RETINOIC ACID INDUCES ABNORMAL HINDBRAIN & CRANIOFACIAL DEVELOPMENT IN MACAQUE

视黄酸导致后脑异常

• 批准号: 6277889
• 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/6277889
• 关键词: Mammalia; Primates; biological products; congenital disorders; growth /development; nervous system; reproductive system

Significance The cellular events leading to birth defects following exposure to an environmental agent are largely unknown. However, recent studies in laboratory species have advanced our understanding of the molecular mechanisms of a known human teratogen, 13-cis retinoic acid (cRA, isotretinoin, Accutane). Objectives The present study was carried out to study the molecular/cellular consequences of embryonic exposure to cRA in the cynomolgus monkey. We have previously demonstrated that the human cRA syndrome can be modeled in this species due to striking similarities in malformations, teratogenic dose, and sensitive period during early pregnancy. Results Immunohistochemistry using antibodies to neurofilaments and cellular retinoic acid binding protein-1 as well as Hox-B1, Krox-20 and Pax-2 gene products showed hypoplasia, abnormal, or delayed development of the hindbrain, cranial neural crest cells, and otocyst. Scanning electron microscopy indicated hypoplasia and/or abnormal development of the first and second pharyngeal arches (the precursors of the face). Coordinated development of all these embryonic structures is necessary for morphogenesis of the brain, ears, and face. Thus, the current observations are consistent with the malformations observed in cynomolgus fetuses exposed to the same regimen of cRA during early pregnancy. These include under development and/or duplication of the ear (external, middle, internal), face and cerebellum as well as cerebellar hypoplasia/aplasia. Future Directions Use of additional molecular markers, including riboprobes, to study alterations in gene expression patterns in the developing brain and craniofacial region after cRA exposure. KEYWORDS retinoids, birth defects, molecular mechanisms

导致出生缺陷的细胞事件 暴露于环境因素后的变化在很大程度上是未知的。 然而，最近在实验室物种中的研究已经推进了我们的研究。 了解一种已知的人类致畸剂的分子机制， 13-顺式维甲酸（cRA，异维甲酸，维甲酸）。 目标本 本研究是为了研究分子/细胞 食蟹猴胚胎暴露于cRA的后果。 我们以前已经证明，人类cRA综合征可以是 由于畸形的惊人相似性， 致畸剂量和孕早期敏感期。 结果免疫组化显示， 细胞视黄酸结合蛋白-1以及Hox-B1、Krox-20 Pax-2基因产物呈发育不全、异常或延迟表达 后脑、颅神经嵴细胞和耳囊的发育。 扫描电子显微镜显示发育不全和/或异常 第一和第二咽弓（前体）的发育 的脸）。 所有这些胚胎的协调发展 结构是必要的形态发生的大脑，耳朵， 脸上 因此，目前的观察结果与 在暴露于相同物质的食蟹猴胎仔中观察到的畸形 妊娠早期的cRA方案。 其中包括根据 耳的发育和/或复制（外耳，中耳， 内部）、面部和小脑以及小脑 发育不全/发育不全。 未来方向使用额外的分子 标记物，包括核糖核酸探针，以研究基因表达的改变 cRA后发育中的大脑和颅面区域的模式 exposure. 关键词类维生素A，出生缺陷，分子机制