ROLE OF MUTAGENESIS IN CARCINOGENESIS

大多数化学致癌物都会导致DNA损伤，并在 特定的遗传位点；然而，某些致癌物质(包括人类 致癌物质己烯雌酚(DES)、石棉、砷和苯) 通常不会导致基因突变。我们已经检查了 这些化学物质可以诱导形态转化、基因突变 和叙利亚仓鼠胚胎(SHE)细胞的染色体突变 文化。我们此前曾提出， DES与其诱导染色体数目变化的能力有关， 即非整倍体。目前，正在检测Des诱导的非整倍体。 在新生小鼠生殖道中测试这些变化是否发生 在体内的靶组织中。另一个重要的机制是 人类致癌物质石棉也进行了检测。我们已经提议 石棉因其诱导能力而诱导细胞转化 染色体的变化。我们发现了一种可能的新奇转变 人类间皮瘤的癌基因，目前我们正在克隆这一基因 吉恩。亚砷酸钠和亚砷酸钠作为基因失活 诱变剂是细胞转化的有效诱导剂，但它是一种弱诱变剂 基因诱变剂。这种化学物质是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 转化涉及一种染色体突变，并暗示 致癌物诱导的非整倍体在癌变中的重要作用。 常用增塑剂邻苯二甲酸二(2-乙基己基)酯(DEHP) 大鼠肝细胞和肝细胞癌组织中过氧化物酶的增殖 啮齿动物。我们已经证明了DEHP诱导了形态 转化、染色体异常和过氧化物酶增殖体 培养的叙利亚仓鼠胚胎(SHE)细胞。转型 DEHP的频率和染色体畸变率在 大鼠肝脏线粒体后上清液的存在。结果是 提示DEHP代谢物可能参与了遗传损伤 在诱导SHE细胞转化中起重要作用。没有明确的关系 在诱导过氧化物酶体增殖和细胞转化之间 被观察到了。

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.