EMBRYOTOXICITY OF ENVIRONMENTAL CHEMICALS

拟议研究的长期目标是更好地了解 外来有机化学物质产生畸形的机制， 其他形式的毒性在人类胚胎发育。 养殖研究 完整的啮齿动物胚胎提供了证据表明，内源性，胚胎， 依赖于P450的生物活化系统将催化 以足够的速率将其它非活性化学品转化为活性中间体 在同一个人身上产生明显的形态学异常， 胚胎 啮齿动物不同组织中几种P450同工酶的证据 胚胎已经获得，其中一个（P450 IA 1）已经被 积极识别和部分特征。 因为几乎没有什么 已知人胚胎组织中P450的补体 在器官形成的关键阶段（妊娠约20-60天） 并且由于现在可用于此类研究的高灵敏度技术， 该建议旨在检测和表征P450的补体 器官发生阶段人类胚胎组织中的同种型。 的组合 高灵敏度探针将用于功能表征 活性P450，免疫交叉反应亚型和相应的 各种人类胚胎组织中的mRNA。 从人类获得的信息 将组织与从啮齿动物和其他动物获得的组织进行比较。 实验动物，以确定哪些胚胎物种可能 与人类胚胎最为相似。 产生活性 培养的整个啮齿动物胚胎的中间体也将与 培养的人类胚胎组织产生相同的能力，或 类似的代谢中间体。 调查的模式/机制 还将进行人胚胎P450的调节。 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被证明 在初步实验中。 研究结果应 为卫生专业人员和管理机构提供更合理的依据 为孕妇提供咨询和建议， 接触药物和其他外来有机/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.