Teratogenicity of acetaldehyde in vitro: relevance to the fetal alcohol syndrome.
Day 10 rat embryos grown in vitro showed significant retardation in growth and development when culture media contained acetaldehyde. A concentration-response range for acetaldehyde-induced embryotoxicity was defined, from no effect at 5 microM to complete lethality at 100 microM. The relative teratogenicity of ethanol and acetaldehyde, and the potential roles of these compounds in producing the Fetal Alcohol Syndrome are discussed. Despite intensive investigation into alcohol teratogenicity, the mechanism that produces the Fetal Alcohol Syndrome (FAS) remains unknown. Observed anomalies may result from direct embryonic exposure to ethanol or one of its metabolites, or from some indirect effect such as altered placental function or maternal nutritional status. Use of in vitro techniques allows study of direct embryonic exposures in the absence of indirect influences. Under such conditions, ethanol has been found to exert direct embryotoxicity (1). Rat embryos, grown as cultured explants and subjected to ethanol concentrations of 32.5 or 65 mM, were retarded in growth and development when compared to untreated controls. In this paper, we report direct embrytoxic effects of acetaldehyde, the primary metabolite of ethanol, at concentrations as low as 25 microM. Acetaldehyde teratogenicity has not been extensively studied. Veghelyi et al. (2) and Lambert, Papp and Nishiura (3) employed a combination of ethanol and disulfiram (an inhibitor of acetaldehyde-oxidizing enzymes). Teratogenic effects exceeded expectations based upon assumption of an additive interaction between these two compounds, and were attributed to elevated maternal blood acetaldehyde. O'Shea and Kauffman (4,5) and Dreosti et al. (6) administered acetaldehyde to pregnant animals by injection. Treatment resulted in retarded growth and development, decreased DNA synthesis, and increased frequencies of malformation and resorption. While these studies imply a role for acetaldehyde in alcohol-induced teratogenesis, indirect effects through altered maternal or placental factors cannot be eliminated. We present here the first concentration-response data for direct embryonic exposure to acetaldehyde.
D000079:Acetaldehyde / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000139:chemically induced / Q000209:etiology*; D005333:Fetus / Q000187:drug effects / Q000502:physiology; D006128:Growth; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
D000431:Ethanol; D000079:Acetaldehyde