8 month, C57BL/6TacfBR-[KO]p53 (p53+/-), female mouse, Mus musculus
6 month carcinogenicity study. The mouse was one of a group of p53+/- mice orally gavaged for 6 months with 400 mg/kg/day p-cresidine as a positive control an International Life Sciences Institute (ILSI)-sponsored short-term carcinogenicity test. The mouse survived until the scheduled necropsy.
The only gross lesion was bilateral granularity of the kidneys.
LABORATORY RESULTS: (clinical pathology, microbiology, etc…)
MORPHOLOGIC DIAGNOSI(E)S AND ETIOLOGY:
Urinary bladder: transitional cell carcinoma, invasive
Urinary bladder: transitional epithelium hyperplasia
Etiology: p-cresidine toxicity
Kidney papilla: necrosis with detachment
Kidney: tubular degeneration and scarring, segmental
Almost all of the 30 mice dosed with p-cresidine in this study had hyperplasia of the urinary bladder epithelium, and 9/30 also had transitional cell carcinomas, as expected. The carcinoma in this case has invaded through to the serosal surface of the bladder wall (serosa is shown in image from file, p-cresidine mouse bladder 10X serosa.tif).
Unexpected were the severe renal lesions in this mouse and in most of the p-cresidine dosed mice. The kidney has a large piece of completely necrotic papilla that appears to have detached from the remnant viable papilla. Large areas of the cortex and medulla have tubular degeneration and scarring.
The cause of the renal lesions is unclear. A possibility is that urothelial proliferation in the bladder led to partial ureteral obstruction with subsequent vesicoureteral reflux. Urinary tract obstruction can lead to renal papillary necrosis and to pyelonephritis. In the present study there did not appear to be a direct correlation between extent of bladder urothelial proliferation and severity of renal lesions, nor did an infectious process appear to be involved.
A number of chemicals, in addition to non-steroidal anti-inflammatory drugs, that can cause renal papillary necrosis have been identified. The necrotic renal papilla may slough, as occurred with this mouse. Cortical degeneration and scarring frequently are concurrent with, and possibly secondary to, papillary necrosis. Nephrotoxicity caused by ethoxyquin in rats has involved papillary necrosis in conjunction with pyelonephritis, and a single dose of bromoethylamine hydrobromide has been reported to induce papillary necrosis in rats. Mice dosed with 2,2-Bis(bromomethyl)-1,3-propanediol for 13 weeks were reported to have renal papillary necrosis, tubular regeneration with fibrosis, and hyperplasia of the urinary bladder epithelium, the same set of lesions as in the mice dosed with p-cresidine presented here.
- Tennant RW, Spalding J, French JE. Evaluation of transgenic mouse bioassays for identifying carcinogens and noncarcinogens. Mutation Research 365:119-27, 1996.
- Tennant RW, French JE, Spalding JW. Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environmental Health Perspectives. 103:942-50, 1995.
- Rubin RH, Cotran RS, Tolkoff-Rubin NE. Urinary tract infection, pyelonephritis, and reflux nephropathy. In: Brenner & Rector's The Kidney. Brenner BM, ed., 5th Ed, Volume II, W.B. Saunders, Philadelphia, 1597-1654, 1996.
- Bach PH, Thanh NTK. Renal papillary necrosis--40 years on. Toxicologic Pathology 26:73-91, 1998.
- Hard GC, Neal GE. Sequential study of the chronic nephrotoxicity induced by dietary administration of ethoxyquin in Fischer 344 rats. Fundamental and Applied Toxicology 18:278-287, 1992.
- Eknoyan G. Renal papillary necrosis. In: Massry & Glassock's Textbook of Nephrology. Massry SG, Glassock RJ, eds., 3rd Ed, Volume 1, Williams & Wilkins, Baltimore,765-771, 1995.
- Elwell MR, Dunnick JK, Brown HR, Montgomery CA. Kidney and urinary bladder lesions in F344/N rats and B6C3F1 mice after 13 weeks of 2,2-Bis(bromomethyl)-1,3-propanediol administration. Fundamental and Applied Toxicology 12:480-490, 1989
- Murray G, Wyllie RG, Hill GS, Ramsden PW, Heptinstall RH. Experimental papillary necrosis of the kidney. I. Morphologic and functional data. American Journal of Pathology 67:285-302, 1972.
Urinary bladder H&E
Urinary bladder H&E