Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust
Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust
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DOI：
10.1006/taap.2001.9176
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发表时间：
2001-06-15
影响因子：
3.8
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
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作者：
Aoki, Y;Sato, H;Yamamoto, M
柴油机尾气（DE）是一种有毒的致突变剂和/或致癌物，因为其成分可形成DNA加合物。DE的易感性和这种DNA加合物形成的效率的机制需要澄清。转录因子Nrf 2是必不可少的诱导型和/或组成型表达的一组解毒和抗氧化酶，我们假设nrf 2基因敲除小鼠可能作为一个很好的模型系统，用于分析DE毒性。为了验证这一假设，在暴露于DE（3 mg/m3悬浮颗粒物）4周后，检查了nrf 2（-/-）和nrf 2（+1-）小鼠的肺中外源性DNA加合物的产生。尽管暴露于DE后nrf 2（+/-）和nrf 2（-/-）小鼠肺中的相对加合物水平（RAL）显著增加，但暴露于DE的nrf 2（-/-）小鼠肺中RAL的增加约为暴露于DE的nrf 2（+/-）小鼠的2.3倍。相比之下，即使暴露于DE后，nrf 2（-/-）小鼠肺中的细胞色素P4501 A1 mRNA水平与nrf 2（+/-）小鼠肺中的细胞色素P4501 A1 mRNA水平相似，这表明II相药物代谢酶的活性受到抑制在Nrf 2-null突变小鼠暴露于DE后DNA加合物水平升高方面很重要。重要的是，在DE暴露后，在nrf 2（-/-）小鼠的支气管表皮中观察到氧化DNA加合物8-羟基脱氧鸟苷的严重增生和蓄积。这些结果表明nrf 2种系突变小鼠对DE暴露的易感性增加，并表明nrf 2基因敲除小鼠可能代表了评估呼吸DE毒性的有价值模型。(C)北京：科学出版社.
Diesel exhaust (DE) has been recognized as a noxious mutagen and/or carcinogen, because its components can form DNA adducts. Mechanisms governing the susceptibility to DE and the efficiency of such DNA adduct formation require clarification. The transcription factor Nrf2 is essential for inducible and/or constitutive expression of a group of detoxification and antioxidant enzymes, and we hypothesized that the nrf2 gene knockout mouse might serve as an excellent model system for analyzing DE toxicity. To address this hypothesis, lungs from nrf2(-/-) and nrf2(+1-) mice were examined for the production of xenobiotic-DNA adducts after exposure to DE (3 mg/m(3) suspended particulate matter) for 4 weeks. Whereas the relative adduct levels (RAL) were significantly increased in the lungs of both nrf2(+/-) and nrf2(-/-) mice upon exposure to DE, the increase of RAL in the lungs from nrf2(-/-) mice exposed to DE were approximately 2.3-fold higher than that of nrf2(+/-) mice exposed to DE. In contrast, cytochrome P4501A1 mRNA levels in the nrf2(-/-) mouse lungs were similar to those in the nrf2(+/-) mouse lungs even after exposure to DE, suggesting that suppressed activity of phase II drug-metabolizing enzymes is important in giving rise to the increased level of DNA adducts in the Nrf2-null mutant mouse subjected to DE. Importantly, severe hyperplasia and accumulation of the oxidative DNA adduct 8-hydroxydeoxyguanosine were observed in the bronchial epidermis of nrf2(-/-) mice following DE exposure. These results demonstrate the increased susceptibility of the nrf2 germ line mutant mouse to DE exposure and indicate the nrf2 gene knockout mouse may represent a valuable model for the assessment of respiratory DE toxicity. (C) 2001 Academic Press.