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: 6106413
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6106413
• 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.

我们已经发现，当我们的人类细胞系AHH-1， 细胞色素P-450 1A 1，持续暴露于低浓度的 空气传播的强诱变剂，如苯并（a）芘和萘并（a）芘， 它们在5天后从高突变率转变为低突变率。 这一低突变率仅比观察到的高出约三倍。 同时未处理对照组中的自发突变。外贸 放射性苯并（a）芘显示，DNA加合物的形成速率为 这种现象不变。突变率相对于 恒定DNA加合速率的变化是四倍 这表明诱导后DNA加合过程，如DNA修复， 正在发生。 因为这种现象如果在体内发生，将代表主要的 防止气传诱变的生理反应 有毒物质到目前为止，我们的研究表明， 苯并（a）芘的突变抗性赋予突变交叉抗性 空气传播的强效诱变剂环戊[c，d]芘二是 发现另一种强有力的空气诱变剂萘并（a）芘诱导 对突变的抗性，其时间依赖性模式类似于 苯并（a）芘。最后，我们发现了源自AHH-1的人类细胞系 在短时间内对空气样品提取物的突变非常敏感 长期高剂量条件下使用一个有用的模式，为拟议的长期 样品、源样品及其提取物的剂量模拟条件 和亚组分在这些人体细胞上的作用 更接近暴露条件的条件， 人支气管树，（B）发现其“突变抗性状态” 是由暴露于未加工的空气颗粒， 和颗粒提取物亚组分，和（c.）进行适当 在细胞和分子水平上研究这一过程。