Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2002 Oct;110(Suppl 5):749–752. doi: 10.1289/ehp.02110s5749

Arsenite cocarcinogenesis: an animal model derived from genetic toxicology studies.

Toby G Rossman 1, Ahmed N Uddin 1, Fredric J Burns 1, Maarten C Bosland 1
PMCID: PMC1241238  PMID: 12426125

Abstract

Although epidemiologic evidence shows an association between inorganic arsenic in drinking water and increased risk of skin, lung, and bladder cancers, no animal model for arsenic carcinogenesis has been successful. This lack has hindered mechanistic studies of arsenic carcinogenesis. Previously, we and others found that low concentrations (< or =5 microm) of arsenite (the likely environmental carcinogen), which are not mutagenic, can enhance the mutagenicity of other agents, including ultraviolet radiation (UVR) and alkylating agents. This enhancing effect appears to result from inhibition of DNA repair by arsenite, but not via inhibition of DNA repair enzymes. Rather, low concentrations of arsenite disrupt p53 function and upregulate cyclin D1. Failure to find an animal model for arsenic carcinogenesis might be because arsenite is not a carcinogen per se but acts as an enhancing agent (cocarcinogen) with a genotoxic partner. We tested this hypothesis with solar UVR in hairless but immunocompetent Skh1 mice. Mice were given 10 mg/L sodium arsenite in drinking water (or not) and irradiated with 1.7 KJ/m(2) solar UVR 3 times weekly. As expected, no tumors appeared in any organs in control mice or in mice given arsenite alone. After 26 weeks irradiated mice given arsenite had a 2.4-fold increase in skin tumor yield compared with mice given UVR alone. The tumors were mostly squamous cell carcinomas, and those occurring in mice given UVR plus arsenite were much larger and more invasive. These results are consistent with the hypothesis that arsenic acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or enhancing positive growth signaling. Skin cancers in populations drinking water containing arsenic may be caused by the enhancement by arsenic compounds of carcinogenesis induced by UVR (or other environmental agents). It is possible that lung and bladder cancers associated with arsenic in drinking water may also require a carcinogenic partner.

