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. 2005 Aug 19;95(5):393–398. doi: 10.1111/j.1349-7006.2004.tb03221.x

Dose‐related changes of oxidative stress and cell proliferation in kidneys of male and female F344 rats exposed to potassium bromate

Takashi Umemura 1,✉, Yasuki Kitamura 1, Keita Kanki 1, Satoshi Maruyama 1, Kazushi Okazaki 1, Takayoshi Imazawa 1, Tetsuji Nishimura 2, Ryuichi Hasegawa 3, Akiyoshi Nishikawa 1, Masao Hirose 1
PMCID: PMC11158485  PMID: 15132765

Abstract

It is still of importance to investigate renal carcinogenesis by potassium bromate (KBrO3), a by‐product of water disinfection by ozonation, for assessment of the risk to man. Five female F344 rats in each group were given KBrO3 at a dose of 300 mg/kg by single i.g. intubation or at a dose of 80 mg/kg by single i.p. injection, and were killed 48 h after the administration for measurements of thiobarbituric acid‐reactive substances (TBARS) and 8‐oxodeoxyguanosine (8‐oxodG) levels in the kidney. Both levels in the treated animals were significantly elevated as compared with the control values. In a second experiment, 5 male and female F344 rats in each group were administered KBrO3 at concentrations of 0, 15, 30, 60, 125, 250 and 500 ppm in the drinking water for 4 weeks. KBrO3 in the drinking water did not elevate TBARS in either sex at any of the doses examined, but 8‐oxodG formation in both sexes at 250 ppm and above was significantly higher than in the controls. Additionally, the bromodeoxyuridine‐labeling index for proximal convoluted tubules was significantly increased at 30 ppm and above in the males, and at 250 ppm and above in the females. α2u‐Globulin accumulation in the kidneys of male rats was increased with statistical significance at 125 ppm and above. These findings suggest that DNA oxidation induced by KBrO3 may occur independently of lipid peroxidation and more than 250 ppm KBrO3 in the drinking water can exert a carcinogenic effect by way of oxidative stress.

