9-CIS-RETINOIC ACID - A DIRECT-ACTING DYSMORPHOGEN

Experiments in vitro with cultured rat conceptuses demonstrated that 9 -cis-retinoic acid (9-cis-RA) (300 ng/mL amniotic fluid) produced bran chial arch and somite defects similar to those elicited by equal conce ntrations of all-trans-retinoic acid (all-trans-RA), but with an incre ase in cephalic defects that included missing optic vesicles. After co nceptuses were intraamniotically microinjected with 600 ng 9-cis-RA/mL amniotic fluid on day 10 of gestation, an unusual heart defect was al so observed. HPLC analyses indicated that 9-cis-RA readily underwent c onversion to the less active metabolite. 13-cis-retinoic acid (13-cis- RA), in cultured conceptuses during the first 4 hr after treatment but only after 6 hr could elevated levels of the potent dysmorphogen all- trans-RA be detected. In separate experiments, conversion of 13-cis-RA or of all-trans-RA to 9-cis-RA could not be detected during a 6-hr em bryo culture period. Endogenous levels of 9-cis-RA in whole rat embryo s also were below limits of detection but small quantities of this iso mer could be detected in neonatal rat eye and human embryonic brain. O ur present study strongly suggests that 9-cis-RA is a direct-acting dy smorphogen with probable specific target sites of action.