EMBRYOTOXICITY OF ENVIRONMENTAL CHEMICALS

描述（改编自研究者摘要）： 长期目标是更好地了解 外来的有机化学物质会导致人类持续性的出生缺陷。 是 预计这样的理解将导致人类的最小化， 出生缺陷是现代社会的一个大问题。 具体而言是 研究旨在阐明个体的机械作用， 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 化学物质产生畸形/胚胎毒性。 重点是 器官形成，因为这是妊娠期， 据说孕体对化学伤害最敏感。 这项研究将 重点关注在三种特定的人类胚胎组织中表达的P450亚型- 大脑肾上腺和肝脏 关注前两者是因为高 作为胚胎毒性作用的靶位点和对肝脏的重要性， 背景信息和相对高水平的某些同种型。 CYP 1B 1在这些组织中的表达和表达调控将是 因为在每个组织中检测到P4501 B1 mRNA， 三种感兴趣的组织，因为1B 1似乎可能发挥重要作用， 在发育过程中的作用，因为1B 1可以深刻地调节 由环境化学品（例如，TCDD）和内源性化学品（例如， cAMP）。 下一步将优先考虑现在也发现是 在人类胚胎组织中表达。 P450 2 E1、3A 7和1A 1。 2 E1存在于人胚胎的头部组织中，3A 7存在于 在人类胚胎肝脏中含量相对较高，并且已发现1A 1 在人类胚胎肝脏和大脑中。 其他P450亚型的证据 在这些组织中已经发现，并将努力识别和 确定其作为化学诱导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被用来 描述这些异构体，特别是在其机制方面， 胚胎组织中的调节。 啮齿动物全胚胎培养系统将 用于检查单个P450的机械作用 同种型可在特定化学品的胚胎毒性效应中发挥作用。 结果 获得应提供卫生专业人员和监管机构， 就妇女接触毒品问题提供咨询的合理依据 和环境化学物质的影响。

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.