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Aneuploidy Induction and Cell Transformation by Diethylstilbestrol: A Possible Chromosomal Mechanism in Carcinogenesis

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [J. A. M., J. C. B.], and Nippon Dental University Tokyo, 1-9-20 Fujimi, Chiyoda-ku, Tokyo, Japan [T. T., H. M.]

Diethylstilbestrol (DES) has been demonstrated previously to induce morphological and neoplastic transformation of Syrian hamster embryo cells in the absence of any measurable induction of gene mutation. To determine if DES induces cell transformation by a genetic mechanism at the chromosomal level, the effect of DES on structural aberrations and numerical chromosome changes was examined in asynchronous and synchronized cells. Over the concentration range which is optimal for cell transformation, DES failed to induce any increase in chromosome aberrations in the cells. In contrast, significant numerical chromosome changes were observed in DES-treated cultures. The percentage of metaphases with a near diploid chromosome number increased to 19% at 48 hr after treatment. By comparison, cells from control cultures contained only 1 to 2% aneuploid metaphases with a near diploid chromosome number. No significant increase in the number of metaphases with a near tetraploid number (>70) of chromosomes was observed in the DES-treated cultures. DES induced both chromosome loss and gain, and no significant difference was detected between the number of hyperdiploid and hypodiploid cells. Chromosome loss or gain was observed for chromosomes in each karyotype group. These findings suggest that DES induces chromosome nondisjunction. Synchronized cell cultures were obtained by first growing the cells in 1% serum and then in 10% serum with hydroxyurea which blocked the cells at the G₁-S border. Upon release of the hydroxyurea block, the cells entered into S phase in a very synchronous manner. The cells were treated for 3 hr during one of four time periods after hydroxyurea release. During the first period, the cells were primarily in early S phase, while the second period included cells in late S phase. During the third period most of the cells were undergoing mitosis, while in the fourth period most of the cells were in G1 phase, although some mitotic cells were observed. Treatment of the synchronized cells with DES during early or late S phase resulted in little morphological transformation. However, treatment during the third period, when the majority of the cells were in mitosis, resulted in a peak of transformation which was 15 times the level observed in cultures treated in early or late S phase. Treatment during the fourth time period resulted in a reduced level of cell transformation. Treatment of synchronized cultures with DES resulted also in a cell cycle-dependent induction of aneuploid cells which paralleled the induction of cell transformation, with the greatest level observed following treatment during mitosis. No increase in the percentage of polyploid metaphases or chromosome aberrations was observed in the DES-treated synchronized cells. Parallel dose-response curves for cell transformation and aneuploidy induction by DES were observed when the synchronized cultures were treated during the mitotic phase of the cell cycle. Possible mechanisms for DES-induced aneuploidy and the evidence supporting a role for nonrandom numerical chromosome changes in neoplastic development, as well as significance of aneuploidy in cancer, are discussed.

¹ To whom requests for reprints should be addressed, at National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, N. C. 27709.

Received 10/ 6/82. Accepted 5/ 3/83.

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