title: Hexavalent chromium induces chromosome instability in human urothelial cells.
abstract: Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants. However, the impact of hexavalent chromium (Cr(VI)) on bladder cells has not been studied. We compared chromate toxicity in two bladder cell lines; primary human urothelial cells and hTERT-immortalized human urothelial cells. Cr(VI) induced a concentration- and time-dependent increase in chromosome damage in both cell lines, with the hTERT-immortalized cells exhibiting more chromosome damage than the primary cells. Chronic exposure to Cr(VI) also induced a concentration-dependent increase in aneuploid metaphases in both cell lines which was not observed after a 24h exposure. Aneuploidy induction was higher in the hTERT-immortalized cells. When we correct for uptake, Cr(VI) induces a similar amount of chromosome damage and aneuploidy suggesting that the differences in Cr(VI) sensitivity between the two cells lines were due to differences in uptake. The increase in chromosome instability after chronic chromate treatment suggests this may be a mechanism for chromate-induced bladder cancer, specifically, and may be a mechanism for metal-induced bladder cancer, in general.
authors.affiliation: Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Science, University of Southern Maine, Science Building, 96 Falmouth Street, Portland, ME 04103, USA.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Wise
authors.affiliation: Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Science, University of Southern Maine, Science Building, 96 Falmouth Street, Portland, ME 04103, USA; Department of Radiation Oncology, Dana Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, USA.
authors.forename: Amie L
authors.initials: AL
authors.lastname: Holmes
authors.affiliation: Department of Pathology, Boston University School of Medicine, 670 Albany St., Boston, MA 02118, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Liou
authors.affiliation: Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Adam
authors.affiliation: Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Science, University of Southern Maine, Science Building, 96 Falmouth Street, Portland, ME 04103, USA. Electronic address: john.wise@louisville.edu.
authors.forename: John Pierce
authors.initials: JP
authors.lastname: Wise
mesh_terms: D002478:Cells, Cultured; D002857:Chromium / Q000633:toxicity*; D043171:Chromosomal Instability / Q000187:drug effects* / Q000502:physiology*; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006801:Humans; D019459:Urothelium / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*
chemical_list: D002857:Chromium; C074702:chromium hexavalent ion
keywords: Aneuploidy; Bladder cancer; Chromate; Chromium; Genotoxicity; Urothelial