RETINOIDS--CONCEPTAL BIOTRANSFORMATION/DYSMORPHOGENESIS

类维生素A--概念生物转化/形态发生障碍

• 批准号: 3254201
• 负责人: MONT R JUCHAU
• 金额: $ 17.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3254201
• 关键词: all trans retinol; cis trans isomerization; congenital disorders; embryo /fetus culture; embryogenesis; enzyme mechanism; glucuronosyltransferase; high performance liquid chromatography; histogenesis; histology; isomerase; laboratory rat; mammalian embryology; microinjections; nutrition related tag; retinoate; retinoids; scanning electron microscopy; teratogens; vitamin metabolism

The long-range goal of the proposed research is to provide a better understanding of the mechanisms whereby retinoids produce dysmorphogenesis in developing embryos. Concern for dysmorphogenic, teratogenic and other embryotoxic effects of retinoids is very high because of widespread usage of these agents in therapy, as nutritional supplements and, potentially, as cancer chemopreventives. At least one retinoid (13-cis-retinoic acid) is recognized as a potent human teratogen and others are highly suspect. Recently, evidence has accumulated to suggest that biotransformation of retinoids may play a critical role in the morphogenic as well as dysmorphogenic effects of these important chemicals. In addition, recently published data have shown that tissues of the conceptus per se actively participate in a variety of biotransforming reactions that play pivotal roles in the dysmorphogenicity of several model chemicals. The specific purpose of the proposed study is to initiate investigations into the expression within specific conceptal tissues of functional proteins capable of catalyzing conversion of 13-cis-retinoic acid, all-trans-retinoic acid and retinol (as model substrates/dysmorphogens) to respective metabolic products. Tissues will be investigated during the critical stage of organogenesis and will include the embryo proper, visceral yolk sac, ectoplacental cone, parietal yolk sac (including Reichert's membrane) and decidua. In experiments with cultured whole conceptuses, generation of specific metabolites will be compared and, where applicable, correlated with the incidence of specific dysmorphogenic effects. The parent retinoids will be placed in the culture medium and also will be placed in direct contact with embryonic tissues via microinjections into the amniotic cavity and/or exocoelomic space. Biotransformation reactions to be investigated include isomerizations, dehydrogenations, glucuronidations and monooxygenations. Newly developed and highly sensitive hplc techniques will permit analyses of small quantities of metabolites, rendering the proposed studies feasible. Relevance of obtained information will be probed by comparisons with data obtained from experiments in vivo. Results should provide health professionals and regulatory agencies a more rational basis for providing advice and counsel to pregnant women with respect to their exposure to various retinoidal substances.

拟议的研究的远程目标是提供更好的 了解类视黄素会产生畸形发生的机制 在开发胚胎中。 关注畸形，致畸和其他 由于使用广泛的用法 这些药物在治疗中，作为营养补充剂，可能是 癌症化学预防。 至少一个类维生素类（13- cis-反毒酸）是 被公认为有效的人性致病和其他人是高度疑问。 最近，有证据表明，生物转化 类视网膜类似可能在形态学和 这些重要化学物质的畸形作用。 此外，最近 已发表的数据表明，概念的组织本身是积极的 参与各种发挥关键的生物转化反应 在几种模型化学物质的畸形性中作用。 具体 拟议的研究的目的是开始研究 功能蛋白的特定概念组织中的表达 13-秒近红酸的催化转化率的催化转化率 和视黄醇（作为模型底物/变形剂）到各自代谢 产品。 在关键阶段将研究组织 器官发生，并将包括适当的胚胎，内脏蛋黄囊， 牙本质锥，顶蛋黄囊（包括Reichert的膜）和 Decidua。 在具有培养的整个概念的实验中 将比较特定的代谢产物，并在适用的情况下相关 特异性畸形作用的发生率。 父母 视网膜类似将放置在培养基中，也将放置在 通过微分注射直接与胚胎组织接触到羊水 腔和/或外循环集团空间。生物转化反应为 所研究的包括异构化，脱氢，葡萄糖醛酸化和 单氧。 新开发和高度敏感的HPLC技术 将允许分析少量代谢物，从而使 提出的研究可行。 获得的信息的相关性将是 通过与从体内实验获得的数据进行比较探测。 结果 应该为卫生专业人员和监管机构提供更合理的 向孕妇提供建议和律师的依据 它们暴露于各种视网膜类似物质中。