Effect of co-administration of retinoids on rat embryo development in vitro.
BACKGROUND
Excess retinyl palmitate (vitamin A) induces a variety of malformations in many mammalian species, yet retinyl palmitate is not thought to be the proximate teratogen. Many metabolites are generated after oral dosing several of which are, individually teratogenic. It is not known whether these metabolites when present simultaneously interact in an additive or synergistic manner.


METHODS
Whole rat embryos were cultured with retinol, all-trans retinoic acid (tRA), 4-oxo all-trans retinoic acid (4otRA) or 9-cis retinoic acid (9cRA). Retinoids were added singly or in paired combinations at the start of culture and embryos were examined for evidence of dysmorphogenesis at the end of culture. Retinoids were added at both subthreshold and supra-threshold concentrations.


RESULTS
Co-administration of subthreshold concentrations of tRA and 4otRA, retinol and tRA or 4otRA and 4otRA and 9cRA resulted in a greater frequency of abnormal embryos compared to single administration of each retinoid.


CONCLUSIONS
Knowledge of the way in which retinyl palmitate metabolites interact should refine our ability to predict risk from a potentially teratogenic event e.g., accidental overdose with RP during human pregnancy.
Ritchie
Helen E
HE
School of Biomedical Sciences, University of Sydney, Cumberland Campus, Lidcombe, NSW, Australia.
Brown-Woodman
Patricia D
PD
Korabelnikoff
Ann
A
D000014:Abnormalities, Drug-Induced; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000633:toxicity*; D013723:Teratogens / Q000633:toxicity*
D004338:Drug Combinations; D012176:Retinoids; D013723:Teratogens