The role of pharmacokinetics in determining the response of rodent embryos to teratogens in whole-embryo culture.
The rodent embryo's response to teratogenic insult in whole-embryo culture during the period of neurulation was characterized by determining the role of pharmacokinetics and embryonic recovery in producing abnormal growth and development. Five known teratogens, hydroxyurea, cyclophosphamide, cadmium, diphenylhydantoin, and the ketone body beta-hydroxybutyrate were employed. The dose and exposure times in vitro were designed to reproduce the peak serum concentrations and half-life of the compounds present following the administration of a teratogenic or maximum maternally tolerated dose of the agents in vivo. The results showed: first, that both the serum concentration and duration of exposure to an agent play a role in determining the embryonic response in vitro; secondly, that compounds that do not produce effects during the period of neurulation or that require maternal metabolic activation are not teratogenic in culture; and thirdly, that embryos have the capacity to recover from certain teratogenic insults in vitro. Thus, both pharmacokinetics and the potential for embryonic recovery should be considered when applying the whole-embryo culture technique to studies in teratology and toxicology.
Sadler
T W
TW
Department of Cell Biology and Anatomy, 111 Swing Building, CB 7090, School of Medicine, University of North Carolina, Chapel Hill, NC 27514, USA.
Shum
L
L
Warner
C W
CW
Smith
M K
MK