Abstract
Ferric nitrilotriacetate (Fe‐NTA), an iron chelate, induces necrosis of renal proximal convoluted tubules as a consequence of lipid peroxidation, and a high incidence of renal cell carcinoma (RCC) is also observed in rats and mice. The incidence of RCC and the extent of lipid peroxidation are greater in males than females. In the present study, the effects of castration or ovariectomy, and sex hormone treatment on Fe‐NTA‐induced renal carcinogenesis in rats were examined. Male and female Wistar rats were each divided into 5 groups. In group 1, rats were sham‐operated and treated intraperitoneally (i.p.) with nitrilotriacetate (NTA). In group 2, sham‐operated rats were treated with Fe‐NTA (5‐10 mg iron/kg/day, i.p.). Castrated or ovariectomized rats treated with Fe‐NTA served as group 3, Group 4 or 5 was treated in the same way as group 3, but in addition received either testosterone (group 4) or estradiol (group 5). NTA, Fe‐NTA or sex hormone treatments were initiated 4 weeks after the operation. NTA or Fe‐NTA treatments were conducted for 12 weeks, and sex hormones were administered for 10 months. After 10 months of treatment, all rats were autopsied and both kidneys were examined histopathologically. In NTA‐treated groups, there was no pathological change in the kidneys. In Fe‐NTA‐treated groups (groups 2‐5), testosterone treatment or ovariectomy increased the incidence of RCC, and estradiol treatment or castration decreased the incidence of RCC (male: sham operation, castration and testosterone treatment > castration > castration and estradiol treatment, female: ovariectomy and testosterone treatment > ovariectomy > sham operation, ovariectomy and estradiol treatment). These results indicate that sex differences observed in the incidence of RCC induced by Fe‐NTA are dependent upon sex hormones.
Keywords: Sex difference, Sex hormone, Renal cell carcinoma, Ferric nitrilotriacetate, Rat
Full Text
The Full Text of this article is available as a PDF (281.3 KB).
REFERENCES
- 1. ) Awai , M. , Narasaki , M. , Yamanoi , Y. and Seno , S.Induction of diabetes in animals by parenteral administration of ferric nitrilotriacetate: a model of experimental hemo‐chromatosis . Am. J. Pathol. , 95 , 663 – 674 ( 1979. ). [PMC free article] [PubMed] [Google Scholar]
- 2. ) Toyokuni , S. , Okada , S. , Hamazaki , S. , Fujioka , M. , Li , J.‐L. and Midorikawa , O.Cirrhosis of the liver induced by cupric nitrilotriacetate in Wistar rats: an experimental model of copper toxicosis . Am. J. Pathol. , 134 , 1263 – 1274 ( 1989. ). [PMC free article] [PubMed] [Google Scholar]
- 3. ) Okada , S. , Hamazaki , S. , Ebina , Y. , Li , J.‐L. and Midorikawa , O.Nephrotoxicity and its prevention by vitamin E in ferric nitrilotriacetate‐promoted lipid peroxidation . Biochem. Biophys. Acta , 922 , 28 – 33 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Hamazaki , S. , Okada , S. , Ebina , Y. , Li , J.‐L. and Midorikawa , O.Effect of dietary vitamin E on ferric nitrilotriacetate‐induced nephrotoxicity in rats . Toxicol. Appl. Pharmacol. , 92 , 500 – 506 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 5. ) Okada , S. and Midorikawa , O.Induction of the rat renal adenocarcinoma by Fe‐nitrilotriacetate (Fe‐NTA) . Jpn. Arch. Intern. Med. , 29 , 485 – 491 ( 1982. ). [Google Scholar]
- 6. ) Ebina , Y. , Okada , S. , Hamazaki , S. , Ogino , F. , Li , J.‐L. and Midorikawa , O.Nephrotoxicity and renal cell carcinoma after use of iron‐ and aluminum‐nitrilotriacetate complexes in rats . J. Natl. Cancer Inst , 76 , 107 – 113 ( 1986. ). [PubMed] [Google Scholar]
- 7. ) Li , J.‐L. , Okada , S. , Hamazaki , S. , Ebina , Y. and Midorikawa , O.Subacute nephrotoxicity and induction of renal cell carcinoma in mice treated with ferric nitrilotriacetate . Cancer Res. , 47 , 1867 – 1869 ( 1987. ). [PubMed] [Google Scholar]
- 8. ) Li , J.‐L. , Okada , S. , Hamazaki , S. , Deng , I.‐L. and Midorikawa , O.Sex difference in ferric nitrilotriacetate‐induced lipid peroxidation and nephrotoxicity in mice . Biochem. Biophys. Acta , 963 , 82 – 87 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Okada , S. , Fukunaga , Y. , Hamazaki , S. , Yamada , Y. and Toyokuni , S.Sex differences in the localization and severity of ferric nitrilotriacetate‐induced lipid peroxidation in the mouse kidney . Acta Pathol. Jpn. , 41 , 221 – 226 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 10. ) Toyokuni , S. , Okada , S. , Hamazaki , S. , Minamiyama , Y. , Yamada , Y. , Liang , P. , Fukunaga , Y. and Midorikawa , O.Combined histochemical and biochemical analysis of sex hormone dependence of ferric nitrilotriacetate‐induced renal lipid peroxidation in ddY mice . Cancer Res. , 50 , 5574 – 5580 ( 1990. ). [PubMed] [Google Scholar]
- 11. ) Subbiah , M. T. R. , Kessel , B. , Agrawal , M , Rajan , R. , Abplanalp , W. and Rymaszewski , Z.Antioxidant potential of specific estrogens on lipid peroxidation . J. Clin. Endocrinol. Metab. , 77 , 1095 – 1097 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Negre‐Salvayre , A. , Pieraggi , M.‐T. , Mabile , L. and Salvayre , R.Protective effect of 17β‐estradiol against the cytotoxicity of minimally oxidized LDL to cultured bovine aortic endothelial cells . Atherosclerosis , 99 , 207 – 217 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Ruiz‐Larrea , M. B. , Leal , A. M. , Liza , M. , Lacort , M. and Groof , H.Antioxidant effects of estradiol and 2‐hydroxy‐estradiol on iron‐induced lipid peroxidation of rat liver microsomes . Steroids , 59 , 383 – 388 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 14. ) Hamazaki , S. , Okada , S. , Toyokuni , S. and Midorikawa , O.Thiobarbituric acid‐reactive substance formation of rat kidney brush border membrane vesicles induced by ferric nitrilotriacetate . Arch. Biochem. Biophys. , 274 , 348 – 354 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Okada , S. , Minamiyama , Y. , Hamazaki , S. , Toyokuni , S. and Sotomatsu , A.Glutathione cycle dependency of ferric nitrilotriacetate‐induced lipid peroxidation in mouse proximal tubules . Arch. Biochem. Biophys. , 301 , 138 – 142 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Ruiz‐Larrea , M. B. , Garrido , M. J. and Lacort , M.Estradiol‐induced effects on glutathione metabolism in rat hepatocytes . J. Biochem. , 113 , 563 – 567 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Wachnik , A. , Biro , G. , Biro , L. , Korom , M. , Gergely , A. and Antal , M.Effect of sex hormones on copper, zinc, iron nutritional status and hepatic lipid peroxidation in rats . Nahrung , 37 , 28 – 34 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 18. ) Cotran , R. S. , Kumar , V. and Robbins , S. L.“Robbins Pathologic Basis of Disease,” 4th Ed. , pp. 1074 – 1078 ( 1989. ). Saunders; , Philadelphia . [Google Scholar]