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ACTIVATION OF SIGNAL TRANSDUCTION SYSTEMS AND TARGET GENES BY DIOXIN COMPOUNDS

二恶英化合物激活信号转导系统和靶基因

基本信息

批准号：
10680510
负责人：
KIKUCHI Hideaki
金额：
$ 2.18万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10680510/
关键词：
Dioxin Ah receptor signal transduction Map kinase PD98059 ERK1

项目摘要

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a prototype halogenated aromatic hydrocarbon, and it is considered to be one of the most potent toxicants ever studied. The adverse biological effects of TCDD seen in experimental animals include immune, reproductive, and developmental toxicity, carcinogenicity, wasting syndrome, chlorancne, and lethality. In order to clarify the mechanism of dioxin toxicity, we determined the activity of signal transduction systems and CYP1 A1 induction level as a target gene.1) The activation of ERK1/2 was determined using basic myelin protein as a substrate. After 30 min of the treatment of HepG2 cells with TCDD, the activation of ERK1/2 was observed. Using anti-phospho-ERK antibody, the increase of phosphorylated form of ERK was observed at 30min after the treatment of TCDD.2) MEK inhibitor, PD98059 inhibited the induction of CYP1A1 inHepG2 cells by TCDD treatment, but not that by omeprazole. However PD98059 was reported to inhibit the CYP1A1 induction by antagonizing Ah receptor. Thus, ERK activation does not correlate directly to the induction of CYP1A1, but it has some other target genes.3) To identify the target genes, which is induced by TCDD, we applied the differential display method to mouse B cell line, CH12. We are getting many genes which are induced by TCDD in B cell line.From these observations, there must be Ah receptor mediated pathway and signal transduction mediated pathway in the mechanisms of dioxin toxicity.

TCDD（2，3，7，8-tetrachlorodibenzo-p-dioxin）是一种典型的卤代芳烃，被认为是迄今为止研究过的毒性最强的有毒物质之一。在实验动物中观察到的TCDD的不良生物学效应包括免疫、生殖和发育毒性、致癌性、消耗综合征、氯中毒和致死性。为了阐明二恶英的毒性机制，我们以CYP 1 A1为靶基因，测定了二恶英对细胞信号转导系统的活性和CYP 1 A1的诱导水平。1）以碱性髓鞘蛋白为底物，测定了ERK 1/2的激活。TCDD处理HepG 2细胞30 min后，观察到ERK 1/2的激活。TCDD处理HepG 2细胞30 min后，ERK磷酸化水平明显升高。2）MEK抑制剂PD 98059可抑制TCDD对细胞CYP 1A 1的诱导作用，但对奥美拉唑的诱导作用无影响。然而，据报道，PD 98059通过拮抗Ah受体来抑制CYP 1A 1诱导。因此，ERK的激活与CYP 1A 1的诱导没有直接的关系，但它有一些其他的靶基因。3）为了鉴定TCDD诱导的靶基因，我们应用差异显示技术对小鼠B细胞系CH 12进行了研究。我们在B细胞系中获得了大量TCDD诱导表达的基因，由此推测二恶英的毒性机制中可能存在着Ah受体介导的途径和信号转导介导的途径。