A BEHAVIORAL AND NEUROANATOMICAL INVESTIGATION OF THE LETHALITY CAUSED BY GESTATIONAL DAY 11-13 RETINOIC ACID EXPOSURE

In a companion article, we report that there is a sensitive period for all-trans retinoic acid (RA) lethality on gestational days (GD) 11-13 . When dams were given 10 mg/kg RA daily for 3 consecutive days on GD 11-13, a number of pups were found dead in the home cage on the day of birth, and the remainder inevitably died due to an apparent inability to nurse. Hen we report a set of experiments further investigating th ese effects. Darns were exposed PO to 10 mg/kg RA or oil vehicle on GD 11-13. Fetuses were removed by Cesarean section on the afternoon of G D 21, culled, and fostered to nontreated dams that had given normal va ginal delivery a day earlier. Maternal behavior was observed for the f irst 6 h after fostering. The next morning all surviving pups were giv en a brief behavioral evaluation, including the ability to attach to t he nipple of anesthetized foster dams. At the time of C-section. culls were killed and brains were quickly removed and placed in fixative. A series of paraffin-embedded, cresyl-violet-stained serial sections of a representative brain stem from each litter was prepared. RA exposur e did not increase fetal mortality. Treated litters were as large as c ontrols, and virtually all treated fetuses were alive in utero. Howeve r, unlike controls, some treated fetuses appeared to have difficulty i n initiating spontaneous breathing when delivered by C-section, and co nsiderable physical stimulation was required before normal breathing b egan. As in the previous report, RA-exposed pups did not have milk in their stomachs after 18 h on the foster dam; further, they did not att ach to the maternal nipple, and they had greater difficulty than contr ols in maintaining an upright posture. Examination of serial sections of the medulla indicated that the hypoglossal nucleus appeared grossly normal in the RA-exposed pups. In contrast, the inferior olive and th e area postrema were affected by RA exposure. Both nuclei were normall y located, but exhibited reduced cell density and/or intensity of stai ning. In the inferior olive the dorsal and principal nuclei were prima rily affected, to the degree that about one quarter of treated brains had no identifiable principal nucleus. We conclude that RA exposure on GD 11-13 causes abnormal development of cell-dense regions of the med ial medulla, and these abnormalities may account for the difficulty th ese animals experience in beginning spontaneous breathing and in nursi ng. These breathing and nursing problems in turn almost certainly acco unt for the high mortality seen during natural birth and for the subse quent failure to thrive, respectively. Published by Elsevier Science I nc.