A characteristic pattern of congenital defects involving craniofacial, cardiac, and central nervous system structures has been recognized among human infants exposed in utero to isotretinoin (13 cis retinoic acid), a structural congener of vitamin A. In a recent prospective study, however, the developmental status of a large proportion of exposed babies was characterized as """"""""normal"""""""". Since in some previous animal studies maternal hypervitaminoisis A has resulted in learning and behavioral dysfunction, our objective is to determine, in the rat model, if prenatal exposure to 4-oxo-isotretinoin--the active metabolite of isotretinoin--may result in behavioral and functional alterations in the neonate and young adult, and to correlate such changes with neuropathic alterations. The drug will be orally administered daily to pregnant rats on days 11, 12, and 13, or days 14, 15, 16, 17, and 18 of gestation. Concurrent control rats will receive only the vehicle. Three rats in each group will be killed on either day 13 or day 20 of gestation and their embryos/fetuses processed for (a) histological/electron microscopic evaluation of brain morphology and (b) measurement by HPLC of relative levels of the compound and its major metabolites in fetal blood, various segments of the brain, and other tissues. Other litters will be allowed to deliver but will be limited to a maximum of 8 and given 5 reflex texts and 4 physiologic parameter tests to be initiated on postnatal day 3. An arousal-vocalization test will be completed on day 9. On day 60 of postnatal life the offspring will be given a series of 4 adult behavioral tests. At the termination of the behavioral tests, selected offspring will be analyzed morphologically, as above. This study will extend our knowledge and increase our understanding of the effects of prenatal exposure to isotretinoin metabolites on postnatal growth and neurophysiologic development. These studies will alert us to the type of problems which may be encountered among infants now being born to retinoid-exposed mothers.
| Frierson, M R; Mielach, F A; Kochhar, D M (1990) Computer-automated structure evaluation (CASE) of retinoids in teratogenesis bioassays. Fundam Appl Toxicol 14:408-28 |
| Kochhar, D M; Penner, J D; Satre, M A (1988) Derivation of retinoic acid and metabolites from a teratogenic dose of retinol (vitamin A) in mice. Toxicol Appl Pharmacol 96:429-41 |