References

  • 1. International Agency for Research on Cancer . Potassium bromate. IARC Monogr Eval Carcinog Risks Hum 1999; 73: 481–96. [PMC free article] [PubMed] [Google Scholar]
  • 2. Kurokawa Y, Hayashi Y, Maekawa A, Takahashi M, Kokubo T. Induction of renal cell tumors in F‐344 rats by oral administration of potassium bromate, a food additive. Gann 1982; 73: 335–8. [PubMed] [Google Scholar]
  • 3. The Ministry of Health and Welfare Japan . The Japanese Standards of Food Additives. 5th ed. The Ministry of Health and Welfare: Tokyo ; 1986. p. 433. [Google Scholar]
  • 4. Krasner SW, McGuire MJ, Jacagnelo JG, Patania NL, Reagan KM, Aieta EM. The occurrence of disinfection by‐products in U.S. drinking water. J Am Water Works Assoc 1989; 81: 41–3. [Google Scholar]
  • 5. Jorgenson TA, Meierhenry EF, Rushbrook CJ, Bull RJ, Robinson M. Carcinogenicity of chloroform in drinking water to male Osborne‐Mendel rats and female B6C3F1 mice. Fundam Appl Toxicol 1986; 5: 760–9. [DOI] [PubMed] [Google Scholar]
  • 6. Carmichael NG, Winder C, Borges SH, Backhouse BL, Lewis PD. The health implications of water treatment with ozone. Life Sci 1982; 30: 117–29. [DOI] [PubMed] [Google Scholar]
  • 7. Cavanagh JE, Weinberg HS, Gold A, Sangalah R, Marbury D, Glase WH, Collette TW, Richardson SD, Thruston AD. Ozonation byproducts: identification of bromohydrins from the ozonation of natural waters with enhanced bromide levels. Environ Sci Technol 1992; 26: 1658–62. [Google Scholar]
  • 8. Ishidate M, Sofuni T, Yoshikawa K, Hayashi M, Nohmi T, Sawada T, Matsuoka A. Primary mutagenicity screening of food additives currently used in Japan. Food Chem Toxicol 1984; 22: 623–36. [DOI] [PubMed] [Google Scholar]
  • 9. Ishidate M, Yoshioka K. Chromosome aberration tests with Chinese hamster cells in vitro with and without metabolic activation: a comparative study on mutagens and carcinogens. Arch Toxicol 1980; Suppl 4: 41–4. [DOI] [PubMed] [Google Scholar]
  • 10. Hayashi M, Kishi M, Sofuni T, Ishidate M. Micronucleus tests with mice on 39 food additives and 8 miscellaneous chemical substances. Chem Toxicol 1988; 26: 487–500. [DOI] [PubMed] [Google Scholar]
  • 11. Persons JL, Chipman JK. The role of glutathione in DNA damage by potassium bromate in vitro. Mutagenesis 2000; 15: 311–6. [DOI] [PubMed] [Google Scholar]
  • 12. Ballmaier D, Epe B. Oxidative DNA damage induced by potassium bromate under cell‐free conditions and in mammalian cells. Carcinogensis 1995; 16: 335–42. [DOI] [PubMed] [Google Scholar]
  • 13. Kasai H, Nishimura S, Kurokawa Y, Hayashi Y. Oral administration of the renal carcinogen, potassium bromate, specifically produces 8‐hydroxydeox‐yguanosine in rat target organ DNA. Carcinogenesis 1987; 8: 1959–61. [DOI] [PubMed] [Google Scholar]
  • 14. Cadenas S, Barja G. Resveratol, melatonin, vitamin E and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3 . Free Radic Biol Med 1999; 26: 1531–7. [DOI] [PubMed] [Google Scholar]
  • 15. Arashidani K, Iwamoto‐Tanaka N, Muraoka M, Kasai K. Genotoxicity of ribo‐ and deoxyribonucleosides of 8‐hydroxyguanine, 5‐hydroxycytosine, and 2‐hydroxyadenine: induction of SCE in human lymphocytes and mutagenicity in Salmonella typhimurium TA100. Mutat Res 1998; 403: 223–7. [DOI] [PubMed] [Google Scholar]
  • 16. Cheng KC, Cahill DS, Kasai H, Nishimura S, Loeb LA. 8‐Hydroxyguanine, an abundant form of oxidative DNA damage, causes G‐T and A‐C substitutions. J Biol Chem 1992; 267: 166–72. [PubMed] [Google Scholar]
  • 17. Le Page F, Margot A, Grollman AP, Sarasin A, Gentil A. Mutagenicity of a unique 8‐oxoguanine in a human Ha‐ras sequence in mammalian cells. Carcinogenesis 1995; 16: 2779–84. [DOI] [PubMed] [Google Scholar]
  • 18. Nakae D, Umemura T, Kurokawa Y. Reactive oxygen and nitrogen oxide species‐induced stress, a major intrinsic factor involved in carcinogenesis processes and a possible target for cancer prevention. Asian Pacific J Cancer Prev 2002; 3: 313–8. [PubMed] [Google Scholar]
  • 19. Umemura T, Takagi A, Sai K, Haesgawa R, Kurokawa Y. Oxidative DNA damage and cell proliferation in kidneys of male and female rats during 13‐weeks exposure to potassium bromate (KBrO3). Arch Toxicol 1998; 72: 264–9. [DOI] [PubMed] [Google Scholar]
  • 20. Kurokawa Y, Takamura N, Matsuoka C, Imazawa T, Matsushima Y, Onodera H, Hayashi Y. Comparative studies on lipid peroxidation in the kidney of rats, mice, and hamsters and on the effects of cysteine, glutathione, and diethyl maleate treatment on mortality and nephrotoxicity after administration of potassium bromate. J Am Coll Toxicol 1987; 6: 489–501. [Google Scholar]
  • 21. Chipman JK, Davies JE, Parsons JL, Nair J, O'Neill G, Fawell JK. DNA oxidation by potassium bromate; a direct mechanism or linked to peroxidation Toxicology 1998; 126: 93–102. [DOI] [PubMed] [Google Scholar]
  • 22. Chung FL, Chen HJC, Nath RG. Lipid peroxidation as a potential endogenous source for the formation of exocyclic DNA adducts. Carcinogenesis 1996; 17: 2105–11. [DOI] [PubMed] [Google Scholar]
  • 23. Moller P, Wallin H. Adduct formation, mutagenesis and nucleotide excision repair of DNA damage produced by reactive oxygen species and lipid peroxidation product. Mutat Res 1998; 410: 271–90. [DOI] [PubMed] [Google Scholar]
