The sequence of cellular alterations in urinary bladder epithelium associated with uracil-induced reversible urolithiasis was investigated in male F344 rats. Initial changes were submucosal edema with occasional mucosal erosion or ulceration which appeared on Day 2 of uracil administration. Simple hyperplasia of bladder epithelium was already evident at this time and calculus formation was noted as early as Day 4. Labeling indices in the bladder epithelium assessed by bromodeoxyuridine incorporation were about 32% on Day 4 and then gradually decreased to 6% at Week 8 and 4% at Week 25 of chronic treatment. Histologically, a direct progression from simple hyperplasias, through papillary hyperplasias to papillomatosis, accomplished by Week 5, was evident. Dysplastic lesions were also apparent by Week 25. Topographically, papillomatosis was composed of marked interconnecting mucosal ridges of relatively uniform width. No polyp-like protrusions were present and the vascular pattern revealed by resin perfusion casting demonstrated that these mucosal lesions were supported by a uniform plexus of capillary vessels. After withdrawal of uracil from the diet the labeling index dropped dramatically to 0.002% after 1 week and urolithiasis and papillomatosis had disappeared by Weeks 2 and 3, respectively.

The findings suggest that papillomatosis associated with uracil-calculi is a hyperplastic rather than a neoplastic response and that induction of putative neoplastic lesions is directly related to prolonged vigorous cell proliferation.

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This research was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture and from the Ministry of Health and Welfare of Japan.

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