ROLE OF MUTAGENESIS IN CARCINOGENESIS

诱变在致癌过程中的作用

• 批准号: 3841062
• 负责人: J C BARRETT
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3841062
• 关键词: DNA damage; aneuploidy; arsenic; asbestos; cell transformation; chemical carcinogen; chemical carcinogenesis; chromosome aberrations; cytogenetics; diethylhexylphthalate; diethylstilbestrol; embryo /fetus tissue /cell culture; gene mutation; hepatotoxin; human genetic material tag; human tissue; laboratory mouse; mesothelioma; molecular cloning; molecular oncology; mutagens; neoplasm /cancer genetics; neoplastic transformation; newborn animals; oncogenes; peroxisome

Most chemical carcinogens induce DNA damage and are mutagenic at specific genetic loci; however, certain carcinogens (including the human carcinogens diethylstilbestrol (DES), asbestos, arsenicals and benzene) usually do not induce gene mutations. We have examined the ability of these chemicals to induce morphological transformation, gene mutations and chromosome mutations in Syrian hamster embryo (SHE) cells in culture. We have previously proposed that the mechanism of action of DES is related to its ability to induce numerical chromosome changes, i.e., aneuploidy. Currently, DES-induced aneuploidy is being examined in the newborn mouse genital tract to test whether these changes occur in vivo in the target tissue. The mechanism of another important human carcinogen, asbestos, was also examined. We have proposed that asbestos induces cell transformation due to its ability to induce chromosomal changes. We have identified a possibly novel transforming oncogene in human mesotheliomas, and currently we are cloning this gene. Sodium arsenite and sodium arsenate are inactive as gene mutagens but are potent inducers of cell transformation but is a weak gene mutagen. This chemical is a very effective inducer of aneuploidy in this system. These results further support our hypothesis that cell transformation involves a chromosomal mutation and suggest an important role for carcinogen-induced aneuploidy in carcinogenesis. Di(2- ethylhexyl)phthalate (DEHP), a commonly used plasticizer, induces peroxisome proliferation n liver cells and hepatocellular carcinomas in rodents. We have shown that DEHP induces morphological transformation, chromosome aberrations, and peroxisome proliferations of cultured Syrian hamster embryo (SHE) cells. The transformation frequency and chromosomal aberrations of DEHP was enhanced in the presence of rat live post- mitochondrial supernatant. The results suggest a possible invovement of genetic damage by DEHP metabolites in the induction of transformation of SHE cells. No clear relationship between induction of peroxisome proliferation and cell transformation was observed.

大多数化学致癌物会诱导DNA损伤，并且在特定的 遗传基因座；但是，某些致癌物（包括人类致癌物 二乙基苯甲酸酯（DES），石棉，砷和苯）通常不 诱导基因突变。 我们已经检查了这些化学物质的能力 诱导形态转化，基因突变和染色体 叙利亚仓鼠胚胎（SHE）细胞中的突变。 我们有 以前提出的是，DES的作用机理与它的作用机理有关 能够诱导数字染色体变化的能力，即非整倍性。 目前，正在新生小鼠中检查了DES诱导的非整倍性 生殖道测试这些变化是否发生在靶标的体内 组织。 另一个重要人类致癌石棉的机制是 也检查了。 我们提出的石棉诱导细胞转化 由于它能够诱导染色体变化。 我们已经确定了 可能在人间皮瘤中转化癌基，目前 我们正在克隆这个基因。 砷酸钠和砷酸钠是不活跃的 作为基因诱变剂，但是细胞转化的有效诱导剂，但是 弱基因诱变剂。 该化学物质是非整倍性的非常有效的诱导剂 在这个系统中。 这些结果进一步支持了我们的假设 转化涉及染色体突变，并提出一个重要的 致癌物诱导的非整倍性在癌变中的作用。 di（2- 常用增塑剂苯甲酸乙二醇酯（DEHP）诱导 过氧化物酶体增殖N肝细胞和肝细胞癌 啮齿动物。 我们已经表明，DEHP诱导形态转化， 培养叙利亚人的染色体畸变和过氧化物酶体增殖 仓鼠胚胎（SHE）细胞。 转化频率和染色体 在大鼠现场存在后，DEHP的畸变得到了增强。 线粒体上清液。 结果表明可能有 DEHP代谢产物的遗传损害在诱导转化中 她牢房。 诱导过氧化物酶体之间没有明确的关系 观察到增殖和细胞转化。