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High Dietary Intake of Sodium Selenite Does Not Affect Gene Mutation Frequency in Rat Colon and Liver

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Abstract

Our previous studies have shown that selenium (Se) is protective against dimethylhydrazine (DMH)-induced preneoplastic colon cancer lesions, and protection against DNA damage has been hypothesized to be one mechanism for the anticancer effect of Se. The present study was designed to determine whether dietary selenite affects somatic mutation frequency in vivo. We used the Big Blue transgenic model to evaluate the in vivo mutation frequency of the cII gene in rats fed either a Se-deficient (0 μg Se/g diet) or Se-supplemented diet (0.2 or 2 μg Se/g diet; n = 3 rats/diet in experiment 1 and n = 5 rats/group in experiment 2) and injected with DMH (25 mg/kg body weight, i.p.). There were no significant differences in body weight between the Se-deficient and Se-supplemented (0.2 or 2 μg Se/g diet) rats, but the activities of liver glutathione peroxidase and thioredoxin reductase and concentration of liver Se were significantly lower (p < 0.0001) in Se-deficient rats compared to rats supplemented with Se. We found no effect of dietary Se on liver 8-hydroxy-2′-deoxyguanosine. Gene mutation frequency was significantly lower in liver (p < 0.001) than that of colon regardless of dietary Se. However, there were no differences in gene mutation frequency in DNA from colon mucosa or liver from rats fed the Se-deficient diet compared to those fed the Se-supplemented (0.2 or 2 μg Se/g diet) diet. Although gene mutations have been implicated in the etiology of cancer, our data suggest that decreasing gene mutation is not likely a key mechanism through which dietary selenite exerts its anticancer action against DMH-induced preneoplastic colon cancer lesions in a Big Blue transgenic rat model.

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Abbreviations

ACF:

aberrant crypt foci

DMH:

dimethylhydrazine

GPx:

glutathione peroxidase

TR:

thioredoxin reductase

References

  1. C. B. Allan, G. M. Lacourciere, and T. C. Stadtman, Responsiveness of selenoproteins to dietary selenium, Annu Rev Nutr 19, 1–16 (1999).

    Article  PubMed  CAS  Google Scholar 

  2. C. Ip, Lessons from basic research in selenium and cancer prevention, J Nutr 128, 1845–1854 (1998).

    PubMed  CAS  Google Scholar 

  3. K. El-Bayoumy, The protective role of selenium on genetic damage and on cancer, Mutat Res 475, 123–39 (2001).

    PubMed  CAS  Google Scholar 

  4. G. F. Combs Jr., L. C. Clark, and B. W. Turnbull, An analysis of cancer prevention by selenium, Biofactors 14, 153–9 (2001).

    Article  PubMed  CAS  Google Scholar 

  5. P. D. Whanger, Selenium and its relationship to cancer: an update, Br J Nutr 91, 11–28 (2004).

    Article  PubMed  CAS  Google Scholar 

  6. G. F. Combs Jr., Current evidence and research needs to support a health claim for selenium and cancer prevention, J Nutr 135, 343–7 (2005).

    PubMed  CAS  Google Scholar 

  7. C. Ip, Y. Dong, and H. E. Ganther, New concepts in selenium chemoprevention, Cancer Metastasis Rev 21, 281–9 (2002).

    Article  PubMed  CAS  Google Scholar 

  8. J. Lu and C. Jiang, Selenium and cancer chemoprevention: hypotheses integrating the actions of selenoproteins and selenium metabolites in epithelial and non-epithelial target cells, Antioxid Redox Signal 7, 1715–27 (2005).

    Article  PubMed  Google Scholar 

  9. P. Hasty, The impact of DNA damage, genetic mutation and cellular responses on cancer prevention, longevity and aging: observations in humans and mice, Mech Ageing Dev 126, 71–7 (2005).

    Article  PubMed  CAS  Google Scholar 

  10. Y. Hu, R. V. Benya, R. E. Carroll, and A. M. Diamond, Allelic loss of the gene for the GPX1 selenium-containing protein is a common event in cancer, J Nutr 135, 3021S–3024S (2005).

