DIFFERENTIAL TERATOGENIC RESPONSE OF MOUSE EMBRYOS TO RECEPTOR-SELECTIVE ANALOGS OF RETINOIC ACID

Early events that initiate teratogenesis by Accutane(R) or other retin oids in mammalian embryos remain unknown. It would be helpful for mech anistic considerations to know whether or not retinoids act through re tinoid receptor-dependent pathways, and if they do, which of the two f amilies of receptors (retinoic acid receptors - RAR alpha, beta, gamma or retinoid X receptors - RXR alpha, beta, gamma) are more likely inv olved. We previously used an in vitro bioassay to demonstrate that tho se retinoid analogs with binding affinity and transactivational activi ty limited only to the RXRs have a low potential as teratogens, Here, we have extended the study to examine teratogenicity, in pregnant mice , of a number of synthetic retinoids with varying degrees of receptor selectivity. The ability of each compound to induce fetal limb and cra niofacial defects after a single exposure on day 11 of gestation was a ssessed and compared to that of all-trans retinoic acid (RA). The high est dose selected was 100 mg/kg maternal body weight since such a regi men of all-trans RA affects virtually every exposed embryo without any indication of maternal toxicity, We found that although all RAR agoni sts were strong teratogens, their potencies varied over a wide magnitu de. The teratogenic potencies and receptor transactivation profiles of RAR agonists were not directly correlated since compounds with simila r receptor activities presented major differences in potencies, Three compounds were exclusively RXR agonists, and these were not teratogeni c under our experimental conditions. Two additional compounds which tu rned out to be non-teratogenic were distinguished by the fact that the y activated neither RARs nor RXRs. These data indicate that although R AR-dependent mechanisms are likely involved in retinoid-induced terato genesis, there are additional factors which determine teratogenic pote ncy. The absence of teratogenic response in the case of RXR agonists s uggests that risk-benefit analyses of such receptor-selective compound s may be fruitful in further studies.