Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study.
Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study.
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DOI：
10.1002/1096-9926(200010)62:4
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发表时间：
2000-10
期刊：
影响因子：
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通讯作者：
Guy B. Mulder;N. Manley;J. Grant;K. Schmidt;Weiping Zeng;C. Eckhoff;L. Maggio‐Price
中科院分区：
文献类型：
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作者：
Guy B. Mulder;N. Manley;J. Grant;K. Schmidt;Weiping Zeng;C. Eckhoff;L. Maggio‐Price
背景维生素A及其代谢物已显示在动物和人类中具有致畸性，产生神经嵴衍生结构的缺陷，包括颅面骨骼、心脏和胸腺的异常。我们先前对维甲酸的研究已经证实，妊娠第9天（gd）是诱导小鼠颅面和胸腺缺陷的敏感胚胎年龄。方法孕鼠在妊娠第9天暴露于不同剂量的维生素A（维生素A醋酸酯），观察胚胎咽弓和咽袋形态、神经嵴细胞迁移和标记基因表达的变化。此外，我们研究了单个器官系统是否对低剂量维生素A更敏感，并可能用作妊娠早期维生素A暴露的指标。结果高剂量（100 mg/kg）和中等剂量（50和25 mg/kg）维生素A可导致明显的颅面、心脏流出道和胸腺异常。低剂量的维生素A（10毫克/公斤）产生颅面和胸腺异常，轻度和低反射率。暴露的胚胎表现出形态学变化，在第2和第3咽弓和邮袋，神经嵴迁移的变化，颅神经节的异常，和Hoxa 3的表达改变。结论这些动物研究，沿着最近关于维生素A对人类致畸性的流行病学报告，引起了人们对女性在妊娠早期摄入即使是中等至少量补充维生素A也可能诱发后代缺陷（可能是微妙的）的担忧。
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 day (gd) 9 is a sensitive embryonic age in the mouse for inducing craniofacial and thymic defects. METHODS We exposed pregnant mice to variable doses of vitamin A (retinyl acetate) on gd 9 and embryos were evaluated for changes in developing pharyngeal arch and pouch morphology, neural crest cell migration and marker gene expression. Additionally, we investigated whether a single organ system was 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 abnormalities. Low doses of vitamin A (10 mg/kg) produced craniofacial and thymic abnormalities that were mild and of low penetrance. Exposed embryos showed morphologic changes in the 2nd and 3rd pharyngeal arches and pouches, changes in neural crest migration, abnormalities in cranial ganglia, and altered 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 even moderate to low amounts of supplemental vitamin A during the early gestational period.