  • 24. Kurokawa Y, Takahashi M, Kokubo T, Ohno Y, Hayashi Y. Enhancement by potassium bromate of renal tumorigenesis initiated by N‐ethyl‐N‐hydroxy‐ethylnitrosamine in F‐344 rats. Gann 1983; 74: 607–10. [PubMed] [Google Scholar]
  • 25. Umemura T, Sai K, Takagi A, Hasegawa R, Kurokawa Y. A possible role for oxidative stress in potassium bromate (KBrO3) carcinogenesis. Carcinogenesis 1995; 16: 593–7. [DOI] [PubMed] [Google Scholar]
  • 26. Umemura T, Sai K, Takagi A, Hasegawa R, Kurokawa Y. A possible role for cell proliferation in potassium bromate (KBrO3) carcinogenesis. J Cancer Res Clin Oncol 1993; 119: 463–9. [DOI] [PubMed] [Google Scholar]
  • 27. Sai K, Takagi A, Umemura T, Hasegawa R, Kurokawa Y. Relation of 8‐hydroxydeoxyguanosine formation in rat kidney to lipid peroxidation, glutathione level and relative organ weight after a single administration of potassium bromate. Jpn J Cancer Res 1991; 82: 165–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Nakae D, Mizumoto Y, Kobayashi E, Noguchi O, Konishi Y. Improved genomic/nuclear DNA extraction for 8‐hydroxydeoxyguanosine analysis of small amounts of rat liver tissue. Cancer Lett 1995; 97: 233–9. [DOI] [PubMed] [Google Scholar]
  • 29. Uchiyama M, Mihara M. Determination of malonaldehyde precursor in tissue by the thiobarbituric acid test. Anal Biochem 1978; 86: 271–8. [DOI] [PubMed] [Google Scholar]
  • 30. Rutenburg AM, Kim H, Fiscbein JW, Hanker JS, Wasserkrug HL, Seligman AM. Histochemical and ultrastructual demonstration of gamma‐transpeptidase activity. J Histochem Cytochem 1969; 1: 517–26. [DOI] [PubMed] [Google Scholar]
  • 31. Umemura T, Tokumo K, Williams GM. Cell proliferation induced in the kidneys and livers of rats and mice by short term exposure to the carcinogen p‐dichlorobenzene. Arch Toxicol 1992; 66: 503–7. [DOI] [PubMed] [Google Scholar]
  • 32. Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis 2000; 21: 361–70. [DOI] [PubMed] [Google Scholar]
  • 33. Kurata Y, Diwan BA, Ward JM. Lack of renal tumor‐initiating activity of a single dose of potassium bromate, a genotoxic renal carcinogen in male F344/NCr rats. Food Chem Toxicol 1992; 30: 251–9. [DOI] [PubMed] [Google Scholar]
  • 34. Murata M, Bansho Y, Inoue S, Ito K, Ohnishi S, Midorikawa K, Kawanishi S. Requirement of glutathione and cysteine in guanine‐specific oxidation of DNA by carcinogenic potassium bromate. Chem Biol Toxicol 2001; 14: 678–85. [DOI] [PubMed] [Google Scholar]
  • 35. Zager RA, Burkhart KM. Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin‐induced proximal tubular cell attack. Kidney Int 1998; 53: 1661–72. [DOI] [PubMed] [Google Scholar]
  • 36. Kurokawa Y, Aoki S, Matsushima Y, Takamura N, Imazawa T, Hayashi Y. Dose‐response studies on the carcinogenicity of potassium bromate in F344 rats after long‐term oral administration. J Natl Cancer Inst 1986; 77: 977–82. [PubMed] [Google Scholar]
  • 37. Wolf DC, Crosby LM, George MH, Kilburn SR, Moore TM, Miller RT, DeAngelo AB. Time‐ and dose‐dependent development of potassium bromate‐induced tumors in male Fischer 344 rats. Toxicol Pathol 1998; 26: 724–9. [DOI] [PubMed] [Google Scholar]
  • 38. Short BG, Burnett VL, Swenberg JA. Elevated proliferation of proximal tubule cells and localization of accumulated alpha2u‐globulin in F344 rats during chronic exposure to unleaded gasoline or 2,2,4‐trimethylpentane. Toxicol Appl Pharmacol 1989; 101: 414–31. [DOI] [PubMed] [Google Scholar]
  • 39. Richardson KA, Wimer JL, Smith‐Simpson D, Skoper TR. Assessment of the genotoxic potential of unleaded gasoline and 2,2,4‐trimethylpentane in human lymphoblasts in vitro. Toxicol Appl Pharmacol 1986; 82: 316–22. [DOI] [PubMed] [Google Scholar]
  • 40. Umemura T, Kodama Y, Kurokawa Y, Williams GM. Lack of oxidative DNA damage or initiation of carcinogenesis in the kidneys of male F344 rats given subchronic exposure to p‐dichlorobenzene (pDCB) at a carcinogenic dose. Arch Toxicol 2000; 73: 54–9. [DOI] [PubMed] [Google Scholar]
  • 41. Charbonneau M, Strasser J, Lock EA, Turner MJ, Swenberg JA. Involvement of reversible binding to alpha2u‐globulin in 1,4‐dichlorobenzene‐induced nephrotoxicity. Toxicol Appl Pharmacol 1989; 99: 122–32. [DOI] [PubMed] [Google Scholar]
  • 42. Cerutti PA The role of active oxygen in tumor promotion. In: Curtis C, Harris C, editors. Biochemical and molecular epidemiology of cancer. New York : Alan R Liss; 1986. p. 167–76. [Google Scholar]
  • 43. Kensler TW, Egner PA, Taffe BG, Trush MA. Role of free radicals in tumor promotion and progression. In: Slaga TJ, Klein‐Szanto AJP, Boutwell RK, Stevenson DE, Spitzer HL, D'Motto B, editors. Skin carcinogenesis: Mechanisms and human relevance. New York : Alan R Liss; 1989. p. 233–48. [PubMed] [Google Scholar]
  • 44. Umemura T, Kai S, Hasegawa R, Kanki K, Kitamura Y, Nishikawa A, Hirose M. Prevention of dual promoting effects of pentachlorophenol, an environmental pollutant, on diethylnitrosamine‐induced hepato‐ and cholangiocarcinogenesis in mice by green tea infusion. Carcinogenesis 2003; 24: 1105–9. [DOI] [PubMed] [Google Scholar]
  • 45. Kurokawa Y, Maekawa A, Takahashi M, Hayashi Y. Toxicity and carcinogenicity of potassium bromate–a new renal carcinogen. Environ Health Perspect 1990; 87: 309–35. [DOI] [PMC free article] [PubMed] [Google Scholar]

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