This study examined the response of the Eker rat to nephrotoxic compounds and to genotoxic nonrenal carcinogens. Groups of male Eker rats received either no treatment; a vehicle treatment; treatment with a noncarcinogeni c nephrotoxin (aluminum nitrilotriacetate, 2 mg/kg/day of aluminum, intraperitoneally, 3 days per week or cyclosporine A, 30 mg/kg/day, orally by gavage, 7 days/week); or treatment with a genotoxic nonrenal carcinogen (furan, 8 mg/kg/day, orally by gavage, 5 days/week or 2,4-diaminotoluene, 6.5 mg/kg/day, orally by gavage, 7 days/week or 2-nitropropane, 89 mg/kg/day, orally by gavage, 3 days/week). Duration of treatment was 4 and/or 6 months. Tissues from the Eker rats were evaluated microscopically and numbers of proliferative renal lesions were counted. Administration of nephrotoxic compounds (Al-NTA and cyclosporine) significantly increased the number of preneoplasti c and neoplasti c renal lesions in the Eker rat compared to concurrent vehicle controls. The genotoxi c nonrenal carcinogens had no consistent effect on numbers of preneoplastic or neoplastic renal lesions and did not produce neoplasms in the expected target organ (liver).
Crino PB, Henske EP (1999). New development s in the neurobiology of the tuberous sclerosis complex. Neurology53: 1384—1390.
2.
European Chromosome 16 Tuberous Sclerosis Consortium (1993). Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell75: 1305—1315.
3.
Everitt JI, Goldsworthy TL, Wolf DC, Walker CL (1992). Hereditary renal cell carcinoma in the Eker model: A rodent cancer syndrome with similarities to von-Hippel-Lindau disease. J Urol148: 1932—1936.
4.
Everitt JI, Goldsworthy TL, Wolf DC, Walker CL (1995). Hereditary renal carcinoma in the Eker rat: A unique animal model for the study of cancer susceptibility. Toxicol Lett82/83: 621—625.
5.
Green AJ, Smith M., Yates JRW (1994). Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nature Gen6: 193—196.
6.
Hino O., Klein-Szanto AJP, Freed JJ, Testa JR, Brown DQ, Vilensky M., Yeung RS, Tartof KD, Knudson AG (1993). Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer. Proc Natl Acad Sci USA90: 327—331.
7.
Hino O., Kobayashi T., Mitani H., Kobayashi E., Kubo Y., Tsuchiya H., Kekuchi Y., Nishizawa M., Hirayama Y. (1995). The Eker rat, a model of dominantly inherited cancer syndrome. Transplant Proc27: 1529—1531.
8.
Hino O., Kobayashi T., Tsuchiya H., Kikuchi Y., Kobayashi E., Mitani H., Hirayama Y. (1994). The predisposing gene of the Eker rat inherited cancer syndrome is tightly linked to the tuberous sclerosis (Tsc2) gene. Biochem Biophys Res Comm203: 1302—1308.
9.
Hino O., Mitani H., Knudson AG (1993). Genetic predisposition to transplacentally induced renal cell carcinomas in the Eker rat. Cancer Res53: 5856—5858.
10.
International Conference on Harmonisation (1998). Guidance on testing for carcinogenicity of pharmaceuticals . Fed Regist63: 8963—8986.
11.
Kobayashi T. , Urakami S., Hirayama Y., Yamamoto T., Nishizawa M., Takahara T., Kubo Y., Hino O. (1997). Intragenic Tsc2 somatic mutations as Knudson's second hit in spontaneous and chemically induced renal carcinomas in the Eker rat model. Jpn J Cancer Res88: 254—261.
12.
Kubo Y., Kikuchi Y., Mitani H., Kobayashi E., Kobayashi T., Hino O. ( 1995). Allelic loss at the tuberous sclerosis (Tsc2) gene locus in spontaneou s uterine leiomyosarcoma s and pituitary adenoma s in the Eker rat model. Jpn J Canc Res86: 828—832.
13.
Lau SS, Monks TJ, Everitt JI, Kleymenova E., Walker CW (2001). Carcinogenicity of a nephrotoxic metabolite of the “nongenotoxic” carcinogen hydroquinone. Chem Res Toxicol14: 25—33.
Nellist M., van Slegtenhorst MA, Goedbloed M., van den Ouweland MW, Halley DJJ, van der Sluijs P. (1999). Characterization of the cytosolic tuberin-hamartin complex. J Biol Chem50: 35647—35652.
16.
Tennant RW, Spalding J., French JE (1996). Evaluation of transgenic mouse bioassays for identifying carcinogens and noncarcinogens. Mutation Res365: 119—127.
17.
Van Slegtenhorst MA, de Hoogt R., Hermans C., Nellist M., Janssen B., Verhoef S., Lindhout D., van den Ouweland A., Halley D., Young J., Burley M., Jeremiah S., Woodward K., Nahmias J., Fox M., Ekong R., Osborne J., Wolfe J., Povey S., Snell RG, Cheadle JP, Jones AC, Tachataki M., Ravine D., Sampson JR, Reeve MP, Richardson P., Wilmer F., Munro C., Hawkins TL, Sepp T., Ali JBM, Ward S., Green AJ, Yates JRW, Kwiatkowska J., Henske EP, Short MP, Haines JH, Jozwiak S., Kwiatkowski DJ (1997). Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science277: 805—808.
18.
Walker CL, Goldsworthy TL, Wolf DC, Everitt JI (1992). Predisposition to renal cell carcinoma due to alteration of a cancer susceptibility gene. Science255: 1693—1695.
19.
Wolf DC, Goldsworthy TL, Donner EM, Harden R., Fitzpatrick B., Everitt JI (1998). Estrogen treatment enhances hereditary renal tumor development in Eker rats. Carcinogenesis19: 2043—2947.
20.
Xiao G-H., Yeung RS (1995) Germ-line Tsc2 mutation in a dominantly inherited cancer model defines a novel family of rat intracisternal-A particle elements . Oncogene11: 81—87.
21.
Yeung RS, Guang-Hui X., Everitt JI, Jin F., Walker CL (1995). Allelic loss at the tuberous sclerosis 2 locus in spontaneous tumors in the Eker rat. Mol Carcinogen14: 28—36.
22.
Yeung RS, Guang-Hui X., Jin F., Lee W-C., Testa JR, Knudson AG (1994). Predisposition for renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc Natl Acad Sci USA91: 11413—11416.
23.
Yeung RS, Katsetos CD, Klein-Szanto A. (1997). Subependymal astrocytic hamartomas in the Eker rat model of tuberous sclerosis. Am J Pathol151: 1477—1486.
