ROLE OF MUTAGENESIS IN CARCINOGENESIS

诱变在致癌过程中的作用

• 批准号: 3777496
• 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/3777496
• 关键词: DNA damage; aneuploidy; arsenic; asbestos; cell transformation; chemical carcinogen; chemical carcinogenesis; chromosome aberrations; diethylhexylphthalate; diethylstilbestrol; gene mutation; hepatocellular carcinoma; hepatotoxin; human tissue; laboratory mouse; mesothelioma; molecular cloning; molecular oncology; mutagens; neoplasm /cancer genetics; neoplastic transformation; newborn animals; oncogenes; peroxisome; tissue /cell culture

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 in 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 by DEHP was enhanced in the presence of rat liver post-mitochondrial supernatant. The results suggest a possible involvement 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，并且是诱变的 特定的遗传基因座；但是，某些致癌物（包括人类 致癌物二乙基甲虫（DES），石棉，砷和苯） 通常不会诱导基因突变。 我们已经检查了 这些化学物质诱导形态转化，基因突变 叙利亚仓鼠胚胎（SHE）细胞中的染色体突变 文化。 我们以前曾提出，作用机理 DES与其诱导数字染色体变化的能力有关， 即，非整倍性。 目前，正在检查DES诱导的非整倍性 在新生小鼠生殖道中以测试这些变化是否发生 靶组织中的体内。 另一个重要的机制 还检查了人类致癌物，石棉。 我们提出了 石棉由于能够诱导细胞的能力而诱导细胞转化 染色体变化。 我们已经确定了一个可能新颖的转变 人间皮瘤中的癌基因，目前我们正在克隆这个 基因。砷酸钠和砷酸钠无效作为基因 诱变剂，但是细胞转化的有效诱导剂，但很弱 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 致癌物诱导的非整倍性在癌变中的重要作用。 常用增塑剂DI（2-乙基己基）邻苯二甲酸酯（DEHP）诱导 肝细胞和肝细胞癌的过氧化物酶体增殖 啮齿动物。 我们已经表明DEHP诱导形态学 转化，染色体畸变和过氧化物酶体增殖 培养的叙利亚仓鼠胚胎（SHE）细胞。 转换 DEHP的频率和染色体畸变在 大鼠肝后的线粒体上清液的存在。 结果 提示DEHP代谢产物可能参与遗传损害 在诱导SHE细胞的转化中。 没有明确的关系 在诱导过氧化物酶体增殖与细胞转化之间 被观察到。