Genesis of alcohol-induced craniofacial dysmorphism.
The initial diagnosis of fetal alcohol syndrome (FAS) in the United States was made because of the facial features common to the first cohort of patients. This article reviews the development of an FAS mouse model whose craniofacial features are remarkably similar to those of affected humans. The model is based on short-term maternal treatment with a high dosage of ethanol at stages of pregnancy that are equivalent to Weeks 3 and 4 of human gestation. At these early stages of development, alcohol's insult to the developing face is concurrent with that to the brain, eyes, and inner ear. That facial and central nervous system defects consistent with FAS can be induced by more "realistic" alcohol dosages as illustrated with data from an oral alcohol intake mouse model in which maternal blood alcohol levels do not exceed 200 mg/dl. The ethanol-induced pathogenesis involves apoptosis that occurs within 12 hrs of alcohol exposure in selected cell populations of Day 7, 8, and 9 mouse embryos. Experimental evidence from other species also shows that apoptosis underlies ethanol-induced malformations. With knowledge of sensitive and resistant cell populations at specific developmental stages, studies designed to identify the basis for these differing cellular responses and, therefore, to determine the primary mechanisms of ethanol's teratogenesis are possible. For example, microarray comparisons of sensitive and resistant embryonic cell populations have been made, as have in situ studies of gene expression patterns in the populations of interest. Studies that illustrate agents that are effective in diminishing or exacerbating ethanol's teratogenesis have also been helpful in determining mechanisms. Among these agents are antioxidants, sonic hedgehog protein, retinoids, and the peptides SAL and NAP.
Sulik
Kathleen K
KK
Department of Cell and Developmental Biology and Bowles Center for Alcohol Studies, The University of North Carolina, CB 7090, Chapel Hill, North Carolina 27599, USA. mouse@camed.unc.edu
D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000187:drug effects / Q000648:ultrastructure; D019465:Craniofacial Abnormalities / Q000196:embryology / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000648:ultrastructure; D005124:Eye Abnormalities / Q000196:embryology / Q000209:etiology; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000196:embryology / Q000209:etiology* / Q000473:pathology; D005865:Gestational Age; D006801:Humans; D008445:Maxillofacial Development / Q000187:drug effects; D051379:Mice; D011247:Pregnancy