title: Diuron-induced rat bladder epithelial cytotoxicity.
abstract: Diuron, a substituted urea herbicide, is carcinogenic to the rat urinary bladder at high dietary levels (2500 ppm). To further elucidate the mode of action, this study aimed to determine the time course and sequence of bladder cytotoxic and proliferative changes induced by diuron treatment of male Wistar rats. Rats were randomized into two groups (control and 2500 ppm diuron) and treated for 28 days. Ten rats from each group were terminated on each of study days 1, 3, 7, or 28. Scanning electron micro scopy (SEM) showed urothelial cell swelling beginning on day 1, and by day 28, showed extensive necrosis, exfoliation and piling up of cells suggestive of hyperplasia. No difference in the bromo deoxyuridine labeling index was detected. In a second experiment, rats were randomized into control and diuron-treated groups and treated for 7 days or 8 weeks. After 7 days, transmission electron microscopy showed cell degenerative changes and distention of the cytoplasm, organelles, and nuclei characteristic of cytolysis. This resulted in protrusion of the superficial cells into the lumen, corresponding to the cell swelling observed previously by SEM. After 8 weeks, bladders in the diuron-treated group showed an increased incidence of simple hyperplasia by light microscopy (6/10, p < 0.05) compared with controls (0/10) and a significantly different SEM classification. In summary, our results support the hypothesis that urothelial cytotoxicity followed by regenerative cell proliferation are the sequential key events that occur with high-dose diuron exposure in rats.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA.
authors.forename: Mitscheli S
authors.initials: MS
authors.lastname: Da Rocha
authors.forename: Lora L
authors.initials: LL
authors.lastname: Arnold
authors.forename: Karen L
authors.initials: KL
authors.lastname: Pennington
authors.forename: David
authors.initials: D
authors.lastname: Muirhead
authors.forename: Puttappa R
authors.initials: PR
authors.lastname: Dodmane
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Anwar
authors.forename: Michael
authors.initials: M
authors.lastname: Battalora
authors.forename: João Lauro V
authors.initials: JL
authors.lastname: De Camargo
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004237:Diuron / Q000633:toxicity*; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000648:ultrastructure; D006540:Herbicides / Q000633:toxicity*; D006965:Hyperplasia; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D009336:Necrosis; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration / Q000187:drug effects; D013997:Time Factors; D001743:Urinary Bladder / Q000187:drug effects* / Q000648:ultrastructure; D019459:Urothelium / Q000187:drug effects* / Q000648:ultrastructure
chemical_list: D006540:Herbicides; D004237:Diuron