MUTAGENESIS--INTERACTION OF ENVIRONMENTAL CARCINOGENS

诱变——环境致癌物的相互作用

• 批准号: 6269394
• 负责人: Tom K. Hei
• 金额: $ 18.73万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6269394
• 关键词: DNA damage; alpha radiation; arsenic; cancer risk; chemical carcinogenesis; chromosomes; clinical research; clone cells; gene mutation; genetic mapping; genetic markers; human data; hybrid cells; hypoxanthine phosphoribosyltransferase; mutagen testing; neoplasm /cancer epidemiology; nitrosamines; particle accelerators; physical chemical interaction; polymerase chain reaction; radiation carcinogenesis; radiobiology; radiochemistry; southern blotting; tobacco

Assessment of the carcinogenic and mutagenic effects of two or more environmental agents in than predicted from the sum of risks of the individual agents. Epidemiological studies have shown that uranium miners exposed to high levels of alpha particles form radon progeny show the largest number of radiation induced lung cancers found in any exposed population. Studies designed to identify a link between lung cancer and radon levels in homes have resulted in equivocal conclusions. With the availability of the microbeam facility at the Radiological Research Accelerator Facility, the first objective of this proposal is to examine both the quantitative mutagenic yield and the spectrum of mutations by either a single or a defined number of alpha particle traversals, where this low dose exposure is more consistent with domestic experience. While cigarette smoke remains the single most important modulator in lung cancer incidence among uranium and other miners, recent epidemiological studies have also identified the compounding effect of arsenite in the etiology of radon-induced lung cancer in miners. The second objective, then, is to examine the combined mutagenic effects of alpha particles from radon progeny with either tobacco smoke nitrosamines (NNK) or sodium arsenite. Specifically, the quantitative mutagenic data will be used tin assessing the mode of interaction between radon and these two environmental pollutants. The molecular spectrum will be used to ascertain qualitatively the presence or absence of specific signature changes at the gene level. Mutation will be scored at both the S1 and HGPRT loci using the human- hamster hybrid AL cells. To compare the mutagenic effects with in vivo target tissues, the frequencies and types of mutations induced by alpha particles either alone or in combination with NNK will also be examined using primary human bronchial epithelial cells. The AL cell line contains only one copy of human chromosome II and mutations on marker genes located on this chromosome can be readily scored using an antibody complement lysis technique. By using specific DNA probes of other genes that have been regionally mapped to various site on chromosome II, the molecular mechanisms of mutation in AL cells will also be examined. Because of the demonstrated sensitivity of the AL cell mutagenic system, it will be possible to examine the effects of low level exposure to radon progeny and/or chemicals that are quite impractical to detect in human epidemiological surveys, or indeed in most experimental animal systems.

评估两个或多个的致癌和诱变作用 环保代理比从风险之和 个体代理。 流行病学研究表明铀矿工 暴露于高水平的α颗粒形成ra radon后代的表明 在任何暴露中发现的最大辐射诱导肺癌 人口。 旨在确定肺癌与 房屋中的ra含量导致了模棱两可的结论。 与 放射学研究中微束设施的可用性 加速器设施，该提案的第一个目标是检查 定量诱变产率和突变的光谱 单个或定义数量的α粒子遍历，其中 这种低剂量的暴露与国内经验更一致。 尽管 香烟烟仍然是肺癌中最重要的调节剂 铀和其他矿工之间的发病率，最近的流行病学研究 还确定了砷在病因中的复合作用 ra诱导的矿工诱导的肺癌。 因此，第二个目标是 检查ra的α颗粒的诱变效应 后代，烟草烟雾硝胺（NNK）或砷酸钠。 具体而言，定量诱变数据将用于锡评估 ra和这两个环境之间的相互作用方式 污染物。 分子光谱将用于定性确定 在基因水平上存在特定的特定特征变化。 突变将在S1和HGPRT基因座上使用人类进行评分 仓鼠杂化Al细胞。 将诱变作用与体内进行比较 靶组织，α诱导的突变的频率和类型 粒子单独或与NNK结合也将被检查 使用原代人支气管上皮细胞。 Al细胞系包含 只有一个人类染色体II的副本和位于标记基因的突变 在此染色体上，可以使用抗体补体裂解很容易评分 技术。 通过使用其他已经是其他基因的特异性DNA探针 区域映射到分子II染色体II上的各个位点 还将检查Al细胞中突变的机制。 因为 证明了Al细胞诱变系统的灵敏度，它将是 可能检查低水平暴露于ra子后代的影响 和/或在人类中检测到非常不切实际的化学物质 流行病学调查，或实际上在大多数实验性动物系统中。