title: Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/β-catenin signaling pathway.
abstract: Exposure to carcinogenic metals, such as trivalent arsenic [As(III)] and hexavalent chromium [Cr(VI)], through drinking water is a major global public health problem and is associated with various cancers. However, the mechanism of their carcinogenicity remains unclear. In this study, we used azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse colitis-associated colorectal cancer model to investigate their tumorigenesis. Our results demonstrate that exposure to As(III) or Cr(VI), alone or in combination, together with AOM/DSS pretreatment has a promotion effect, increasing the colorectal tumor incidence, multiplicity, size, and grade, as well as cell inflammatory response. Two-dimensional differential gel electrophoresis coupled with mass spectrometry revealed that As(III) or Cr(VI) treatment alone significantly changed the density of proteins. The expression of β-catenin and phospho-GSK was increased by treatment of carcinogenic metals alone. Concomitantly, the expression of NADPH oxidase1 (NOX1) and the level of 8-OHdG were also increased by treatment of carcinogenic metals alone. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, were decreased. Similarly, in an in vitro system, exposure of CRL-1807 to carcinogenic metals increased reactive oxygen species (ROS) generation, the expression of β-catenin, phospho-GSK, and NOX1. Inhibition of ROS generation by addition of SOD or catalase inhibited β-catenin expression and activity. Our study provides a new animal model to study the carcinogenicity of As(III) and Cr(VI) and suggests that As(III) and Cr(VI) promote colorectal cancer tumorigenesis, at least partly, through ROS-mediated Wnt/β-catenin signaling pathway.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Ardhendu K
authors.initials: AK
authors.lastname: Mandal
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saito
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Pulliam
authors.forename: Eun Y
authors.initials: EY
authors.lastname: Lee
authors.forename: Zun-Ji
authors.initials: ZJ
authors.lastname: Ke
authors.forename: Jian
authors.initials: J
authors.lastname: Lu
authors.forename: Songze
authors.initials: S
authors.lastname: Ding
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Shelton
authors.forename: Thomas
authors.initials: T
authors.lastname: Tucker
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001151:Arsenic / Q000633:toxicity*; D001397:Azoxymethane / Q000633:toxicity; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002460:Cell Line; D002857:Chromium / Q000633:toxicity*; D003092:Colitis / Q000150:complications; D015179:Colorectal Neoplasms / Q000209:etiology*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D060766:Drinking Water / Q000737:chemistry; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000975:Antioxidants; D002274:Carcinogens, Environmental; D060766:Drinking Water; D017382:Reactive Oxygen Species; D014874:Water Pollutants, Chemical; D002857:Chromium; C074702:chromium hexavalent ion; D016264:Dextran Sulfate; D001397:Azoxymethane; D001151:Arsenic