RETINOIDS--CONCEPTAL BIOTRANSFORMATION/DYSMORPHOGENESIS

拟议研究的长期目标是提供更好的 对维甲酸导致畸形发生机制的认识 在胚胎发育过程中。关注畸形、畸形和其他 由于维甲酸的广泛使用，其胚胎毒性作用非常强。 在治疗中，作为营养补充剂和潜在的 癌症化学防腐剂。至少一种维甲酸(13-顺式维甲酸) 被认为是一种有效的人类致畸因素，其他人则高度可疑。 最近，越来越多的证据表明，生物转化 类维甲酸可能在形态发生以及 这些重要化学物质的畸形效应。另外，最近， 已公布的数据表明，胚胎组织本身是活跃的 参与各种起关键作用的生物转化反应 在几种模型化学品的畸形形成中的作用。具体的 拟议研究的目的是启动对 功能蛋白在特定的胚胎组织中的表达 13-顺式-维甲酸、全反式维甲酸的催化转化 和视黄醇(作为模型底物/异构体)对各自的代谢产生影响 产品。将在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， 外胎盘锥体、壁卵黄囊(包括Reichert膜)和 蜕膜。在培养的整个胚胎的实验中，产生 将对特定的代谢物进行比较，并在适用的情况下进行关联 伴随着特殊畸形效应的发生。父辈 类维甲酸将被放置在培养基中，也将被放置在 通过羊膜内微量注射与胚胎组织直接接触 腔和/或外腔隙。生物转化反应即将到来 所研究的包括异构化、脱氢、葡萄糖醛酸化和 单氧合。新开发的高灵敏高效液相色谱技术 将允许对少量代谢物进行分析，使 提出的研究是可行的。所获得的信息的相关性将是 通过与活体实验获得的数据进行比较来探讨。结果 应该为卫生专业人员和监管机构提供更理性的 向孕妇提供关于以下方面的咨询和咨询的依据 他们暴露在各种类维甲酸物质中。

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.