Mutagenesis Advance Access originally published online on June 2, 2009
Mutagenesis 2009 24(4):367-372; doi:10.1093/mutage/gep018
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The benzene metabolite, hydroquinone and etoposide both induce endoreduplication in human lymphoblastoid TK6 cells
Department of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720, USA
Both occupational exposure to the leukemogen benzene and in vitro exposure to its metabolite hydroquinone (HQ) lead to the induction of numerical and structural chromosome changes. Several studies have shown that HQ can form DNA adducts, disrupt microtubule assembly and inhibit DNA topoisomerase II (topo II) activity. As these are potential mechanisms underlying endoreduplication (END), a phenomenon that involves DNA amplification without corresponding cell division, we hypothesized that HQ could cause END. We measured END in the human lymphoblastoid cell line, TK6, treated with HQ (0–20 µM) and etoposide (0–0.2 µM) for 48 h. Etoposide was used as a positive control as it is a topo II poison and established human leukemogen that has previously been shown to induce END in Chinese hamster ovary cells. Both HQ and etoposide significantly induced END in a dose-dependent manner (Ptrend < 0.0001 and Ptrend = 0.0003, respectively). Since END may underlie the acquisition of high chromosome numbers by tumour cells, it may play a role in inducing genomic instability and subsequent carcinogenesis from HQ and etoposide. In order to further explore the cytogenetic effects of HQ and etoposide, we also examined specific structural changes. HQ did not induce translocations of chromosome 11 [t(11;?)] but significantly induced translocations of chromosome 21 [t(21;?)] and structural chromosome aberrations (SCA) (Ptrend = 0.0415 and Ptrend < 0.0001, respectively). Etoposide potently induced all these structural changes (Ptrend < 0.0001). The lack of an effect of HQ on t(11;?) and the reduced ability of HQ to induce t(21;?) and SCA, compared with etoposide, further suggests that HQ acts primarily as a topo II catalytic inhibitor rather than as a topo II poison in intact human cells.
* To whom correspondence should be addressed. Martyn T. Smith, Division of Environmental Health Sciences, School of Public Health, Room 211, Hildebrand Hall, University of California at Berkeley, Berkeley, CA 94720-7360, USA. Tel: +1 510 642 8770; Fax: +1 510 642 0427; Email: martynts{at}berkeley.edu
Received on February 25, 2009; revised on April 9, 2009; accepted on April 24, 2009.