Inhalation of tobacco smoke induces increased proliferation of urinary bladder epithelium and endothelium in female C57BL/6 mice.
Cigarette smoking is the major environmental risk factor for bladder cancer in humans. Aromatic amines, potent DNA-reactive bladder carcinogens present in cigarette smoke, contribute significantly. However, increased cell proliferation, caused by direct mitogenesis or in response to cytotoxicity, may also play a role since urothelial hyperplasia has been observed in human cigarette smokers. We examined the urothelial effects of cigarette smoke (whole body inhalation exposure (Teague) system) in female C57BL/6 mice at various times in two studies, including reversibility evaluations. In both studies, no urothelial hyperplasia was observed by light microscopy in any group. However, in study 1, the Ki-67 labeling index (LI) of the urothelium was significantly increased in the smoke exposed group compared to controls through 3 months, but was not present at 6, 9 or 12 months even with continued exposures. In the groups that discontinued smoke exposure, it returned to the same levels as controls or lower. In study 2, the bromodeoxyuridine LI was similar to controls on day 1 but significantly increased at 5 days in the smoke exposed group. In the group that discontinued smoke exposure for 2 days, the LI was increased compared to controls but not significantly. Superficial urothelial cell cytotoxicity and necrosis were detectable by scanning electron microscopy at 5 days. Changes in LI of submucosal endothelial cells generally followed those of the urothelium and effects were reversible upon cessation of exposure. The increased urothelial proliferation appeared to be due to superficial cell cytotoxicity with consequent regeneration.
Ohnishi
Takamasa
T
Department of Pathology and Microbiology, Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-3135, United States.
Arnold
Lora L
LL
He
Jun
J
Clark
Nicole M
NM
Kawasaki
Shin
S
Rennard
Stephen I
SI
Boyer
Craig W
CW
Cohen
Samuel M
SM
D000818:Animals; D000963:Antimetabolites; D001973:Bromodeoxyuridine; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D008934:Mitogens / Q000633:toxicity; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012907:Smoking / Q000473:pathology*; D001743:Urinary Bladder / Q000473:pathology*
D000963:Antimetabolites; D019394:Ki-67 Antigen; D008934:Mitogens; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D001973:Bromodeoxyuridine