    PubMed  CAS  Google Scholar 

  11. Y. P. Yu, G. Yu, G. Tseng, K. Cieply, J. Nelson, M. Defrances, R. Zarnegar, G. Michalopoulos, and J. H. Luo, Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis, Cancer Res 67, 8043–50 (2007).

    Article  PubMed  CAS  Google Scholar 

  12. J. E. Spallholz, V. P. Palace, and T. W. Reid, Methioninase and selenomethionine but not Se-methylselenocysteine generate methylselenol and superoxide in an in vitro chemiluminescent assay: implications for the nutritional carcinostatic activity of selenoamino acids, Biochem Pharmacol 67, 547–54 (2004).

    Article  PubMed  CAS  Google Scholar 

  13. M. Kaeck, J. Lu, R. Strange, C. Ip, H. E. Ganther, and H. J. Thompson, Differential induction of growth arrest inducible genes by selenium compounds, Biochem Pharmacol 53, 921–6 (1997).

    Article  PubMed  CAS  Google Scholar 

  14. Y. Dong, H. Zhang, L. Hawthorn, H. E. Ganther, and C. Ip, Delineation of the molecular basis for selenium-induced growth arrest in human prostate cancer cells by oligonucleotide array, Cancer Res 63, 52–9 (2003).

    PubMed  CAS  Google Scholar 

  15. C. Ip and D. J. Lisk, Modulation of phase I and phase II xenobiotic-metabolizing enzymes by selenium-enriched garlic in rats, Nutr Cancer 28, 184–8 (1997).

    Article  PubMed  CAS  Google Scholar 

  16. D. J. Waters, S. Shen, D. M. Cooley, D. G. Bostwick, J. Qian, G. F. Combs Jr., L. T. Glickman, C. Oteham, D. Schlittler, and J. S. Morris, Effects of dietary selenium supplementation on DNA damage and apoptosis in canine prostate, J Natl Cancer Inst 95, 237–41 (2003).

    Article  PubMed  CAS  Google Scholar 

  17. D. J. Waters, S. Shen, L. T. Glickman, D. M. Cooley, D. G. Bostwick, J. Qian, G. F. Combs Jr., and J. S. Morris, Prostate cancer risk and DNA damage: translational significance of selenium supplementation in a canine model, Carcinogenesis 26, 1256–62 (2005).

    Article  PubMed  CAS  Google Scholar 

  18. N. Karunasinghe, J. Ryan, J. Tuckey, J. Masters, M. Jamieson, L. C. Clarke, J. R. Marshall, and L. R. Ferguson, DNA stability and serum selenium levels in a high-risk group for prostate cancer, Cancer Epidemiol Biomark Prev 13, 391–7 (2004).

    CAS  Google Scholar 

  19. E. Kowalska, S. A. Narod, T. Huzarski, S. Zajaczek, J. Huzarska, B. Gorski, and J. Lubinski, Increased rates of chromosome breakage in BRCA1 carriers are normalized by oral selenium supplementation, Cancer Epidemiol Biomark Prev 14, 1302–6 (2005).

    Article  CAS  Google Scholar 

  20. R. P. Bird, Role of aberrant crypt foci in understanding the pathogenesis of colon cancer, Cancer Lett 93, 55–71 (1995).

    Article  PubMed  CAS  Google Scholar 

  21. G. Caderni, A. Giannini, L. Lancioni, C. Luceri, A. Biggeri, and P. Dolara, Characterisation of aberrant crypt foci in carcinogen-treated rats: association with intestinal carcinogenesis, Br J Cancer 71, 763–9 (1995).

    PubMed  CAS  Google Scholar 

  22. L. Luo, B. Li, and T. P. Pretlow, DNA alterations in human aberrant crypt foci and colon cancers by random primed polymerase chain reaction, Cancer Res 63, 6166–9 (2003).

    PubMed  CAS  Google Scholar 

  23. Y. Feng, J. W. Finley, C. D. Davis, W. K. Becker, A. J. Fretland, and D. W. Hein, Dietary selenium reduces the formation of aberrant crypts in rats administered 3,2′-dimethyl-4-aminobiphenyl, Toxicol Appl Pharmacol 157, 36–42 (1999).

