Abstract 3102: Hexavalent chromium induces chromosome instability leading to DNA double strand break repair deficiency and neoplastic transformation

Abstract

Abstract Chromosome instability (CIN) is a hallmark of lung cancer with cells exhibiting both translocations and aneuploidy. Hexavalent chromium (Cr(VI)) is a well known respiratory carcinogen. The ability of Cr(VI) to induce chromosomal translocations is unknown. We exposed human lung cells to lead chromate for three sequential 24 h periods, each separated by about a month. After each treatment, cells were seeded at colony forming density, cloned, expanded and retreated. Each generation of clones was tested for chromium sensitivity, chromosome complement, ability to repair DNA double strand breaks (DSB), and growth in soft agar. We found that after the first treatment, lead chromate-treated cells exhibited a normal chromosome complement though a few clones showed a decrease in cell survival. After the second exposure, more than half of the clones acquired an abnormal karyotype including numerical and structural changes. The third treatment resulted in additional abnormal clones as well as previously abnormal clones acquiring more abnormalities. Clones were treated with soluble Cr(VI) for 24 h followed by a 24 h recovery period to measure DNA DSB repair. Abnormal clones showed persistent H2A.X and 53BP1 foci formation after 24 h recovery suggesting that these clones had acquired a DNA DSB repair-deficient phenotype. In addition, clones from the third generation were able to form colonies in soft agar suggesting that the cells have neoplastically transformed. This work was supported by NIEHS grant ES016893 (J.P.W.) and the Maine Center for Toxicology and Environmental Health. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3102. doi:1538-7445.AM2012-3102