Skip to main content
SpringerLink
Log in

Dietary arsenic affects dimethylhydrazine-induced aberrant crypt formation and hepatic global DNA methylation and DNA methyltransferase activity in rats

  • Original Articles
  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Cell culture studies have suggested that arsenic exposure results in decreased S-adenosylmethionine (SAM), causing DNA hypomethylation. Previously, we have shown that hepatic SAM is decreased and/or S-adenosylhomocysteine increased in arsenic-deprived rats; these rats tended to have hypomethylated DNA. To determine, the effect of dietary arsenic on dimethylhydrazine (DMH)-induced aberrant crypt formation in the colon, Fisher 344 weanling male rats were fed diets containing 0,05, or 50 μg As (as NaAsO2)/g. After 12 wk, dietary arsenic affected the number of aberrant crypts (p<0.02) and aberrant crypt foci (p<0.007) in the colon and the amount of global DNA methylation (p<0.04) and activity of DNA methyltransferase (DNMT) (p<0.003) in the liver. In each case, there were more aberrant crypts and aberrant crypt foci, a relative DNA hypomethylation, and increased activity of DNMT in the rats fed 50 μg As/g compared to those fed 0.5 μg As/g. The same phenomenon, an increased number of aberrant crypts and aberrant crypt foci, DNA hypomethylation, and increased DNMT tended to hold when comparing rats fed the diet containing no supplemental arsenic compared to rats fed 0.5 μg As/g. The data suggest that there is a threshold for As toxicity and that possibly too little dietary As could also be detrimental.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. C. Q. Zhao, M. R. Young, B. A. Diwan, T. P. Coogan, and M. P. Waalkes, Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression, Proc Natl Acad Sci USA 94, 10,907–10,912 (1997).

    CAS  Google Scholar 

  2. K. G. Brown and G. L. Ross, Arsenic, drinking water, and health: a position paper of the American Council on Science and Health, Regul. Toxicol. Pharmacol. 36, 162–174 (2002).

    Article  PubMed  CAS  Google Scholar 

  3. G. Kayajanian, As, cancer, and thoughtless policy, Ecotoxicol. Environ. Safety 55, 139–142 (2003).

    Article  CAS  Google Scholar 

  4. S. H. Lamm, D. M. Byrd, M. B. Kruse, M. Feinleib, and S. H. Lai, Bladder cancer and arsenic exposure: differences in the two populations enrolled in a study in southwest Taiwan, Biomed. Environ. Sci. 16, 355–368 (2003).

    Google Scholar 

  5. S. H. Lamm, A. Engel, M. B. Kruse, et al., Arsenic in drinking water and bladder cancer mortality in the U.S.: an analysis based on 133 U.S. counties and thirty years of observation, J. Occup. Environ. Med. 46, 298–306 (2004).

    Article  PubMed  CAS  Google Scholar 

  6. M. Anke, B. Groppel, M. Grün, A. Hennig, and D. Meissner, in 3rd Spurenelement-Symposium, Arsen, M. Anke, H.-J. Schneider, and C. Brückner, eds. Karl-Marx-Universität, Leipzig, pp. 25–32 (1980).

    Google Scholar 

  7. M. Anke, M. Grün, M. Partschefeld, B. Groppel, and A. Hennig, in Trace Elements in Man and Animals—3, M. Kirchgessner, ed., University München, Freising-Weihenstephan, pp. 248–252 (1978).

    Google Scholar 

  8. E. O. Uthus, Evidence for Arsenic essentiality, Environ. Geochem. Health 14, 55–58 (1992).

    Article  CAS  Google Scholar 

  9. E. O. Uthus, W. E. Cornatzer, and F. H. Nielsen, in Arsenic: Industrial, Biomedical, Environmental Perspectives, W. H. Lederer and R. J. Fensterheim, eds., Van Nostrand Reinhold, New York, pp. 173–189 (1983).

    Google Scholar 

  10. E. O. Uthus, Arsenic essentiality: a role affecting methionine metabolism, J. Trace Elements Exp. Med. 16, 345–355 (2003).

    Article  CAS  Google Scholar 

  11. I. Csanaky, B. Nemeti, and Z. Gregus, Dose-dependent biotransformation of arsenite in rats—not S-adenosylmethionine depletion impairs arsenic methylation at high dose, Toxicology 183, 77–91 (2003).

    Article  Google Scholar 

  12. S. Lin, Q. Shi, F. B. Nix, et al., A novel S-adenosyl-l-methionine: arsenic(III) methyltransferase from rat liver cytosol, J. Biol. Chem. 277, 10,795–10,803 (2002).

