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

我们发现，当我们的人类细胞系AHH-1，它表达 细胞色素P-450 1A1持续暴露于低浓度的 有效的空气传播诱变剂，如苯并(A)芘和萘(A)芘 它们在5天后从高突变率转变为低突变率。 这种低突变率只比我们看到的高出三倍左右。 同时未处理的对照人群中的自发突变。研究对象： 放射性苯并(A)芘表明DNA加合物的形成速率为 这一现象没有改变。相对突变率的比率 到恒定的DNA加入率的变化是四倍 提示DNA后加成过程的诱导，如DNA修复 发生的。 因为这种现象如果发生在体内，将代表着一种重大的 防止机载诱变的生理反应 毒药。到目前为止，我们的研究证实了 苯并(A)芘的突变抗性使人对突变产生交叉抗性 由强大的空气传播诱变剂环戊二烯[c，d]芘。其次，我们有 发现另一种有效的空气传播诱变剂--萘并(A)芘 对突变的抗性具有时间依赖性，类似于 苯并(A)芘。最后，我们发现了来自AHH-1的人类细胞系 在短时间内用空气样品提取液对诱变明显敏感 长期高剂量条件为建议的长期使用提供了一种有用的模式 样品、源样品及其提取物的剂量模拟条件 在这些长期的低剂量下，这些人类细胞上的亚组分 更接近暴露条件的条件 人类的细支气管树，(B)发现它处于“抗突变状态” 是由暴露在原始空气颗粒物中，由颗粒物提取物引起的 和颗粒提取物亚组分，以及(c.)开展适当的 在细胞和分子水平上研究这一过程。

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.