EMBRYOTOXICITY OF ENVIRONMENTAL CHEMICALS

拟议研究的长期目标是更好地理解 外来有机化学品产生畸形和 人类胚胎发育过程中的其他形式的毒性。关于人工养殖的研究 完整的啮齿动物胚胎提供了内源性、胚胎、 依赖于P450的生物激活系统将催化 否则，以足够的速率将非活性化学品转化为活性中间体 影响大体可观察到的自身形态异常 胚胎。啮齿动物不同组织中几种P450同工酶的证据 现在已经获得了胚胎，其中一个(P450IA1)已经被 肯定的识别和部分特征。因为几乎什么都没有 关于人类胚胎组织中P450的补体已知 在器官发生的关键阶段(怀孕20-60天左右) 而且由于现在有高度敏感的技术可用于此类研究， 这项建议旨在检测和表征P450的补体 器官发育期人类胚胎组织中的异构体。一种组合 将利用高度敏感的探头来表征功能 活性P450、免疫交叉反应异构体和相应的 人类各种胚胎组织中的mRNAs。从人类获取的信息 组织将与从啮齿动物和其他动物身上获得的组织进行比较 实验动物，努力确定哪些胚胎物种可能 与人类胚胎最为相似。电抗力的产生 通过培养整个啮齿动物胚胎的中间产物也将与 培养的人类胚胎组织产生相同或相同或 相似的代谢中间产物。模式/机制的研究 还将对人类胚胎P450进行监管。的相关性 所获得的信息将在培养的整体实验中进行探索。 胚胎。所提出的方法的可行性已经被证明。 在初步实验中。从研究中获得的结果应该 为卫生专业人员和监管机构提供更合理的基础 为孕妇提供关于以下方面的建议和咨询 接触毒品和其他外国有机/环境化学品。

The long-range goal of the proposed research is to better understand mechanisms whereby foreign organic chemicals produce malformations and other forms of toxicity in developing human embryos. Research on cultured whole rodent embryos has provided evidence that endogenous, embryonic, P450-dependent bioactivating systems will catalyze the conversion of otherwise inactive chemicals to reactive intermediates at rates sufficient to effect grossly observable morphologic abnormalities in the selfsame embryos. Evidence for several P450 isozymes in various tissues of rodent embryos has now been obtained and one of these (P450IA1) has been positively identified and partially characterized. Because almost nothing is known concerning the complement of P450s in human embryonic tissues during the critical stages of organogenesis (days about 20-60 of gestation) and because highly sensitive techniques are now available for such studies, this proposal is designed to detect and characterize the complement of P450 isoforms in tissues of organogenesis-stage human embryos. A combination of highly sensitive probes will be utilized to characterize functionally active P450s, immunologically cross-reactive isoforms and corresponding mRNAs in various human embryonic tissues. Information obtained from human tissues will be compared to that obtained from rodents and other experimental animals in an effort to determine which embryonic species may most closely resemble human embryos. The generation of reactive intermediates by cultured whole rodent embryos will also be compared with the capacity of cultured human embryonic tissues to generate the same or similar metabolic intermediates. Investigations of modes/mechanisms of regulation of human embryonic P450s will also be conducted. Relevance of the obtained information will be probed in experiments with cultured whole embryos. The feasibility of the proposed approaches has been demonstrated in preliminary experiments. Results obtained from the research 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 drugs and other foreign organic/environmental chemicals.