DEVELOPMENTAL STAGE-ASSOCIATED DIFFERENCES IN THE TRANSPLACENTAL DISTRIBUTION OF 13-CIS-RETINOIC AND ALL-TRANS-RETINOIC ACID AS WELL AS THEIR GLUCURONIDES IN RATS AND MICE

In mice and rats, 13-cis-retinoic acid (13-cis-RA) has a much lower te ratogenic potency than all-trans-retinoic acid (all-trans-RA). Previou s studies on Gestational Day (GD) 11 or 12 (in mice or rats, respectiv ely) showed a limited transfer of 13-cis-RA to the embryo, in contrast to the efficient transplacental passage of all-trans-RA. In the prese nt 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 pla sma and embryo samples collected at various time points post-treatment showed that 13-cis-RA was predominantly metabolized to its beta-glucu ronide (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 G D 16 than on GD 12, as indicated by higher ratios of embryonic to mate rnal plasma concentrations (E/M concentration ratio) on GD 16 vs. GD 1 2 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-PA a nd 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 signif icantly the corresponding ones on the earlier gestational days which r esulted in far higher E/M concentration and AUC ratios for each of the se metabolites on the later vs earlier gestational days. This may resu lt from a more efficient placental transfer of the RAGs during later g estational stages and/or higher capacity of the late embryo or other c onceptal tissues to biotransform RAs in situ to their glucuronides. Ou r study suggests that transfer of 13-cis-RA to the rodent embryo may b e enhanced during late organogenesis due to development of the chorioa llantoic placenta. This assumption could be helpful for understanding the reasons for the higher placental transfer and teratogenic potency of 13-cis-RA in the nonhuman primate and presumably also in the human, both of which have a chorioallantoic placenta during the susceptible stages to 13-cis-RA-induced teratogenicity. (C) 1995 Academic Press, I nc.