The effects of prenatal retinoic acid on the viability and behavior of the offspring.

Three experiments were done in Charles River rats to assess the effects of various doses of retinoic acid given at different periods of pregnancy on the postnatal function of the offspring. In the first study doses of 5 mg/kg of body weight were given on days 8-10, 11-13, or 14-16. In the second study, doses of 2.5 or 5 mg/kg were given on days 11-13 or 14-16. In the third study, doses of 2, 4 or 6 mg/kg were given on days 14-16. Five mg/kg given on days 11-13 resulted in significant postnatal mortality, while the viability at all other doses and periods was not affected. The weights of the pups at birth and weaning were normal except in the first study when the pups from dams given 5 mg/kg on days 14-16 were smaller than controls at weaning. The pups from dams treated with 4, 5 or 6 mg/kg consistently showed a delayed response to negative geotropism and auditory startle was delayed in two of the studies at 6 mg/kg. Hyperactivity in preweaning rats tested in photo-cell cages was seen only in the first study, but open-field hyperactivity occurred in all three studies at doses of 4 mg/kg or above. The M-maze performance of the rats from groups dosed with 4, 5 or 6 mg/kg on days 8-10 or 14-16 and the ones dosed with 2.5 mg/kg on days 11-13 was poorer than controls. No differences were seen in either photo-cell or open-field activity at 42 days, but in the final experiment, the rats from the 6 mg/kg group were hyperactive at 100+ days in running wheels. The rats in the 6 mg/kg group performed more poorly at active avoidance and were hypoactive after an amphetamine challenge. These studies show that retinoic acid given prenatally induced functional deficits in the offspring at doses below the "no-effect" level for producing morphological defects and suggests that retinoic acid may be a good model compound for such studies.