Responses of rat urine and urothelium to bladder tumor promoters: possible roles of prostaglandin E2 and ascorbic acid synthesis in bladder carcinogenesis

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Abstract
An investigation of sequential changes in urine composition, levels of DNA synthesis and morphology of bladder epithelium following administration of the tumor promoters sodium ascorbate (AsA-Na) or butylated hydroxyanisole (BHA) and the non-promoter ascorbic acid (AsA) for 36 weeks was performed. In addition, prostaglandin E2 (PGE2), cAMP and AsA content were assessed in bladder tissue after 16 weeks. While AsA-Na caused increase in pH, sodium content and volume, and a decrease in osmolality of the urine throughout the study, these changes were not observed with AsA administration which resulted in a decrease in urinary pH. BHA treatment was not associated with any urinary changes. AsA-Na brought about a significant elevation of DNA synthesis in the bladder epithelium from weeks 2 to 16 and was associated with simple hyperplasia at week 8, which, however, decreased by week 16 and was no longer evident at weeks 24 and 36 when DNA synthesis returned to normal. Under the scanning electron microscope (SEM), morphologic alterations of the urothelial surface in rats given AsA-Na were observed at weeks 8 and 16, but the appearance at week 36 was almost normal. AsA did not cause any changes in these parameters at any time point. BHA induced a significant elevation of DNA synthesis throughout the study, produced simple hyperplasia at week 36 and alterations of the epithelial surface from weeks 4 to 36. Significant increases of PGE2 and AsA in bladder tissue were noted for the AsA-Na or BHA, but not AsA groups. Moreover, cAMP levels in bladder tissue of rats exposed to AsA-Na or BHA were slightly higher than in the controls. The results suggest that changes in PGE2, cAMP and AsA may be involved in promotion of rat bladder carcinogenesis.