ROLE OF MUTAGENESIS IN CARCINOGENESIS

诱变在致癌过程中的作用

• 批准号: 3755413
• 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/3755413
• 关键词: DNA damage; DNA repair; aneuploidy; animal tissue; arsenic; asbestos; chemical carcinogen; chemical carcinogenesis; chromosome aberrations; diethylstilbestrol; embryo /fetus tissue /cell culture; gene mutation; human tissue; laboratory mouse; molecular oncology; mutagens; neoplasm /cancer genetics; neoplastic transformation; oncogenes; peroxisome; reserpine; 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引起 DNA 损伤，并且在以下情况下具有致突变性： 特定的基因位点；然而，某些致癌物（包括人类 致癌物己烯雌酚（DES）、石棉、砷和苯） 通常不会诱发基因突变。 我们考察了以下人员的能力 这些化学物质诱导形态转变、基因突变 以及叙利亚仓鼠胚胎（SHE）细胞中的染色体突变 文化。 我们之前已经提出了作用机制 DES 与其诱导染色体数量变化的能力有关， 即非整倍体。 目前，DES 诱导的非整倍性正在接受检查 在新生小鼠生殖道中测试这些变化是否发生 体内靶组织中。 另一个重要的机制 还对人类致癌物石棉进行了检查。 我们已提议 石棉因其诱导细胞转化的能力而诱导细胞转化 染色体变化。 我们已经确定了一种可能新颖的转变 人类间皮瘤中的癌基因，目前我们正在克隆该基因 基因。亚砷酸钠和砷酸钠作为基因无活性 诱变剂，但是细胞转化的有效诱导剂，但作用较弱 基因诱变剂。 这种化学物质是一种非常有效的非整倍体诱导剂 在这个系统中。 这些结果进一步支持了我们的假设，即细胞 转化涉及染色体突变并表明 致癌物诱导的非整倍体在致癌过程中发挥重要作用。 邻苯二甲酸二(2-乙基己基)酯 (DEHP) 是一种常用的增塑剂，可诱导 肝细胞和肝细胞癌中过氧化物酶体的增殖 啮齿动物。 我们已经证明 DEHP 会诱导形态学 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。 转变 DEHP 的频率和染色体畸变在 大鼠肝脏线粒体后上清液的存在。 结果 表明 DEHP 代谢物可能涉及遗传损伤 诱导SHE细胞转化。 没有明确的关系 诱导过氧化物酶体增殖和细胞转化之间 被观察到。