ROLE OF MUTAGENESIS IN CARCINOGENESIS

大多数化学致癌物会引起DNA损伤，并在特定的遗传位点上具有诱变性；然而，某些致癌物（包括人类致癌物己烯雌酚（DES）、石棉、砷、苯和睾酮）通常不会引起基因突变。我们研究了雌激素和抗雌激素诱导细胞转化和遗传效应的能力，用雌激素、17 -雌二醇（E2）或己烯雌酚（DES）或抗雌激素、他莫昔芬（TAM）、托瑞米芬（TOR）或ICI 164,384处理叙利亚仓鼠胚胎（SHE）细胞。每种化学物质在1-30uM下处理48小时后，SHE细胞的形态转变呈剂量相关。与其他抗雌激素（TAM和ICI 164,348）相比，TOR表现出更高的转化能力。在用任何化学物质处理的SHE细胞中，没有观察到染色体畸变频率的显著增加。然而，用每种化学物质处理SHE细胞诱导非整倍体细胞在接近二倍体范围内的剂量依赖性增加。我们的研究结果表明，雌激素和抗雌激素诱导数字染色体异常的能力可能与它们的细胞转化活性和潜在的致癌性有关。今年将是该项目的最后一年，该项目的组成部分将在项目# ES-23020中进行。- SHE细胞模型，雌激素，睾酮

Most chemical carcinogens induce DNA damage and are mutagenic at specific genetic loci; however, certain carcinogens (including the human carcinogens diethylstilbestrol (DES), asbestos, arsenicals, benzene and testosterone) usually do not induce gene mutations. We examined the ability of estrogens and anti-estrogens to induce cellular transformation and genetic effects, Syrian hamster embryo (SHE) cells were treated with estrogens, 17beta-estradiol (E2) or diethylstilbestrol (DES), or with anti-estrogens, tamoxifen (TAM), toremifene (TOR) or ICI 164,384. Treatment with each chemical at 1-30uM for 48 hrs caused morphological transformation of SHE cells in a dose related fashion. The highest frequency was exhibited in SHE cells treated with DES. TOR showed a higher transforming ability when compared to the other anti-estrogens (TAM and ICI 164,348). No significant increases in the frequencies of chromosomal aberrations were observed in SHE cells that were treated with any of the chemicals. However, treatment of SHE cells with each chemical induced a dose- dependent increase of aneuploid cells in the near diploid range. Our results indicate that the ability of the estrogens and anti-estrogens to induce numerical chromosomal abnormality may be involved in their cell transformation activity and potential carcinogenicity. This will be the final year for this project, components of this project will be conducted in project # ES-23020 in FY00. - SHE cell model, estrogen, testosterone