HUMAN CELL MODELS--LONGTERM LOW DOSE EXPOSURES AND MUTANT RESISTANT STATE

人体细胞模型——长期低剂量暴露和突变抵抗状态

• 批准号: 6338776
• 负责人: William G Thilly
• 金额: $ 22.21万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-03 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338776
• 关键词: DNA damage; DNA repair; adduct; air pollution; air sampling /monitoring; benzopyrenes; cell line; cytochrome P450; dosage; environmental toxicology; gender difference; gene expression; lung injury; mutagens; polymerase chain reaction; toxin metabolism

We have discovered that when our human cell line, AHH-1, which expresses cytochrome P-450 1A1, is exposed continuously to low concentrations of potent airborne mutagens such as benzo(a)pyrene and naphtho(a)pyrene that they switch from a high mutation rate to a low mutation rate after 5 days. This low mutations rate is only some three fold higher than seen for spontaneous mutation in the concurrent untreated controls. Studies with radioactive benzo(a)pyrene show that the rate of DNA adduct formation is unchanged by this phenomenon. The ratio of the rate of mutation relative to the rate of constant DNA adduction is changed by a factor of four suggesting induction of a post-DNA adduction process such as DNA repair is occurring. Because such a phenomenon would, if occurring in vivo, represent a major physiologic response protecting against induction of mutations by airborne toxicants. Our studies so far establish that the induction of the mutation-resistance by benzo(a)pyrene confers cross-resistance to mutation by the potent airborne mutagen, cyclopenta[c,d]pyrene. Secondly, we have found that another potent airborne mutagen naphtho(a)pyrene induces resistance to mutation in a time dependent pattern similar to that of benzo(a)pyrene. Finally, we have found human cell lines derived from AHH-1 which are markedly sensitive to mutation by air sample extract under short term high dose conditions giving use a useful mode for proposed long term dose mimicking conditions of samples, source samples and their extracts and subfractions on these human cells under these long term low dose conditions which more closely approximate the conditions of exposure in the human bronciolar tree, (b) discover it the "mutation resistant state" is induced by exposure to raw air particulates, by particulate extracts and by particulate extract subfractions, and (c.) carry out appropriate studies of the process at the cellular and molecular levels.

我们发现，当我们的人类细胞系AHH-1表达时 细胞色素P-450 1A1，不断暴露于低浓度 有效的机载诱变剂，例如苯并（a）pyrene和naphtho（a）pyrene 他们在5天后从高突变率转换为低突变率。 这种低突变速率仅比看到 未经处理的对照中的自发突变。研究 放射性苯并（a）pyrene表明​​DNA加合物形成的速率为 与这种现象不变。突变相对速率的比率 恒定DNA内收率的速度被更改为四倍 提示诱导DNA后DNA诸如DNA修复等DNA的诱导是 发生。 因为这样的现象将在体内发生，代表一个主要 生理反应防止空气传播的突变诱导 有毒物质。到目前为止，我们的研究确定了 苯并（A）pyrene的突变抗性赋予突变的交叉抵抗 由有效的空气诱变者Cyclopenta [C，D] Pyrene。其次，我们有 发现另一个有效的空气传播诱变剂（a）pyrene诱导 在时间依赖性模式中对突变的抵抗力类似 苯并（a）pyrene。最后，我们发现了源自AHH-1的人类细胞系 在短时间下，空气样品提取物对突变显着敏感 术语高剂量条件提供给拟议的长期使用有用的模式 模仿样品，源样品及其提取物的剂量条件 在这些长期低剂量下这些人类细胞的亚馏分 条件更紧密地近似于暴露条件 人类野马树，（b）发现它是“抗突变状态” 通过颗粒提取物暴露于原始空气颗粒引起的诱导 并通过颗粒提取物子隔离率，（c。）进行适当的 在细胞和分子水平上进行该过程的研究。