    Article  PubMed  CAS  Google Scholar 

  24. C. D. Davis, Y. Feng, D. W. Hein, and J. W. Finley, The chemical form of selenium influences 3,2′-dimethyl-4-aminobiphenyl-DNA adduct formation in rat colon, J Nutr 129, 63–9 (1999).

    PubMed  CAS  Google Scholar 

  25. C. D. Davis and E. O. Uthus, Dietary selenium and azadeoxycytidine treatment affect dimethylhydrazine-induced aberrant crypt formation in rat colon and DNA methylation in HT-29 cells, J Nutr 132, 292–297 (2002).

    PubMed  CAS  Google Scholar 

  26. E. O. Uthus and S. A. Ross, Dietary selenium affects homocysteine metabolism differently in Fisher-344 rats and CD-1 mice, J Nutr 137, 1132–6 (2007).

    PubMed  CAS  Google Scholar 

  27. P. G. Reeves, F. H. Nielsen, and G. C. Fahey Jr., AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet, J Nutr 123, 1939–51 (1993).

    PubMed  CAS  Google Scholar 

  28. P. G. Reeves, Components of the AIN-93 diets as improvements in the AIN-76A diet, J Nutr 127, 838S–841S (1997).

    PubMed  CAS  Google Scholar 

  29. J. W. Finley, L. Mathys, T. Shuler, and E. Korynta, Selenium contents of food purchased in North Dakota, Nutr Res 16, 723–728 (1996).

    Article  CAS  Google Scholar 

  30. D. Paglia and W. Valentine, Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase, J Lab Clin Med 70, 158–169 (1967).

    PubMed  CAS  Google Scholar 

  31. A. Holmgren and M. Bjornstedt, Thioredoxin and thioredoxin reductase, Methods Enzymol 252, 199–208 (1995).

    Article  PubMed  CAS  Google Scholar 

  32. K. E. Hill, G. W. McCollum, and R. F. Burk, Determination of thioredoxin reductase activity in rat liver supernatant, Anal Biochem 253, 123–5 (1997).

    Article  PubMed  CAS  Google Scholar 

  33. K. M. Pozharisski, Morphology and morphogenesis of experimental epithelial tumors of the intestine, J Natl Cancer Inst 54, 1115–35 (1975).

    PubMed  CAS  Google Scholar 

  34. E. S. Fiala, Investigations into the metabolism and mode of action of the colon carcinogens 1,2-dimethylhydrazine and azoxymethane, Cancer 40, 2436–45 (1977).

    Article  PubMed  CAS  Google Scholar 

  35. C. S. Potten, Y. Q. Li, P. J. O’Connor, and D. J. Winton, A possible explanation for the differential cancer incidence in the intestine, based on distribution of the cytotoxic effects of carcinogens in the murine large bowel, Carcinogenesis 13, 2305–12 (1992).

    Article  PubMed  CAS  Google Scholar 

  36. A. Likhachev, A. S. Petrov, L. G. P’Rvanova, and K. M. Pozharisskii, Mechanism of methylation of DNA bases by symmetrical dimethylhydrazine, Bull Exper Biol Med 86, 1604–1606 (1978).

    Google Scholar 

  37. A. C. Povey, A. F. Badawi, D. P. Cooper, C. N. Hall, K. L. Harrison, P. E. Jackson, N. P. Lees, P. J. O'Connor, and G. P. Margison, DNA alkylation and repair in the large bowel: animal and human studies, J Nutr 132, 3518S–3521S (2002).

    PubMed  CAS  Google Scholar 

  38. J. M. Gee, H. Hara, and I. T. Johnson, Suppression of intestinal crypt cell proliferation and aberrant crypt foci by dietary quercetin in rats, Nutr Cancer 43, 193–201 (2002).

