title: Developmental stage-associated differences in the transplacental distribution of 13-cis- and all-trans-retinoic acid as well as their glucuronides in rats and mice.
abstract: In mice and rats, 13-cis-retinoic acid (13-cis-RA) has a much lower teratogenic potency than all-trans-retinoic acid (all-trans-RA). Previous studies on Gestational Day (GD) 11 or 12 (in mice or rats, respectively) showed a limited transfer of 13-cis-RA to the embryo, in contrast to the efficient transplacental passage of all-trans-RA. In the present study we examined if the distribution between maternal circulation and embryo of 13-cis- and all-trans-RA as well as their metabolites is different at gestational times when the placenta is developing from a choriovitelline to a chorioallantoic type. In the first experiment, 13-cis-RA was administered orally to pregnant rats (75 mg/kg/day) daily, from either GD 7 to 12 or 11 to 16. In the second experiment, 13-cis-RA or all-trans-RA was given orally to pregnant mice once on either GD 11 or 14, at two dose levels (10 and 100 mg/kg). HPLC analysis of plasma and embryo samples collected at various time points post-treatment showed that 13-cis-RA was predominantly metabolized to its beta-glucuronide (13-cis-RAG) while all-trans-RA was primarily biotransformed to all-trans-4-oxo-RA and to a lesser extent to all-trans-RAG. 13-cis-RA showed a more efficient transplacental passage to the rat embryo on GD 16 than on GD 12, as indicated by higher ratios of embryonic to maternal plasma concentrations (E/M concentration ratio) on GD 16 vs. GD 12 and its E/M ratio of area-under-the-concentration-time-curve values (E/M AUC ratio; twofold higher on GD 16 vs. GD 12). In the mouse, the E/M concentration ratio of 13-cis-RA was significantly higher on GD 14 than on GD 11 only at the low dose. On the other hand, all-trans-RA and all-trans-4-oxo-RA showed an efficient transfer to the mouse embryo at both gestational times. In both species, 13-cis- and all-trans-RAG embryonic concentrations on the later gestational days exceeded significantly the corresponding ones on the earlier gestational days which resulted in far higher E/M concentration and AUC ratios for each of these metabolites on the later vs earlier gestational days. This may result from a more efficient placental transfer of the RAGs during later gestational stages and/or higher capacity of the late embryo or other conceptal tissues to biotransform RAs in situ to their glucuronides.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Institut für Toxikologie und Embryopharmacologie, Freie Universität Berlin, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Tzimas
authors.forename: M D
authors.initials: MD
authors.lastname: Collins
authors.forename: H
authors.initials: H
authors.lastname: Nau
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism*; D005260:Female; D005865:Gestational Age; D005965:Glucuronates / Q000493:pharmacokinetics*; D015474:Isotretinoin / Q000493:pharmacokinetics*; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D014212:Tretinoin / Q000493:pharmacokinetics*
chemical_list: D005965:Glucuronates; D014212:Tretinoin; D015474:Isotretinoin