The Journal of Urology | 2019
MP63-02\u2003E-CIGARETTE SMOKE IS POTENTIALLY BLADDER CARCINOGENIC - IT INDUCES DNA DAMAGE AND UROTHELIAL HYPERPLASIA IN MICE
Abstract
INTRODUCTION AND OBJECTIVES: Electronic-cigarette smoke (ECS) is designed to deliver nicotine via controlled heating of nicotine-containing organic solution. This process involves neither tobacco leaves nor burning. ECS is therefore considered a safe alternative to tobacco smoke (TS), because ECS delivers a TS ‘high’ without carrying the TS negative effects. However, we found that ECS induces mutagenic DNA adducts in the mouse bladder mucosa. We also found that nicotine not only induces the same DNA adducts, reduces DNA repair capacity but also enhances human urothelial cells’ mutational and tumorigenic transformation susceptibility in vitro. We propose that ECS may induce bladder cancer. In this study we tested the ECS bladder tumorigenicity in mice. METHODS: 1. ECS exposure. Mice were exposed to ECS generated from e-juice [nicotine plus Vehicle (polypropylene glycol and glycerin)], Vehicle or filtered ambient air 4 h/day, 5 d/wk for 52 weeks. 2. Histopathology. Bladders were fixed in buffered Formalin and embedded in paraffin at the end of exposure. Urothelial cross-sections were stained with H&E or antibodies for proliferation markers MCM-2 and PCNA and basal cell marker KRT5. RESULTS: Although no tumor was detected in the bladders of all the experimental groups, simple urothelial hyperplasia, characterized by significantly increased urothelial layers (5-8 layers), as opposed to 3 layers in normal mice, were evident in mice exposed to ECS. These lesions showed significant expansion of Krt5-positive basal urothelial cells, and marked elevation of cell proliferation markers, MCM2 and PCNA. Nodular hyperplasia was also frequently observed, with fibrovascular cores and branching proliferative urothelial structures. Overall, 18 of 30 (60%) ECS-exposed mice, 1 of 16 (6.3%) vehicle-exposed mice and 0 of 17 (0%) filtered air-exposed mice developed urothelial hyperplasia (p<0.001). CONCLUSIONS: ECS induces urothelial hyperplasia in mice. These results combined with our recent findings that ECS induces mutagenic DNA adducts in bladder mucosa and that nicotine reduces DNA repair capacity, sensitizes cultured human urothelial cells to mutation and tumorigenic cell transformation, indicate that ECS is a potential bladder carcinogen. Longer-term exposure of additional mice is underway to provide a more definitive conclusion. Source of Funding: This research was supported by grants from NIH (R01CA190678, 1P01CA165980, and ES00260) and Center of Excellence for Urological Research at New York University School of Medicine.