ROLE OF MUTAGENESIS IN CARCINOGENESIS

大多数化学致癌物诱导DNA损伤， 特定的遗传位点;然而，某些致癌物质（包括人类 致癌物己烯雌酚（DES）、石棉、砷和苯） 通常不会引起基因突变。 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， DES与其诱导染色体数目变化的能力有关， 也就是说，非整倍性 目前，DES诱导的非整倍体正在研究中 在新生小鼠的生殖道，以测试这些变化是否发生 在体内的靶组织中。 另一个重要的机制 人类致癌物石棉也被检测。 我们建议 石棉由于其诱导细胞转化的能力而诱导细胞转化， 染色体变化。 我们发现了一种可能是新颖的 癌基因在人类间皮瘤，目前我们正在克隆这个 基因亚砷酸钠和砷酸钠作为基因是失活的 诱变剂，但细胞转化的有效诱导剂，但是一个弱 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，并表明 致癌物诱导非整倍体在肿瘤发生中的重要作用。 邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种常用的增塑剂， 过氧化物酶体增殖在肝细胞和肝癌中的作用 啮齿动物 我们已经证明，DEHP诱导形态学 转化、染色体畸变和过氧化物酶体增殖 叙利亚仓鼠胚胎（SHE）细胞。 转型 DEHP引起的染色体畸变频率和染色体畸变在 存在大鼠肝线粒体后上清液。 结果 表明DEHP代谢物可能涉及遗传损伤 诱导SHE细胞转化。 无明确关系 诱导过氧化物酶体增殖和细胞转化之间的关系 观察了

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.