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Molecular Mechanisms of Toxic Expression Induced by Endocrine Disruptors via AHR

内分泌干扰物通过 AHR 诱导毒性表达的分子机制

基本信息

批准号：
15390040
负责人：
YAMAZAKI Hiroshi
金额：
$ 8.64万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390040/
关键词：
AHR PAHs TCDD CYP1A1 CYP1B1 個人差

项目摘要

Polycychc aromatic hydrocarbons (PAHs) which are known as the Environmental Endocrine Disruptors exert the various toxicological effects via aryl hydrocarbon receptor (AHR). However the mechanisms of toxic expression induced by PAHs have not been clarified yet. Therefore, the purpose of this study was to clarify the mechanisms of toxic expression induced by PAHs using differential display method and DNA microarray method. First, total RNA were prepared from the wild type mouse and AHR knock out mouse livers treated. with 3-methylcholanthrene (MC). We found the novel AHR target genes using differential display method and DNA microarray method. Interestingly, the mRNA expressions of the peroxisome prolifilator-activated receptor (PPAR) α target genes were suppressed by PAH treatment through AHR. We also demonstrated that AHR inhibited PPARα signals through the suppression of its heterodimeric partner, retinoid X receptor (RXR)α. The genes responsible for the fatty acid metabolism were regulated by PPARα. Therefore, it was suggested that the suppression of the PPARα signal was important for the occurrence of fatty liver.

多环芳烃(PAHs)被称为环境内分泌干扰物，通过芳香烃受体(AHR)发挥多种毒理作用。然而，多环芳烃诱导细胞毒性表达的机制尚不清楚。因此，本研究的目的是利用差异显示技术和DNA微阵列技术研究多环芳烃诱导细胞毒性表达的机制。首先，从野生型小鼠中提取总RNA，并对AHR基因敲除小鼠的肝脏进行处理。3-甲基胆蒽(MC)。我们利用差异显示法和DNA微阵列技术发现了新的AHR靶基因。有趣的是，过氧化物酶体增殖物激活受体(PPAR)α靶基因的表达被多环芳烃处理通过AHR抑制。我们还证明了AHR通过抑制其异二聚体伙伴维甲酸X受体(RXR)α而抑制PPARα信号。参与脂肪酸代谢的基因受PPARα调控。因此，PPARα信号的抑制在脂肪肝的发生中起重要作用。

项目成果

期刊论文数量（44）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Toide K, Yamazaki H, et al.: "Aryl hydrocarbon hydroxylase represents CYP1B1, and not CYP1A1, in human freshly isolated white cells"Cancer Epidem Biomarker Prev. 12. 219-222 (2003)

Toide K、Yamazaki H 等人：“在人类新鲜分离的白细胞中，芳基烃羟化酶代表 CYP1B1，而不是 CYP1A1”Cancer Epidem Biomarker Prev.

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Toide K, Yamazaki H, Kamataki T: "Reply : Correspondence re : K.Toide et al."Cancer Epidem Biomarker Prev. 12. 1118 (2003)

Toide K、Yamazaki H、Kamataki T：“回复：通讯：K.Toide 等人”Cancer Epidem Biomarker Prev。

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Establishment of ten strains of genetically engineered Salmonella typhimurium TA1538 each co-expressing a form of human cytochrome P450 with NADPH-cytochrome P450 reductase sensitive to various promutagens.

DOI：
10.1016/j.mrgentox.2004.06.003
发表时间：
2004-08
期刊：
Mutation research
影响因子：
0
作者：
Y. Yamazaki;Ken-Ichi Fujita;K. Nakayama;A. Suzuki;Katsunori Nakamura;H. Yamazaki;T. Kamataki
通讯作者：
Y. Yamazaki;Ken-Ichi Fujita;K. Nakayama;A. Suzuki;Katsunori Nakamura;H. Yamazaki;T. Kamataki

Identification of a novel polymorphic enhancer of the human CYP3A4 gene