    Article  PubMed  CAS  Google Scholar 

  39. E. I. Salim and S. Fukushima, Chemopreventive potential of volatile oil from black cumin (Nigella sativa L.) seeds against rat colon carcinogenesis, Nutr Cancer 45, 195–202 (2003).

    Article  PubMed  Google Scholar 

  40. T. K. Smith, R. Mithen, and I. T. Johnson, Effects of Brassica vegetable juice on the induction of apoptosis and aberrant crypt foci in rat colonic mucosal crypts in vivo, Carcinogenesis 24, 491–5 (2003).

    Article  PubMed  CAS  Google Scholar 

  41. M. Ravnik-Glavac, A. Cerar, and D. Glavac, Animal model in the study of colorectal carcinogenesis, Pflugers Arch 440, R55–7 (2000).

    Article  PubMed  CAS  Google Scholar 

  42. A. Tomasi, E. Albano, B. Botti, and V. Vannini, Detection of free radical intermediates in the oxidative metabolism of carcinogenic hydrazine derivatives, Toxicol Pathol 15, 178–83 (1987).

    Article  PubMed  CAS  Google Scholar 

  43. Y. Sun, Free radicals, antioxidant enzymes, and carcinogenesis, Free Radic Biol Med 8, 583–99 (1990).

    Article  PubMed  CAS  Google Scholar 

  44. M. Sengottuvelan and N. Nalini, Dietary supplementation of resveratrol suppresses colonic tumour incidence in 1,2-dimethylhydrazine-treated rats by modulating biotransforming enzymes and aberrant crypt foci development, Br J Nutr 96, 145–53 (2006).

    Article  PubMed  CAS  Google Scholar 

  45. M. Sengottuvelan, P. Viswanathan, and N. Nalini, Chemopreventive effect of trans-resveratrol—a phytoalexin against colonic aberrant crypt foci and cell proliferation in 1,2-dimethylhydrazine induced colon carcinogenesis, Carcinogenesis 27, 1038–46 (2006).

    Article  PubMed  CAS  Google Scholar 

  46. K. Felix, S. Gerstmeier, A. Kyriakopoulos, O. M. Howard, H. F. Dong, M. Eckhaus, D. Behne, G. W. Bornkamm, and S. Janz, Selenium deficiency abrogates inflammation-dependent plasma cell tumors in mice, Cancer Res 64, 2910–7 (2004).

    Article  PubMed  CAS  Google Scholar 

  47. R. Irons, B. A. Carlson, D. L. Hatfield, and C. D. Davis, Both selenoproteins and low molecular weight selenocompounds reduce colon cancer risk in mice with genetically impaired selenoprotein expression, J Nutr 136, 1311–7 (2006).

    PubMed  CAS  Google Scholar 

  48. V. Diwadkar-Navsariwala, G. S. Prins, S. M. Swanson, L. A. Birch, V. H. Ray, S. Hedayat, D. L. Lantvit, and A. M. Diamond, Selenoprotein deficiency accelerates prostate carcinogenesis in a transgenic model, Proc Natl Acad Sci U S A 103, 8179–84 (2006).

    Article  PubMed  CAS  Google Scholar 

  49. G. F. Combs Jr., Chemopreventive mechanisms of selenium, Med Klin 94 Suppl 3, 18–24 (1999).

    Article  Google Scholar 

  50. M. Berggren, A. Gallegos, J. Gasdaska, and G. Powis, Cellular thioredoxin reductase activity is regulated by selenium, Anticancer Res 17, 3377–80 (1997).

    PubMed  CAS  Google Scholar 

  51. L. V. Papp, J. Lu, A. Holmgren, and K. K. Khanna, From selenium to selenoproteins: synthesis, identity, and their role in human health, Antioxid Redox Signal 9, 775–806 (2007).

    Article  PubMed  CAS  Google Scholar 

  52. J. E. Spallholz, Free radical generation by selenium compounds and their prooxidant toxicity, Biomed Environ Sci 10, 260–70 (1997).

    PubMed  CAS  Google Scholar 

  53. M. S. Stewart, R. L. Davis, L. P. Walsh, and B. C. Pence, Induction of differentiation and apoptosis by sodium selenite in human colonic carcinoma cells (HT29), Cancer Lett 117, 35–40 (1997).

