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C.J. Calvano, R. LeFevre, R.M. Hoar, R.F. Mankes; Association between In Utero Estrogen Exposure and Degree of Cranio-facial Ossification in Fetal Alcohol Syndrome . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1089.
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Purpose: Fetal alcohol syndrome (FAS) is characterized by mental and growth retardation and by facial dysmorphology. Estradiol regulates growth and bone metabolism and has been implicated as a feto-protective hormone in several teratogenic models. This study sought to determine the relationship between fetal estradiol levels and craniofacial ossification anomalies in a rodent FAS model. Methods: Pregnant rats were fed a 35% ethanol derived calorie liquid diet from day 6 to 15 of gestation, with pair fed controls. Standard teratologic measures were made at term in addition to multi-compartment sex steroid analyses and fetal ossification and structural defect assessment. Results: As determined by intrauterine position (IUP), increased feminization was associated with decreased craniofacial ossification defects in alcohol exposed fetuses. Masculinized males were most affected while feminized females were least affected. While the fetal serum estradiol levels increased in proportion to the degree of intrauterine feminization as would be predicted by IUP in isocaloric controls, estradiol levels in alcoholic fetuses did not vary significantly with increasing feminization. There was, however, a distinct gender effect and overall adherence to the IUP hypothesis with the vast majority of craniofacial anomalies presenting in males which were masculinized (29%) or feminized (21%) as compared to alcoholic females (5.6% and 2.2% for masculinized and feminized females, respectively). Conclusions: This study suggests that estrogen or more likely totogestational estrogenic exposure may be fetoprotective against craniofacial ossification defects. We also postulate a specific regulatory feedback system by which ethanol and estradiol interact with various intermediaries including prostaglandins to influence developmental bone metabolism.
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