Full Text

The Full Text of this article is available as a PDF (138.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barchowsky A., Roussel R. R., Klei L. R., James P. E., Ganju N., Smith K. R., Dudek E. J. Low levels of arsenic trioxide stimulate proliferative signals in primary vascular cells without activating stress effector pathways. Toxicol Appl Pharmacol. 1999 Aug 15;159(1):65–75. doi: 10.1006/taap.1999.8723. [DOI] [PubMed] [Google Scholar]
  2. Bates M. N., Smith A. H., Hopenhayn-Rich C. Arsenic ingestion and internal cancers: a review. Am J Epidemiol. 1992 Mar 1;135(5):462–476. doi: 10.1093/oxfordjournals.aje.a116313. [DOI] [PubMed] [Google Scholar]
  3. Boffetta P., Jourenkova N., Gustavsson P. Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons. Cancer Causes Control. 1997 May;8(3):444–472. doi: 10.1023/a:1018465507029. [DOI] [PubMed] [Google Scholar]
  4. Borgoño J. M., Vicent P., Venturino H., Infante A. Arsenic in the drinking water of the city of Antofagasta: epidemiological and clinical study before and after the installation of a treatment plant. Environ Health Perspect. 1977 Aug;19:103–105. doi: 10.1289/ehp.19-1637404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cebrián M. E., Albores A., Aguilar M., Blakely E. Chronic arsenic poisoning in the north of Mexico. Hum Toxicol. 1983 Jan;2(1):121–133. doi: 10.1177/096032718300200110. [DOI] [PubMed] [Google Scholar]
  6. Chen C. J., Chen C. W., Wu M. M., Kuo T. L. Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water. Br J Cancer. 1992 Nov;66(5):888–892. doi: 10.1038/bjc.1992.380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chen H., Liu J., Merrick B. A., Waalkes M. P. Genetic events associated with arsenic-induced malignant transformation: applications of cDNA microarray technology. Mol Carcinog. 2001 Feb;30(2):79–87. doi: 10.1002/1098-2744(200102)30:2<79::aid-mc1016>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  8. Chiou H. Y., Hsueh Y. M., Liaw K. F., Horng S. F., Chiang M. H., Pu Y. S., Lin J. S., Huang C. H., Chen C. J. Incidence of internal cancers and ingested inorganic arsenic: a seven-year follow-up study in Taiwan. Cancer Res. 1995 Mar 15;55(6):1296–1300. [PubMed] [Google Scholar]
  9. De Hertog SA, Wensveen C. A., Bastiaens M. T., Kielich C. J., Berkhout M. J., Westendorp R. G., Vermeer B. J., Bouwes Bavinck J. N., Leiden Skin Cancer Study Relation between smoking and skin cancer. J Clin Oncol. 2001 Jan 1;19(1):231–238. doi: 10.1200/JCO.2001.19.1.231. [DOI] [PubMed] [Google Scholar]
  10. Germolec D. R., Spalding J., Boorman G. A., Wilmer J. L., Yoshida T., Simeonova P. P., Bruccoleri A., Kayama F., Gaido K., Tennant R. Arsenic can mediate skin neoplasia by chronic stimulation of keratinocyte-derived growth factors. Mutat Res. 1997 Jun;386(3):209–218. doi: 10.1016/s1383-5742(97)00006-9. [DOI] [PubMed] [Google Scholar]
  11. Germolec D. R., Spalding J., Yu H. S., Chen G. S., Simeonova P. P., Humble M. C., Bruccoleri A., Boorman G. A., Foley J. F., Yoshida T. Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors. Am J Pathol. 1998 Dec;153(6):1775–1785. doi: 10.1016/S0002-9440(10)65692-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hei T. K., Liu S. X., Waldren C. Mutagenicity of arsenic in mammalian cells: role of reactive oxygen species. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8103–8107. doi: 10.1073/pnas.95.14.8103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hopenhayn-Rich C., Biggs M. L., Smith A. H. Lung and kidney cancer mortality associated with arsenic in drinking water in Córdoba, Argentina. Int J Epidemiol. 1998 Aug;27(4):561–569. doi: 10.1093/ije/27.4.561. [DOI] [PubMed] [Google Scholar]
  14. Hu Y., Su L., Snow E. T. Arsenic toxicity is enzyme specific and its affects on ligation are not caused by the direct inhibition of DNA repair enzymes. Mutat Res. 1998 Sep 11;408(3):203–218. doi: 10.1016/s0921-8777(98)00035-4. [DOI] [PubMed] [Google Scholar]
  15. Ishinishi N., Yamamoto A., Hisanaga A., Inamasu T. Tumorigenicity of arsenic trioxide to the lung in Syrian golden hamsters by intermittent instillations. Cancer Lett. 1983 Dec;21(2):141–147. doi: 10.1016/0304-3835(83)90200-8. [DOI] [PubMed] [Google Scholar]
  16. Ivankovic S., Eisenbrand G., Preussmann R. Lung carcinoma induction in BD rats after a single intratracheal instillation of an arsenic-containing pesticide mixture formerly used in vineyards. Int J Cancer. 1979 Dec 15;24(6):786–788. doi: 10.1002/ijc.2910240615. [DOI] [PubMed] [Google Scholar]
  17. Karagas M. R., McDonald J. A., Greenberg E. R., Stukel T. A., Weiss J. E., Baron J. A., Stevens M. M. Risk of basal cell and squamous cell skin cancers after ionizing radiation therapy. For The Skin Cancer Prevention Study Group. J Natl Cancer Inst. 1996 Dec 18;88(24):1848–1853. doi: 10.1093/jnci/88.24.1848. [DOI] [PubMed] [Google Scholar]
  18. Klein C. B., Su L., Rossman T. G., Snow E. T. Transgenic gpt+ V79 cell lines differ in their mutagenic response to clastogens. Mutat Res. 1994 Jan 16;304(2):217–228. doi: 10.1016/0027-5107(94)90214-3. [DOI] [PubMed] [Google Scholar]
  19. Landolph J. R. Molecular mechanisms of transformation of C3H/10T1/2 C1 8 mouse embryo cells and diploid human fibroblasts by carcinogenic metal compounds. Environ Health Perspect. 1994 Sep;102 (Suppl 3):119–125. doi: 10.1289/ehp.94102s3119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Li J. H., Rossman T. G. Comutagenesis of sodium arsenite with ultraviolet radiation in Chinese hamster V79 cells. Biol Met. 1991;4(4):197–200. doi: 10.1007/BF01141180. [DOI] [PubMed] [Google Scholar]