    CAS  Google Scholar 

  13. M. Vahter, Genetic polymorphism in the biotransformation of inorganic arsenic and its role in toxicity, Toxicol. Lett. 112–113, 209–217 (2000).

    Article  PubMed  Google Scholar 

  14. T. Ramirez, V. Garcia-Montalvo, C. Wise, R. Cea-Olivares, L. A. Poirier, and L. A. Herrera, S-Adenosyl-l-methionine is able to reverse micronucleus formation induced by sodium arsenite and other cytoskeleton disrupting agents in cultured human cells, Mutat. Res. 528, 61–74 (2003).

    Google Scholar 

  15. H. Chen, J. Liu, B. A. Merrick, and M. P. Waalkes, Genetic events associated with arsenic-induced malignant transformation: applications of cDNA microarray technology, Mol. Carcinog. 30, 79–87 (2001).

    Article  PubMed  Google Scholar 

  16. J. D. Finkelstein and J. J. Martin, Methionine metabolism in mammals: adaptation to methionine excess, J. Biol. Chem. 261, 1582–1587 (1986).

    PubMed  CAS  Google Scholar 

  17. A. F. Perna, D. Ingrosso, V. Zappia, P. Galletti, G. Capasso, and N. G. De Santo, Enzymatic methyl esterification of erythrocyte membrane proteins is impaired in chronic renal failure. J. Clin. Invest. 91, 2497–2503 (1993).

    Article  PubMed  CAS  Google Scholar 

  18. M. Balaghi and C. Wagner, DNA methylation in folate deficiency: use of CpG methylase, Biochem. Biophys. Res. Commun. 193, 1184–1190 (1993).

    Article  PubMed  CAS  Google Scholar 

  19. M. M. Simile, R. Pascale, M. R. De Miglio, et al., Correlation between S-adenosyl-l-methionine content and production of c-myc c-Ha-ras, and c-Ki-ras mRNA transcripts in the early stages of rat liver carcinogenesis, Cancer Lett. 79, 9–16 (1994).

    Article  Google Scholar 

  20. Y. I. Kim, J. K. Christman, J. C. Fleet, et al., Moderate folate deficiency does not cause global hypomethylation of hepatic and colonic DNA or c-myc-specific hypomethylation of colonic DNA in rats, Am. J. Clin. Nutr. 61, 1083–1090 (1995).

    PubMed  CAS  Google Scholar 

  21. E. O. Uthus, High dietary arsenic exacerbates copper deprivation in rats, J. Trace Elements Exp. Med. 14, 43–55 (2001).

    Article  CAS  Google Scholar 

  22. E. O. Uthus, Diethyl maleate, an in vivo chemical depletor of glutathione, affects the response of male and female rats to arsenic deprivation, Biol. Trace Element Res. 46, 247–259 (1994).

    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, E. O. Uthus, and J. W. Finley, Dietary selenium and arsenic affect DNA methylation in vitro in Caco-2 cells and in vivo in rat liver and colon. J. Nutr. 130, 2903–2909 (2000).

    PubMed  CAS  Google Scholar 

  25. E. O. Uthus, K. Yokoi, and C. D. Davis, Selenium deficiency in Fisher-344 rats decreases plasma and tissue homocysteine concentrations and alters plasma homocysteine and cysteine redox status, J. Nutr. 132, 1122–1128 (2002).

    PubMed  CAS  Google Scholar 

  26. J. P. Issa, P. M. Vertino, J. Wu, et al., Increased cytosine DNA-methyltransferase activity during colon cancer progression, J. Natl. Cancer Inst. 85, 1235–1240 (1993).

    Article  PubMed  CAS  Google Scholar 

  27. C. D. Davis and E. O. Uthus, Dietary folate and selenium affect dimethylhydrazine-induced aberrant crypt formation, global DNA methylation and one-carbon metabolism in rats, J. Nutr. 133, 2907–2914 (2003).

    Google Scholar 

  28. J. Wagner, N. Claverie, and C. Danzin, A rapid high-performance liquid chromatographic procedure for the simultaneous determination of methionine, ethionine, S-adenosylmethionine, S-adenosylethionine, and the natural polyamines in rat tissues, Anal. Biochem. 140, 108–116 (1984).

    Article  PubMed  CAS  Google Scholar 

  29. P. Durand, L. J. Fortin, S. Lussier-Cacan, J. Davignon, and D. Blache, Hyperhomocysteinemia induced by folic acid deficiency and methionine load—applications of a modified HPLC method, Clin. Chim. Acta 252, 83–93 (1996).