    Article  PubMed  CAS  Google Scholar 

  54. M. P. Rayman, Selenium in cancer prevention: a review of the evidence and mechanism of action, Proc Nutr Soc 64, 527–42 (2005).

    Article  PubMed  CAS  Google Scholar 

  55. H. J. Helbock, K. B. Beckman, M. K. Shigenaga, P. B. Walter, A. A. Woodall, H. C. Yeo, and B. N. Ames, DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine, Proc Natl Acad Sci U S A 95, 288–93 (1998).

    Article  PubMed  CAS  Google Scholar 

  56. D. J. Howard, R. B. Ota, L. A. Briggs, M. Hampton, and C. A. Pritsos, Oxidative stress induced by environmental tobacco smoke in the workplace is mitigated by antioxidant supplementation, Cancer Epidemiol Biomark Prev 7, 981–8 (1998).

    CAS  Google Scholar 

  57. R. W. Welch, E. Turley, S. F. Sweetman, G. Kennedy, A. R. Collins, A. Dunne, M. B. Livingstone, P. G. McKenna, V. J. McKelvey-Martin, and J. J. Strain, Dietary antioxidant supplementation and DNA damage in smokers and nonsmokers, Nutr Cancer 34, 167–72 (1999).

    Article  PubMed  CAS  Google Scholar 

  58. Y. J. Sung, C. C. Juan, H. C. Lee, P. H. Yin, C. W. Chi, H. H. Ku, A. F. Li, Y. H. Wei, and H. J. Tsay, Oxidative stress is insignificant in N1S1-transplanted hepatoma despite markedly declined activities of the antioxidant enzymes, Oncol Rep 6, 1313–9 (1999).

    PubMed  CAS  Google Scholar 

  59. C. L. Shen, W. Song, and B. C. Pence, Interactions of selenium compounds with other antioxidants in DNA damage and apoptosis in human normal keratinocytes, Cancer Epidemiol Biomark Prev 10, 385–90 (2001).

    CAS  Google Scholar 

  60. B. J. Wycherly, M. A. Moak, and M. J. Christensen, High dietary intake of sodium selenite induces oxidative DNA damage in rat liver, Nutr Cancer 48, 78–83 (2004).

    Article  PubMed  CAS  Google Scholar 

  61. S. Boiteux and J. P. Radicella, Base excision repair of 8-hydroxyguanine protects DNA from endogenous oxidative stress, Biochimie 81, 59–67 (1999).

    Article  PubMed  CAS  Google Scholar 

  62. S. Samanta, V. Swamy, D. Suresh, M. Rajkumar, B. Rana, A. Rana, and M. Chatterjee, Protective effects of vanadium against DMH-induced genotoxicity and carcinogenesis in rat colon: removal of O(6)-methylguanine DNA adducts, p53 expression, inducible nitric oxide synthase downregulation and apoptotic induction, Mutat Res 650, 123–31 (2008).

    PubMed  CAS  Google Scholar 

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Acknowledgments

We are grateful to Karen LoneFight, Kim Baurichter, and LuAnn Johnson for technical support.

Conflict of Interest

Author disclosures: H. Zeng, E. O. Uthus, S. A. Ross, and C.D. Davis, no conflicts of interest.

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Correspondence to Eric O. Uthus.

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The US Department of Agriculture, Agricultural Research Service, Northern Plains Area, is an equal opportunity/affirmative action employer and all agency services are available without discrimination.

Mention of a trademark or proprietary product does not constitute a guarantee or warranty of the product by the US Department of Agriculture and does not imply its approval to the exclusion of other products that may also be suitable.

This work was supported by the US Department of Agriculture and National Cancer Institute.

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Zeng, H., Uthus, E.O., Ross, S.A. et al. High Dietary Intake of Sodium Selenite Does Not Affect Gene Mutation Frequency in Rat Colon and Liver. Biol Trace Elem Res 131, 71–80 (2009). https://doi.org/10.1007/s12011-009-8348-3

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