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Sensitive detection of air-born mutagens and their evaluation using gene knockout mice

空气中诱变剂的灵敏检测及其使用基因敲除小鼠的评估

基本信息

批准号：
14207100
负责人：
AOKI Yasunobu
金额：
$ 32.03万
依托单位：
National Institute for Environmental Studies
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207100/
关键词：
mutagen gpt delta mouse diesel exhaust Nrf2 benzo[a]pyrene nitropyrene transgenic mouse in vivo mutagenesis 変異原物質検出 Nrf2ノックアウトマウス benzo[a]pyrene 変異物質検出 1,6-ジニトロピレン Benzo(a)pyrene

项目摘要

A transcription factor, Nrf2, is essential for expression of phase II enzymes and antioxidant enzymes, and contributes to a protection system against xenobiotics. We intended to reveal how mutant frequency is increased under Nrf2-deficient condition. We used gpt delta mice as a model animal for determining characteristics of in vivo mutagenesis caused by environmental mutagens. Intratracheal instillation of mutagens such as benzo[a]pyrene (B[a]P) and 1,6-dinitropyrene(1,6-DNP) caused to increase the mutant frequency linearly depending of the dose, and in vivo mutagenic potency of 1,6-DNA was shown to be higher than that of B[a]P. A predominant base substitution caused by B[a]P and 1,6-DNP was G>T and G>A, respectively, and positions of mutation hotspots on gpt gene was different between these compounds. Exposure of diesel exhaust for 12 weeks at the concentration of 3 mg/m^3 resulted to elevate the mutant frequency depending on duration of exposure. As a result of intratracheal instillation, mutagenicity of diesel exhaust particles (DEP) was shown to be derived from the extract of DEP. A predominant base substitution induced by exposure of diesel exhaust, as well as administration of DEP, was G>A, and the positions of mutation hotspots were identical to those of 1,6-DNP, suggesting that major mutagens in diesel exhaust are nitropyrenes and related compounds. We produced Nrf2-deficient gpt delta mice, and B[a]P was administered to lungs of the Nrf2(+/-) and Nrf2(-/-) mice. The mutant frequency in B[a]P-treated Nrf2(-/-) mice became twice compared to Nrf2(+/-) mice.

转录因子Nrf 2对于II相酶和抗氧化酶的表达是必需的，并且有助于针对外源性物质的保护系统。我们的目的是揭示Nrf 2缺陷条件下突变频率如何增加。我们使用gpt delta小鼠作为模型动物，用于确定由环境诱变剂引起的体内诱变的特征。体内滴注苯并[a]芘（B[a]P）和1，6-二硝基芘（1，6-DNP）可使突变频率随剂量的增加而线性增加，1，6-DNA的体内诱变能力高于B[a] P。B[a]P和1，6-DNP引起的碱基替换分别为G>T和G>A。不同化合物的GPT基因突变热点位置不同。暴露于浓度为3 mg/m^3的柴油机废气12周后，根据暴露时间的长短，突变频率升高。经气管内滴注试验，柴油机排气颗粒物（DEP）的致突变性来源于DEP的提取物。柴油机尾气和DEP诱发的突变位点以G>A为主，突变热点位置与1，6-DNP相同，表明柴油机尾气中的主要诱变剂是硝基芘类化合物。我们生产了Nrf 2缺陷型gpt δ小鼠，并将B[a]P施用于Nrf 2（+/-）和Nrf 2（-/-）小鼠的肺。与Nrf 2（+/-）小鼠相比，B[a] P处理的Nrf 2（-/-）小鼠中的突变频率变为两倍。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Distinct response to dioxin in an arylhydrocarbon receptor (AHR)-humanized mouse

DOI：
10.1073/pnas.1037886100
发表时间：
2003-05-13
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Moriguchi, T;Motohashi, H;Yamamoto, M
通讯作者：
Yamamoto, M

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