  21. Li J. H., Rossman T. G. Inhibition of DNA ligase activity by arsenite: a possible mechanism of its comutagenesis. Mol Toxicol. 1989 Winter;2(1):1–9. [PubMed] [Google Scholar]
  22. Li J. H., Rossman T. G. Mechanism of comutagenesis of sodium arsenite with n-methyl-n-nitrosourea. Biol Trace Elem Res. 1989 Jul-Sep;21:373–381. doi: 10.1007/BF02917278. [DOI] [PubMed] [Google Scholar]
  23. Livingstone L. R., White A., Sprouse J., Livanos E., Jacks T., Tlsty T. D. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell. 1992 Sep 18;70(6):923–935. doi: 10.1016/0092-8674(92)90243-6. [DOI] [PubMed] [Google Scholar]
  24. Lynn S., Lai H. T., Gurr J. R., Jan K. Y. Arsenite retards DNA break rejoining by inhibiting DNA ligation. Mutagenesis. 1997 Sep;12(5):353–358. doi: 10.1093/mutage/12.5.353. [DOI] [PubMed] [Google Scholar]
  25. Milner J. E. The effect of ingested arsenic on methylcholanthrene-induced skin tumors in mice. Arch Environ Health. 1969 Jan;18(1):7–11. doi: 10.1080/00039896.1969.10665366. [DOI] [PubMed] [Google Scholar]
  26. Moore M. M., Harrington-Brock K., Doerr C. L. Relative genotoxic potency of arsenic and its methylated metabolites. Mutat Res. 1997 Jun;386(3):279–290. doi: 10.1016/s1383-5742(97)00003-3. [DOI] [PubMed] [Google Scholar]
  27. Pershagen G., Nordberg G., Björklund N. E. Carcinomas of the respiratory tract in hamsters given arsenic trioxide and/or benzo[a]pyrene by the pulmonary route. Environ Res. 1984 Aug;34(2):227–241. doi: 10.1016/0013-9351(84)90091-4. [DOI] [PubMed] [Google Scholar]
  28. Rees J. L., Healy E. Molecular genetic approaches to non-melanoma and melanoma skin cancer. Clin Exp Dermatol. 1996 Jul;21(4):253–262. doi: 10.1111/j.1365-2230.1996.tb00089.x. [DOI] [PubMed] [Google Scholar]
  29. Rossman T. G., Stone D., Molina M., Troll W. Absence of arsenite mutagenicity in E coli and Chinese hamster cells. Environ Mutagen. 1980;2(3):371–379. doi: 10.1002/em.2860020307. [DOI] [PubMed] [Google Scholar]
  30. Rossman T. G., Uddin A. N., Burns F. J., Bosland M. C. Arsenite is a cocarcinogen with solar ultraviolet radiation for mouse skin: an animal model for arsenic carcinogenesis. Toxicol Appl Pharmacol. 2001 Oct 1;176(1):64–71. doi: 10.1006/taap.2001.9277. [DOI] [PubMed] [Google Scholar]
  31. Rossman T. G., Wolosin D. Differential susceptibility to carcinogen-induced amplification of SV40 and dhfr sequences in SV40-transformed human keratinocytes. Mol Carcinog. 1992;6(3):203–213. doi: 10.1002/mc.2940060306. [DOI] [PubMed] [Google Scholar]
  32. Tinwell H., Stephens S. C., Ashby J. Arsenite as the probable active species in the human carcinogenicity of arsenic: mouse micronucleus assays on Na and K arsenite, orpiment, and Fowler's solution. Environ Health Perspect. 1991 Nov;95:205–210. doi: 10.1289/ehp.9195205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Trouba K. J., Wauson E. M., Vorce R. L. Sodium arsenite-induced dysregulation of proteins involved in proliferative signaling. Toxicol Appl Pharmacol. 2000 Apr 15;164(2):161–170. doi: 10.1006/taap.1999.8873. [DOI] [PubMed] [Google Scholar]
  34. Tseng W. P., Chu H. M., How S. W., Fong J. M., Lin C. S., Yeh S. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J Natl Cancer Inst. 1968 Mar;40(3):453–463. [PubMed] [Google Scholar]
  35. Tseng W. P. Effects and dose--response relationships of skin cancer and blackfoot disease with arsenic. Environ Health Perspect. 1977 Aug;19:109–119. doi: 10.1289/ehp.7719109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tsuda T., Babazono A., Yamamoto E., Kurumatani N., Mino Y., Ogawa T., Kishi Y., Aoyama H. Ingested arsenic and internal cancer: a historical cohort study followed for 33 years. Am J Epidemiol. 1995 Feb 1;141(3):198–209. doi: 10.1093/oxfordjournals.aje.a117421. [DOI] [PubMed] [Google Scholar]
  37. Vogt B. L., Rossman T. G. Effects of arsenite on p53, p21 and cyclin D expression in normal human fibroblasts -- a possible mechanism for arsenite's comutagenicity. Mutat Res. 2001 Jul 1;478(1-2):159–168. doi: 10.1016/s0027-5107(01)00137-3. [DOI] [PubMed] [Google Scholar]
  38. Warner M. L., Moore L. E., Smith M. T., Kalman D. A., Fanning E., Smith A. H. Increased micronuclei in exfoliated bladder cells of individuals who chronically ingest arsenic-contaminated water in Nevada. Cancer Epidemiol Biomarkers Prev. 1994 Oct-Nov;3(7):583–590. [PubMed] [Google Scholar]
  39. Wilbourn J., Haroun L., Heseltine E., Kaldor J., Partensky C., Vainio H. Response of experimental animals to human carcinogens: an analysis based upon the IARC Monographs programme. Carcinogenesis. 1986 Nov;7(11):1853–1863. doi: 10.1093/carcin/7.11.1853. [DOI] [PubMed] [Google Scholar]
  40. Ziegler A., Jonason A. S., Leffell D. J., Simon J. A., Sharma H. W., Kimmelman J., Remington L., Jacks T., Brash D. E. Sunburn and p53 in the onset of skin cancer. Nature. 1994 Dec 22;372(6508):773–776. doi: 10.1038/372773a0. [DOI] [PubMed] [Google Scholar]
  41. de Gruijl F. R. Skin cancer and solar UV radiation. Eur J Cancer. 1999 Dec;35(14):2003–2009. doi: 10.1016/s0959-8049(99)00283-x. [DOI] [PubMed] [Google Scholar]
  42. zur Hausen H. Papillomavirus infections--a major cause of human cancers. Biochim Biophys Acta. 1996 Oct 9;1288(2):F55–F78. doi: 10.1016/0304-419x(96)00020-0. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES