Abstract
We investigated the effect of zinc on the formation of colonic aberrant crypt foci induced by azoxymethane (AOM) followed by dextran sodium sulfate (DSS) in mice with high iron diet (HFe; 450 ppm iron). Sixweek old ICR mice were fed on high iron diets with combination of three different levels of zinc in diets, low-zinc (LZn; 0.01 ppm), medium-zinc (MZn; 0.1 ppm), and high-zinc (HZn; 1 ppm) for 12 weeks. Animals were received weekly intraperitoneal injections of AOM (10 mg/kg B.W. in saline) for 3 weeks followed by 2% DSS (molecular weight 36,000~50,000) in the drinking water for a week. To confirm the iron storage in the body, the hepatic iron concentration has been determine chemically and compared with histological assessment visualized by Prussian blue reaction. Aberrant crypt (AC) and aberrant crypt foci (ACF) were analyzed in the colonic mucosa of mouse fed high dietary iron. Superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBARS) level were also investigated. Apoptosis in the preneoplastic lesion was determined by terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling (TUNEL). In addition, immunohistochemistry of β-catenin was also performed on the mucous membrane of colon. The number of large ACF (≥4 AC/ACF), which possess greater tumorigenic potential, was significantly lower in MZn and HZn groups compared with LZn group. Cytosolic SOD activity in the liver was significantly higher in HZn group compared with LZn group. Hepatic MDA level was decreased significantly in HZn group compared with MZn and LZn groups. Apoptotic index was significantly higher in HZn group. Taken together, these findings indicate that dietary zinc might exert a protective effect against colonic preneoplastic lesion induced by AOM/DSS in ICR mice with high iron status, and suggest that dietary supplement of zinc might play a role in suppressing colon carcinogenesis in mice.
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Bartsch, H. and Nair, J. (2002). Potential role of lipid peroxidation derived DNA damage in human colon carcinogenesis: studies on exocyclic base adducts as stable oxidative stress markers. Cancer Detect. Prev., 26, 308–312.
Bettger, W.J., Reeves, P.G., Savage, J.E. and O’Dell, B.L. (1980). Interaction of zinc and vitamin E in the chick. Proc. Soc. Exp. Biol. Med., 163, 432–436.
Bird, R.P. (1998). Aberrant crypt foci system to study cancer preventive agents in the colon. In Tumor Marker Protocols. (M. Hanausek and Z. Walaszek Eds.). Humana Press, Totowa, pp. 465–474.
Bird, R.P. (1987). Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett., 37, 147–151.
Chang, W.W. (1984). Histogenesis of colon cancer in experimental animals. Scand. J. Gastroenterol. Suppl., 104, 27–43.
Corpet, D.E. and Pierre, F. (2005). How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men. Eur. J. Cancer, 41, 1911–1922.
Dani, V., Goel, A., Vaiphei, K. and Dhawan, D.K. (2007). Chemopreventive potential of zinc in experimentally induced colon carcinogenesis. Toxicol. Lett., 171, 10–18.
Davis, C.D. and Feng, Y. (1999). Dietary copper, manganese and iron affect the formation of aberrant crypts in colon of rats administered 3,2’-dimethyl-4-aminobiphenyl. J. Nutr., 129, 1060–1067.
Doll, R. and Peto, R. (1981). The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Natl. Cancer Inst., 66, 1191–1308.
Evans, P. and Halliwell, B. (2001). Micronutrients: oxidant/antioxidant status. Br. J. Nutr., 85 Suppl 2, S67–74.
Feron, V.J., Til, H.P., de Vrijer, F., Woutersen, R.A., Cassee, F.R. and van Bladeren, P.J. (1991). Aldehydes: occurrence, carcinogenic potential, mechanism of action and risk assessment. Mutat. Res., 259, 363–385.
Gavrieli, Y., Sherman, Y. and Ben-Sasson, S.A. (1992). Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol., 119, 493–501.
Grasl-Kraupp, B., Ruttkay-Nedecky, B., Koudelka, H., Bukowska, K., Bursch, W. and Schulte-Hermann, R. (1995). In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology, 21, 1465–1468.
Halliwell, B. and Gutteridge, J.M.C. (1989). Protection against oxidants in biological systems: The superoxide theory of oxygen toxicity. In Free Radicals in Biology and Medicine. (B. Halliwell and J.M.C. Gutteridge Eds.). Clarendon Press, Oxford, pp. 86–179.
Hann, H.W., Stahlhut, M.W. and Blumberg, B.S. (1988). Iron nutrition and tumor growth: decreased tumor growth in irondeficient mice. Cancer Res., 48, 4168–4170.
Hata, K., Yamada, Y., Kuno, T., Hirose, Y., Hara, A., Qiang, S.H. and Mori, H. (2004). Tumor formation is correlated with expression of beta-catenin-accumulated crypts in azoxymethaneinduced colon carcinogenesis in mice. Cancer Sci., 95, 316–320.
Hirose, Y., Kuno, T., Yamada, Y., Sakata, K., Katayama, M., Yoshida, K., Qiao, Z., Hata, K., Yoshimi, N. and Mori, H. (2003). Azoxymethane-induced beta-catenin-accumulated crypts in colonic mucosa of rodents as an intermediate biomarker for colon carcinogenesis. Carcinogenesis, 24, 107–111.
Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E. and Forman, D. (2011). Global cancer statistics. CA. Cancer J. Clin., 61, 69–90.
Kobayashi, M., Honma, T., Matsuda, Y., Suzuki, Y., Narisawa, R., Ajioka, Y. and Asakura, H. (2000). Nuclear translocation of beta-catenin in colorectal cancer. Br. J. Cancer, 82, 1689–1693.
Korea National Statistical Office (2011). Death and cause of death statistics 2010, KNSO, Daejeon.
Lee, D.H., Anderson, K.E., Harnack, L.J., Folsom, A.R. and Jacobs, D.R., Jr. (2004). Heme iron, zinc, alcohol consumption, and colon cancer: Iowa Women’s Health Study. J. Natl. Cancer Inst., 96, 403–407.
McLellan, E.A. and Bird, R.P. (1988). Aberrant crypts: potential preneoplastic lesions in the murine colon. Cancer Res., 48, 6187–6192.
McLellan, E.A., Medline, A. and Bird, R.P. (1991). Dose response and proliferative characteristics of aberrant crypt foci: putative preneoplastic lesions in rat colon. Carcinogenesis, 12, 2093–2098.
Miller, J.R. and Moon, R.T. (1996). Signal transduction through beta-catenin and specification of cell fate during embryogenesis. Genes Dev., 10, 2527–2539.
Mori, H., Yamada, Y., Kuno, T. and Hirose, Y. (2004). Aberrant crypt foci and beta-catenin accumulated crypts; significance and roles for colorectal carcinogenesis. Mutat. Res., 566, 191–208.
Perse, M. and Cerar, A. (2011). Morphological and molecular alterations in 1,2 dimethylhydrazine and azoxymethane induced colon carcinogenesis in rats. J. Biomed. Biotechnol., 2011, 473964.
Rael, L.T., Thomas, G.W., Craun, M.L., Curtis, C.G., Bar-Or, R. and Bar-Or, D. (2004). Lipid peroxidation and the thiobarbituric acid assay: standardization of the assay when using saturated and unsaturated fatty acids. J. Biochem. Mol. Biol., 37, 749–752.
Rosenberg, D.W., Giardina, C. and Tanaka, T. (2009). Mouse models for the study of colon carcinogenesis. Carcinogenesis, 30, 183–196.
Ross, J.S. (1981). Experimental large intestinal adenocarcinoma induced by hydrazine and human colorectal cancer: a comparative study. In Colonic Carcinogenesis. (R.A. Malt and R.N. Williamson Eds.). MTP Press Limited, Lancaster, Boston, The Hague, pp. 187–207.
Schrauzer, G.N. (1977). Trace elements, nutrition and cancer: perspectives of prevention. Adv. Exp. Med. Biol., 91, 323–344.
Sky-Peck, H.H. (1986). Trace metals and neoplasia. Clin. Physiol. Biochem., 4, 99–111.
Stevens, R.G. and Kalkwarf, D.R. (1990). Iron, radiation, and cancer. Environ. Health Perspect., 87, 291–300.
Stohs, S.J. and Bagchi, D. (1995). Oxidative mechanisms in the toxicity of metal ions. Free Radic. Biol. Med., 18, 321–336.
Sun, J.Y., Jing, M.Y., Weng, X.Y., Fu, L.J., Xu, Z.R., Zi, N.T. and Wang, J.F. (2005). Effects of dietary zinc levels on the activities of enzymes, weights of organs, and the concentrations of zinc and copper in growing rats. Biol. Trace Elem. Res., 107, 153–165.
Takahashi, M., Fukuda, K., Sugimura, T. and Wakabayashi, K. (1998). Beta-catenin is frequently mutated and demonstrates altered cellular location in azoxymethane-induced rat colon tumors. Cancer Res., 58, 42–46.
Tanaka, T., de Azevedo, M.B., Duran, N., Alderete, J.B., Epifano, F., Genovese, S., Tanaka, M. and Curini, M. (2010). Colorectal cancer chemoprevention by 2 beta-cyclodextrin inclusion compounds of auraptene and 4’-geranyloxyferulic acid. Int. J. Cancer, 126, 830–840.
Tanaka, T., Kohno, H., Suzuki, R., Yamada, Y., Sugie, S. and Mori, H. (2003). A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci., 94, 965–973.
Wurzelmann, J.I., Silver, A., Schreinemachers, D.M., Sandler, R.S. and Everson, R.B. (1996). Iron intake and the risk of colorectal cancer. Cancer Epidemiol. Biomarkers Prev., 5, 503–507.
Yamada, Y., Yoshimi, N., Hirose, Y., Kawabata, K., Matsunaga, K., Shimizu, M., Hara, A. and Mori, H. (2000). Frequent betacatenin gene mutations and accumulations of the protein in the putative preneoplastic lesions lacking macroscopic aberrant crypt foci appearance, in rat colon carcinogenesis. Cancer Res., 60, 3323–3327.
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Park, H., Kang, B.S., Kim, D.Y. et al. Suppressive Effect of Zinc on the Formation of Colonic Preneoplastic Lesions in the Mouse Fed High Levels of Dietary Iron. Toxicol Res. 28, 39–49 (2012). https://doi.org/10.5487/TR.2012.28.1.039
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DOI: https://doi.org/10.5487/TR.2012.28.1.039