Fetal Alcohol Spectrum Disorder as a Retinoic Acid Deficiency Syndrome

Multiple models were proposed to explain the mechanism(s) of alcohol (ethanol) teratogenesis inducing the wide range of developmental defects, neurobehavioral anomalies, and mental disabilities known collectively as Fetal Alcohol Spectrum Disorder (FASD). Competition between alcohol clearance and retinoic acid (RA) biosynthesis was proposed as both processes employ the same families of enzymes. Excess of ethanol or its clearance metabolite, acetaldehyde, will compete with vitamin A (retinol) or retinaldehyde and hamper the production of RA with teratogenic outcomes. Taking advantage of the ease of manipulation, external development, and large clutch sizes in Xenopus , we have been studying and characterizing the alcohol/RARetinoic acid (RA) competition modelCompetition model. Xenopus embryosEmbryos recapitulate many of the developmentalDevelopmental malformations of Fetal Alcohol Syndrome (FASFetal alcohol syndrome (FAS)), the more severe form of FASDFetal alcohol spectrum disorder (FASD). The effect of ethanol on development is most severe during gastrulaGastrula stages and continues, but with milder outcomes throughout development. Ethanol targets the “embryonic organizerEmbryonic organizer,” the earliest site of RARetinoic acid (RA) signaling. To support the connection between ethanol and RARetinoic acid (RA), we show that all abnormal embryonic processes or molecular events induced by ethanol can be reproduced by reducing RARetinoic acid (RA) signaling levels. Importantly, the effects of ethanol can be rescued by increasing RARetinoic acid (RA) signaling, and RARetinoic acid (RA) reduction hypersensitizes the embryoEmbryos to alcohol exposure. Biochemical studies demonstrated that RARetinoic acid (RA) biosynthetic enzymes can readily function in ethanol clearance. Additional syndromes linked to reduced RARetinoic acid (RA) signaling with partially overlapping phenotypes with FASDFetal alcohol spectrum disorder (FASD) are discussed.