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D001202:Ascitic Fluid; D002220:Carbamazepine / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D003470:Culture Media / Q000737:chemistry; D046508:Culture Techniques; D004333:Drug Administration Routes; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects*; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D007267:Injections; D009436:Neural Tube Defects / Q000139:chemically induced; D011247:Pregnancy; D051381:Rats; D000267:Tissue Adhesions / Q000139:chemically induced / Q000473:pathology; D015017:Yolk Sac / Q000002:abnormalities / Q000098:blood supply / Q000187:drug effects
D000927:Anticonvulsants; D003470:Culture Media; D002220:Carbamazepine