DEVELOPMENTAL TOXICITY OF EXCESSIVE VITAMIN INTAKE IN MACAQUE

猕猴摄入过多维生素的发育毒性

• 批准号: 6277887
• 负责人: ANDREW G HENDRICKX
• 金额: $ 5.99万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6277887
• 关键词: Mammalia; Primates; biological products; congenital disorders; growth /development

Significance Although vitamin A is an essential nutrient for normal cellular function, recent epidemiological studies have suggested, but not proven, that ingestion of excess vitamin A supplements during early pregnancy may cause birth defects. Objectives The present study was carried out to determine safe levels of vitamin A during pregnancy in the cynomolgus monkey which can be used for risk assessment. The cynomolgus monkey, a well established model for normal and abnormal human development, mimics the human malformation syndrome associated with the vitamin A analog, isotretinoin (Accutane). Results Oral exposure to excessive doses of vitamin A (retinyl palmitate, AROVIT) administered at 7,500 to 80,000 IU/kg on gestational days 16-27 resulted in dose-related increases in abortions and malformations which affected typical retinoid target tissues, including the craniofacial region, heart, and thymus. The no observed adverse effect level (NOAEL) and lowest observed adverse effect level (LOAEL) were 7,500 and 20,000 IU/kg, respectively. Based on the similarities between monkeys and humans in response to isotretinoin, the monkey data can be used to extrapolate a hypothetical safe dose of vitamin A in humans. Thus, considering weight differences (4 kg monkey and 50 kg woman), the monkey NOAEL, which is equivalent to 30,000 IU/day can be extrapolated to a theoretical human NOAEL of ~300,000 IU/day vitamin A. Since this level is ~100x the RDA (2,670 IU) for vitamin A, these results indicate that the current recommendation for vitamin A use during pregnancy provides a large margin of safety. Future Directions Use of the monkey retinoid model to study the molecular mechanisms of craniofacial dysmorphogenesis induced by excess vitamin A. KEYWORDS vitamin A, birth defects, retinoids, risk assessment

虽然维生素A是一种必需的营养素， 正常的细胞功能，最近的流行病学研究 这表明，但没有证明，摄入过量的维生素A， 怀孕早期补充可能导致出生缺陷。 目的本研究旨在确定安全水平 在食蟹猴怀孕期间， 用于风险评估。 食蟹猴是一种公认的 正常和异常人类发育的模型，模仿人类 与维生素A类似物相关的畸形综合征， 异维甲酸（Accutane）。 结果口服过量的 维生素A（棕榈酸视黄酯，AROVIT），7,500 - 80000 在妊娠第16-27天，IU/kg导致剂量相关的 影响典型类维生素A靶点的流产和畸形 组织，包括颅面区域、心脏和胸腺。 无 观察到的不良反应水平（NOAEL）和最低观察到的不良反应水平 作用水平（LOAEL）分别为7，500和20，000 IU/kg。 基于 猴子和人类在应对 异维甲酸，猴子的数据可以用来外推 假设人体内维生素A的安全剂量。 因此，考虑 体重差异（4 kg猴和50 kg女性），猴NOAEL， 相当于30，000 IU/天，可以外推至 理论人体NOAEL约为300，000 IU/天维生素A。由于这一水平 是维生素A RDA（2，670 IU）的约100倍，这些结果表明， 目前建议在怀孕期间使用维生素A， 一个很大的安全边际 未来的方向猴子的使用 类维生素A模型用于研究颅面神经损伤的分子机制 过量维生素A引起的形态发育不良。关键词维生素A， 出生缺陷，类维生素A，风险评估