Changes in urine composition, bladder epithelial morphology, and DNA synthesis in male F344 rats in response to ingestion of bladder tumor promoters.

An investigation of changes in urine composition, morphology of bladder epithelium, and levels of DNA synthesis following 4 or 8 weeks oral administration of bladder tumor promoters or analogs without promotion potential was performed. The sodium salts of L-ascorbate, o-phenylphenate, and bicarbonate increased the pH value, sodium content, volume, and MgNH4PO4 crystalluria of the urine, while the parent compounds, L-ascorbic acid and o-phenylphenol, which in contrast are not tumor promoters, did not induce these changes. Sodium chloride ingestion caused natriuresis without increasing urinary pH. Diphenyl administration produced only microcalculi consisting of p-phenylphenol. Treatment with the antioxidants butylated hydroxytoluene, butylated hydroxyanisole, and ethoxyquin was also not associated with any changes in urinary pH or Na ions. However, tert-butylhydroquinone did cause an increase in pH. Administration of the strong bladder carcinogens N-butyl-N-(4-hydroxybutyl)nitrosamine and N-ethyl-N-(4-hydroxybutyl)nitrosamine did not result in alteration of urine composition, with the exception of a decrease in phosphorus concentration. However, all the bladder promoters and carcinogens, without exception, brought about an elevation of DNA synthesis in the urothelium and produced morphologic surface alterations such as formation of pleomorphic or short, uniform microvilli and ropy or leafy microridges. Thus, an ability to induce proliferation and cell surface alteration was characteristic of the complete range of bladder promoters investigated. The results suggest that considerable variation in the mechanisms underlying these changes may be involved for different individuals or groups of agents.