Effects of excess vitamin A on development of cranial neural crest-derivedstructures: A neonatal and embryologic study

Background: Vitamin A and its metabolites have been shown to be teratogenic in animals and humans producing defects of neural crest derived structures that include abnormalities of the craniofacial skeleton, heart, and thymus . Our prior studies with retinoic acid have established that gestational da y (gd) 9 is a sensitive embryonic age in the mouse for inducing craniofacia l and thymic defects. Methods: We exposed pregnant mice to variable doses of vitamin A (retinyl a cetate) on gd 9 and embryos were evaluated for changes in developing pharyn geal arch and pouch morphology, neural crest cell migration and marker gene expression. Additionally, we investigated whether a single organ system wa s more sensitive to low doses of vitamin A and could potentially be used as an indicator of vitamin A exposure during early gestation. Results: High (100 mg/kg) and moderate (50 and 25 mg/kg) doses of vitamin A resulted in significant craniofacial, cardiac outflow tract and thymic abn ormalities. Low doses of vitamin A(10 mg/kg) produced craniofacial and thym ic abnormalities that were mild and of low penetrance. Exposed embryos show ed morphologic changes in the 2nd and 3rd pharyngeal arches and pouches, ch anges in neural crest migration, abnormalities in cranial ganglia, and alte red expression of Hoxa3. Conclusions: These animal studies, along with recent epidemiologic reports on human teratogenicity with vitamin A, raise concerns about the potential for induction of defects (perhaps subtle) in offspring of women ingesting e ven moderate to low amounts of supplemental Vitamin A during the early gest ational period. (C) 2000 Wiley-Liss, Inc.