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Sodium Arsenite Disturbs Mitosis and Induces Chromosome Loss in Human Fibroblasts¹

Institute of Biomedical Sciences, Academic Sinica, Taipei 115 [L. H. Y., I. C. H., T-C. L.], and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 107 [L. H. Y.], Taiwan, Republic of China

Arsenite, a unique human carcinogen, induces many types of cytogenetic alterations, such as sister chromatid exchanges, chromosome aberrations, and endoreduplication in a variety of in vivo and in vitro systems. Cytogenetic alterations are frequently associated with cancer development. The purpose of this study was to explore how arsenite induces cytogenetic alterations in human skin fibroblasts (HFW). The present results show that treatment of G₂-enriched HFW cells with 5 µM arsenite results in significant delay of cell cycle progression, accumulation of mitotic cells, and prolongation of mitosis. Arsenite-induced G₂ and mitotic delay are accompanied by accumulation of cyclin B1 and hyperphosphorylation of cdc2 and Mos proteins. In addition to mitotic delay and prolongation, arsenite treatment also induced out-of-phase centromere separation and alterations of chromosome segregation, such as the appearance of c-metaphase, ball-metaphase, and lagged chromosomes. Unlike spindle poisons, arsenite at the dose range used did not inhibit the spindle fiber formation but conceivably deranges the spindle apparatus. By analyzing the karyotype of established subclones surviving arsenite injury, 18% (8 of 44) showed one chromosome loss, whereas all 26 subclones derived from the untreated cultures were diploid. Furthermore, most arsenite-treated clones manifest prolonged life span (86 ± 18 population doublings) as compared to those derived from the untreated cultures (44 ± 11 population doublings). Unfortunately, none became immortal. Collectively, treatment of the G₂-enriched HFW cells with arsenite can disturb the mitotic events and subsequently induce chromosome loss.

¹ This work was supported by Academia Sinica and a grant from the National Science Council, Republic of China.

² To whom requests for reprints should be addressed. Phone: 886-2-7899014; Fax: 886-2-7825573; E-mail: bmtcl@ibms.sinica.edu.tw.

Received 12/ 2/96. Accepted 9/19/97.

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