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

Journal Article · Sun Jul 01 04:00:00 EDT 2012 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2012.04.014· OSTI ID:22215343

Wang, Xin; Mandal, Ardhendu K. ^[1]; Saito, Hiroshi ^[2]; Pulliam, Joseph F.; Lee, Eun Y. ^[3]; Ke, Zun-Ji; Lu, Jian; Ding, Songze ^[1]; Li, Li ^[4]; Shelton, Brent J.; Tucker, Thomas ^[5]; Evers, B. Mark ^[2]; Zhang, Zhuo ^[1]; Shi, Xianglin ^[1]

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1. Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536 (United States)
2. Department of Surgery and Physiology, Lucille P. Markey Cancer Center, University of Kentucky, Lexington, KY 40536 (United States)
3. Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536 (United States)
4. Department of Family Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States)
5. Markey Cancer Control Program, University of Kentucky, Lexington, KY 40504 (United States)

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. -- Highlights: ► Carcinogenic metals in drinking water promote colorectal tumor formation in vivo. ► Carcinogenic metals induce β-catenin activation in vivo and in vitro. ► ROS generation induced by carcinogenic metals mediated β-catenin activation.

• OSTI ID: 22215343
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 262; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIOXIDANTS
ARSENIC
CARCINOGENS
CATALASE
CATTLE
CHROMIUM
DEXTRAN
DICHROMATES
DRINKING WATER
ELECTROPHORESIS
EOSIN
GELS
HEMATOXYLIN
IN VITRO
IN VIVO
INFLAMMATION
INHIBITION
MASS SPECTROSCOPY
MICE
NEOPLASMS
OXIDASES
PUBLIC HEALTH
SODIUM
SODIUM SULFATES
SUPEROXIDE DISMUTASE
TETRAZOLIUM