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.

大多数化学致癌物诱导DNA损伤，并在特定条件下具有诱变性。 遗传位点;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 诱导基因突变。 我们已经研究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）细胞培养中的突变。 我们有 以前提出DES的作用机制与其 诱导染色体数目变化的能力，即，非整倍性 目前，DES诱导的非整倍体正在新生小鼠中进行检查 生殖道，以测试这些变化是否发生在体内的目标 组织. 另一种重要的人类致癌物石棉的机制是 也检查了。 我们提出石棉诱导细胞转化 因为它能引起染色体变化 我们已经确定了一 可能是人类间皮瘤中新的转化癌基因，目前 我们正在克隆这个基因。 亚砷酸钠和砷酸钠不活泼 作为基因诱变剂，但也是细胞转化的有效诱导剂， 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， 转化涉及染色体突变，并提出了一个重要的 致癌物诱导的非整倍体在致癌作用中的作用。 二（2- 邻苯二甲酸乙基己酯（DEHP），一种常用的增塑剂， 过氧化物酶体增殖在肝细胞和肝细胞癌中的作用 啮齿动物 我们已经证明DEHP会引起形态转变， 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。 转化频率和染色体 DEHP的畸变在大鼠肝后存在的情况下增强， 线粒体上清液。 结果表明，可能涉及 DEHP代谢物在诱导转化中的遗传损伤 SHE细胞。 过氧化物酶体的诱导与 观察增殖和细胞转化。