The ability of 17 beta-estradiol to induce morphological transformation of Syrian hamster embryo cells was examined and dose-dependent increases were observed over the concentration range of 1-10 micrograms/ml. However, treatment of the cells with 17 beta-estradiol failed to induce any detectable increases in gene mutations, chromosome aberrations, sister chromatid exchanges or unscheduled DNA synthesis. In contrast, over the dose range that was effective in inducing cell transformation, 17 beta-estradiol induced numerical chromosome changes (both chromosome gains and losses). These findings are similar to the reported observations with the synthetic estrogen, diethylstilbestrol, and support the hypothesis that aneuploidy induction is important in cell transformation and possibly carcinogenesis induced by estrogens.
Treatment of Syrian hamster embryo cells in culture with 0.01-0.1 micrograms/ml of colcemid for 48 h resulted in morphological and neoplastic transformation of the cells. Cell transformation was observed with doses which were non-cytotoxic and did not cause mitotic inhibition of the cells. Higher dose of colcemid (greater than 0.1 microgram/ml) resulted in mitotic inhibition of the cells and a significant loss of colony forming ability, but no increase in the frequency of morphological transformation. Treatment of the cells with transforming doses of colcemid did not result in any measurable induction of gene mutations or structural chromosome aberrations; however, numerical chromosome changes in the treated cells were observed. A 14-fold increase in the number of aneuploid cells with a near diploid chromosome complement was found in cultures treated with 0.1 micrograms/ml colcemid and both chromosome loss and gain were induced. The dose response curves for colcemid induced morphological transformation and aneuploidy were similar. These results are consistent with a role of carcinogen-induced chromosome non-disjunction in carcinogenesis.
It was shown previously that diethylstilbestrol (DES) can induce morphological and neoplastic transformation of Syrian hamster embryo cells in culture in the absence of detectable gene mutations or DNA damage. However, in the presence of exogenous metabolic activation with rat liver post-mitochondrial supernatant, DES can induce unscheduled DNA synthesis. In this report we have examined whether with exogenous metabolic activation DES can also induce biological effects possibly related to its carcinogenicity, i.e. specific locus mutations in Syrian hamster embryo cells and cell transformation. We observed that DES was mutagenic only in the presence of exogenous metabolic activation. DES induced morphological transformation both in the absence and presence of exogenous metabolic activation. Enhanced cell transformation was observed in the presence of exogenous metabolic activation. These results indicate that two pathways may exist for the induction of cell transformation by DES. One does not apparently involve direct DNA damage, and the other, which requires rat liver post-mitochondrial supernatant-mediated exogenous metabolic activation, is associated with DNA damage and mutagenicity. These results may provide an experimental model to elucidate the biological properties of DES metabolites.
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