title: The benzene metabolite, hydroquinone and etoposide both induce endoreduplication in human lymphoblastoid TK6 cells.
abstract: 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 microM) and etoposide (0-0.2 microM) 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 (P(trend) < 0.0001 and P(trend) = 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) (P(trend) = 0.0415 and P(trend) < 0.0001, respectively). Etoposide potently induced all these structural changes (P(trend) < 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.
authors.affiliation: Department of Environmental Health Sciences, University of California, Berkeley, 94720, USA.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Ji
authors.forename: Luoping
authors.initials: L
authors.lastname: Zhang
authors.forename: Weihong
authors.initials: W
authors.lastname: Guo
authors.forename: Cliona M
authors.initials: CM
authors.lastname: McHale
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
mesh_terms: D001554:Benzene / Q000633:toxicity; D045744:Cell Line, Tumor; D002875:Chromosomes / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000633:toxicity*; D023281:Genomics; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects*; D008677:Metaphase; D009152:Mutagenicity Tests / Q000379:methods*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D059005:Topoisomerase II Inhibitors
chemical_list: D006873:Hydroquinones; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D001554:Benzene; C031927:hydroquinone