Ethanol consumption during pregnancy can cause fetal alcohol syndrome (FAS). Although the exact mechanism is unknown, nutritional alterations caused by ethanol exposure may be an etiologic factor in FAS. Thc congenital heart defects seen in FAS are similar to those found in vitamin A teratogenesis. Because ethanol ingestion alters vitamin A metabolism, we hypothesized that the cardiac manifestations seen in FAS result from an altcration in vitamin A metabolism or function in the developing fetus. Twenty-day gestation fetal rat hearts from ethanol-exposed and control pregnancies were analyzed for I ) levels of endogenous retinol, rctinyl palmitate, and retinoic acid by quantitative HPLC; 2) binding activity levels of both retinol by cellular retinol binding protein and retinoic acid by cellular retinoic acid binding protein using specific competitive binding assays; and 3 ) relative abundance of cellular retinol binding protein and rctinoic acid receptor a, 0, and y subtype message as expressed in mRNA. Levels of retinol and retinyl palmitate were significantly higher ( p < 0.01) and the level of retinoic acid was significantly lower (p < 0.02) in the ethanol-exposed fetal hearts. Binding activity levels of cellular retinol binding protein Consumption of ethanol during pregnancy results in an increased incidence of spontaneous abortions (I), an increase in perinatal mortality (2), and the birth of a child with FAS, which is defined by the clinical triad of growth retardation, CNS dysfunction, and craniofacial abnormalities (3). Other common features of FAS may include congenital heart defects and skeletal anomalies (3, 4).The mechanism by which ethanol causes FAS is unknown. Various hypotheses include a direct teratogenic effect of ethanol and/or acctaldehydc on the fetus, altered maternalJplacenta1 physiology, and nutritional alterations caused by ethanol ingestion (5-8). An alteration in vitamin A metabolism or function resulting from ethanol ingestion may potentially explain some of the dcvelopme~~tal abnormalities seen in FAS.Rcccivcd July 5, 1994; accepted Octohcr 30, 1904
GAPDH, glyceraldehyde 3-phosphate dehydrogenaseRetinol is the main circulating form of vitamin A. It can be estcrified for storage, mainly in the liver, or it can bind to CRBP. This binding step is necessary for entrance into the ccllular cytosol. In the cytosol, some of the retinol is metabolized to retinoic acid, which can then bind to CRABP. Retinoic acid can be broken down to other metabolites or it can be transferred into the nucleus and serve as a ligand for RAR ( a , p, and y isoforms). Bound RAR acts as a transcription factor, which can bind to several retinoic acid responsive genes and regulate promoter activity (9,10).Vitamin A status is effected by ethanol ingestion. Adult alcoholics have decreased liver retinol levels and increased levels of retinol in their esophagus and trachea (11). Ethanol ingestion by pregnant rats increases retinol levcls in 10-d embryo and 20-d fetal brain (12) and increases both retinol and retinyl pal...