EMBRYOTOXICITY OF ENVIRONMENTAL CHEMICALS

环境化学品的胚胎毒性

• 批准号: 2872269
• 负责人: MONT R JUCHAU
• 金额: $ 24.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2872269
• 关键词: biotransformation; carcinogen testing; complementary DNA; cytochrome P450; embryo /fetus culture; embryo /fetus toxicology; environmental toxicology; enzyme activity; enzyme induction /repression; human fetus tissue; immunocytochemistry; isozymes; mutagen testing; teratogens

DESCRIPTION (Adapted from the Investigator's Abstract): The broad, long term objective is to provide a better understanding of mechanisms whereby foreign organic chemicals produce persistent birth defects in humans. It is expected that such an understanding will lead to a minimization of human birth defects, an enormous problem in modern society. Specifically, the research is designed to elucidate the mechanistic roles of individual embryonic P450 cytochromes (whose genes are expressed during organogenesis in human embryonic tissues) as determinants of the capacity of certain chemicals to produce dysmorphogenesis/embryotoxicity. Focus is on organogenesis because this is the period of gestation during which the conceptus reputedly is most sensitive to chemical insult. The research will focus on P450 isoforms expressed in three specific human embryonic tissues - brain, adrenal gland and liver. Focus on the former two is because of high importance as target sites for embryotoxic effects and on the liver because of background information and relatively high levels of certain isoforms. Expression and regulation of expression of CYP1B1 in these tissues will be given high priority because P4501B1 mRNA has been detected in each of the three tissues of interest, because 1B1 seems likely to play an important role in developmental processes, and because 1B1 can be profoundly regulated by both environmental chemicals (e.g., TCDD) and endogenous chemicals (e.g., cAMP). Next priority will be given to isoforms now also found to be expressed in human embryonic tissues. These are P450s 2E1, 3A7 and 1A1. 2E1 has been detected in human embryonic cephalic tissues, 3A7 is present in relatively high quantities in human embryonic liver, and 1A1 has been found in human embryonic liver and brain. Evidence for still other P450 isoforms in these tissues has been found and efforts will be made to identify and determine their roles as determinants of chemically induced embryotoxicity. The tools of modern molecular biology and biochemistry will be used to characterize these isoforms, particularly in terms of mechanisms of their regulation in embryonic tissues. A rodent whole embryo culture system will be utilized for examination of the mechanistic roles that individual P450 isoforms can play in the embryotoxic effects of specific chemicals. Results obtained should provide health professionals and regulatory agencies a more rational basis for advising women with respect to their exposures to drugs and environmental chemicals during pregnancy.

描述（改编自调查员的摘要）： 术语目标是提供对机制的更好理解 外国有机化学物质在人类中产生持续的先天缺陷。 这是 期望这种理解将导致人类的最小化 出生缺陷，现代社会中的一个巨大问题。 具体来说， 研究旨在阐明个人的机械作用 胚胎P450细胞色素（其基因在器官发生过程中表达 在人类胚胎组织中）作为某些能力的决定因素 产生变形的化学物质/胚胎。 重点是 器官发生，因为这是妊娠期 据说概念对化学侮辱最敏感。 研究将 专注于在三个特定的人类胚胎组织中表达的P450同工型 - 大脑，肾上腺和肝脏。 专注于前两个是因为高 作为胚胎作用和对肝脏的目标部位的重要性，因为 背景信息和相对较高的某些同工型。 CYP1B1在这些组织中的表达和调节将是 考虑到很高的优先级，因为在每个中都检测到了P4501B1 mRNA 感兴趣的三个组织，因为1B1似乎很可能发挥重要作用 在发展过程中的作用，并且因为1B1可以受到深刻的调节 通过环境化学品（例如TCDD）和内源性化学物质（例如， 营）。 现在也发现的同工型将获得下一个优先级 在人类胚胎组织中表达。 这些是P450S 2E1、3A7和1A1。 2e1在人类胚胎的头膜组织中已检测到，3A7存在于 发现人胚胎肝脏中的数量相对较高，已经发现1A1 在人类胚胎肝和大脑中。 其他P450同工型的证据 在这些组织中，已经发现并努力识别和 确定它们作为化学诱导的胚胎毒性决定因素的作用。 现代分子生物学和生物化学的工具将用于 表征这些同工型，特别是在其机制方面 胚胎组织中的调节。 啮齿动物整个胚胎培养系统将 用于检查单个P450的机械作用 同工型可以在特定化学物质的胚胎作用中发挥作用。 结果 获得的应为卫生专业人员和监管机构提供更多 为妇女提供对毒品的暴露的理性基础 和怀孕期间的环境化学物质。