    Article  PubMed  CAS  Google Scholar 

  30. F. J. Hernandez-Blazquez, M. Habib, J. M. Dumollard, et al., Evaluation of global DNA hypomethylation in human colon cancer tissues by immunohistochemistry and image analysis, Gut 47, 689–693 (2000).

    Article  PubMed  CAS  Google Scholar 

  31. A. P. Feinberg, C. W. Gehrke, K. C. Kuo, and M. Ehrlich, Reduced genomic 5-methyl-cytosine content in human colonic neoplasia, Cancer Res. 48, 1159–1161 (1988).

    PubMed  CAS  Google Scholar 

  32. A. G. Halline, P. K. Dudeja, and T. A. Brasitus, 1,2-Dimethylhydrazine-induced premalignant alterations in the S-adenosylmethionine/S-adenosylhomocysteine ratio and membrane lipid lateral diffusion of the rat distal colon, Biochim. Biophys. Acta 944, 101–107 (1988).

    Article  PubMed  CAS  Google Scholar 

  33. J. D. Finkelstein, Pathways and regulation of homocysteine metabolism in mammals, Semin. Thromb. Hemost. 26, 219–225 (2000).

    Article  PubMed  CAS  Google Scholar 

  34. C. Schmutte, A. S. Yang, T. T. Nguyen, R. W. Beart, and P. A. Jones, Mechanisms for the involvement of DNA methylation in colon carcinogenesis, Cancer Res. 56, 2375–2381 (1996).

    PubMed  CAS  Google Scholar 

  35. H. V. Aposhian, Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity, Annu. Rev. Pharmacol. Toxicol. 37, 397–419 (1997).

    Article  PubMed  CAS  Google Scholar 

  36. T. G. Rossman, A. N. Uddin, F. J. Burns, and M. C. Bosland, Arsenite is a cocarcinogen with solar ultraviolet radiation for mouse skin: an animal model for arsenic carcinogenesis. Toxicol. Appl. Pharmacol. 176, 64–71 (2001).

    Article  PubMed  CAS  Google Scholar 

  37. T. G. Rossman, A. N. Uddin, F. J. Burns, and M. C. Bosland, Arsenite cocarcinogenesis: an animal model derived from genetic toxicology studies, Environ. Health Perspect. 110(Suppl. 5) 749–752 (2002).

    PubMed  CAS  Google Scholar 

  38. E. O. Uthus and Y. J. Kang. Effect of buthionine sulfoximine on the response to arsenic deprivation in female rats, J. Trace Elements Exp. Med. 11, 29–36 (1998).

    Article  CAS  Google Scholar 

  39. L. S. Chuang, H. I. Ian, T. W. Koh, H. H. Ng, G. Xu, and B. F. Li, Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1, Science 277, 1996–2000 (1997).

    Article  PubMed  CAS  Google Scholar 

  40. A. M. De Marzo, V. L. Marchi, E. S. Yang, R. Veeraswamy, X. Lin, and W. G. Nelson, Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis, Cancer Res. 59, 3855–3860 (1999).

    PubMed  Google Scholar 

  41. C. H. Lin, S. Y. Hsieh, I. S. Sheen, et al., Genome-wide hypomethylation in hepatocellular carcinogenesis, Cancer Res. 61, 4238–4243 (2001).

    PubMed  CAS  Google Scholar 

  42. Y. Saito, Y. Kanai, M. Sakamoto, H. Saito, H. Ishii, and S. Hirohashi, Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis, Hepatology 33, 561–568 (2001).

    Article  PubMed  CAS  Google Scholar 

  43. S. B. Baylin, Tying it all together: epigenetics, genetics, cell cycle, and cancer, Science 277, 1948–1949 (1997).

    Article  PubMed  CAS  Google Scholar 

  44. S. Sibani, S. Melnyk, I. P. Pogribny, et al., Studies of methionine cycle intermediates (SAM, SAH), DNA methylation and the impact of folate deficiency on tumor numbers in Min mice. Carcinogenesis 23, 61–65 (2002).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. ARS, Grand Forks Human Nutrition Research Center, United States Department of Agriculture, 58202, Grand Forks, ND

    Eric O. Uthus

  2. Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, NIH, DHHS, 20892, Rockville, MD

    Cindy Davis

Authors
  1. Eric O. Uthus
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cindy Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

Uthus, E.O., Davis, C. Dietary arsenic affects dimethylhydrazine-induced aberrant crypt formation and hepatic global DNA methylation and DNA methyltransferase activity in rats. Biol Trace Elem Res 103, 133–145 (2005). https://doi.org/10.1385/BTER:103:2:133

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/BTER:103:2:133

Index Entries

Search

Navigation