RETINOIDS--CONCEPTAL BIOTRANSFORMATION/DYSMORPHOGENESIS

拟议研究的长期目标是提供一个更好的 了解维甲酸产生畸形的机制 在发育中的胚胎。 对畸形、畸形和其他问题的担忧 由于广泛使用，类维生素A的胚胎毒性作用非常高 这些药物在治疗中，作为营养补充剂， 癌症化学预防剂 至少一种类视色素（13-顺式-视黄酸）， 被认为是一种强有力的人类致畸剂，其他人则高度怀疑。 最近，越来越多的证据表明， 类维生素A可能在形态发生中起关键作用， 这些重要化学物质的不良影响。 此外，近日 已发表的数据表明，孕体组织本身积极地 参与各种生物转化反应， 在几种模型化学品的畸形形成中的作用。 具体 拟议研究的目的是启动调查， 在特定的孕体组织内表达功能蛋白， 催化13-顺式-视黄酸、全反式-视黄酸 和视黄醇（作为模型底物/畸形形成物）， 产品. 将在以下关键阶段对组织进行研究： 器官发生，包括胚胎本身，内脏卵黄囊， 胎盘外锥、壁卵黄囊（包括赖歇特膜）和 蜕膜 在用培养的整个孕体进行的实验中， 将对特定代谢物进行比较，并在适用时进行关联 与特定畸形发生效应的关系。 母 将类维生素A置于培养基中， 通过羊膜显微注射直接接触胚胎组织 腔和/或外体腔空间。生物转化反应 研究包括异构化、异构化、葡萄糖醛酸化和 单氧化作用 新开发的高灵敏度hplc技术 将允许分析少量的代谢物， 建议可行的研究。 获得的信息的相关性将是 通过与体内实验获得的数据进行比较来探索。 结果 应该为卫生专业人员和监管机构提供更合理的 为孕妇提供咨询和辅导的基础， 他们接触各种类维生素A物质。

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.