ETHANOL INHIBITION OF RETINOIC ACID SYNTHESIS AS A POTENTIAL MECHANISM FOR FETAL ALCOHOL SYNDROME

Retinoic acid (RA) is known to act as a signaling molecule during embr yonic: development, but little is known about the regulation of RA syn thesis from retinol, The rate-limiting step in RA synthesis is the oxi dation of retinol, a reaction that can be catalyzed by alcohol dehydro genase (ADH), Ethanol is also a substrate for ADH, and high levels of ethanol inhibit ADH-catalyzed retinol oxidation, This has prompted us to hypothesize that ethanol-induced defects observed in fetal alcohol syndrome involve ethanol inhibition of ADH-catalyzed RA synthesis, Her e, we have examined the effect of ethanol on RA levels in cultured mou se embryos by using a bioassay, Treatment with 100 mM ethanol, but not 10 mM, led to a significant decrease in RA detection in 7.5-day-old e mbryos, Using whole-mount in situ hybridization, we detected mRNA for class IV ADH, but not ethanol-active cytochrome P450 2E1, in 7.5- and 8.5-day-old embryos, indicating that an ADH-linked pathway exists at t hese stages for metabolizing retinol and ethanol. Thus, the observed e thanol-induced reduction in RA may be caused by ethanol. inhibition of retinol oxidation catalyzed by class IV ADH, in our postulated mechan ism for fetal alcohol syndrome, this enzyme may well play a crucial ro le.