title: Time course of urothelial changes in rats and mice orally administered arsenite.
abstract: Inorganic arsenic (arsenite and arsenate) at high exposures is a known human carcinogen, inducing tumors of the urinary bladder, skin, and lungs. In two experiments, we examined the urothelial proliferative effects of treatment with 173 ppm sodium arsenite (100 ppm arsenic) in the drinking water for 6 and 24 hr, and 3, 7, and 14 days in female F344 rats and 43.3 ppm sodium arsenite (25 ppm arsenic) in female C57BL/6 wild-type and arsenic (+3 oxidation state) methyltransferase knockout (As3mt KO) mice that are unable to methylate arsenicals. In the rat and both mouse genotypes, scanning electron microscopy showed cytotoxic urothelial changes as early as 6 hr after the start of arsenic exposure. The severity of As(III)-induced cytotoxic urothelial changes increased over time in the rat and in the As3mt KO mouse. Light microscopy showed an increase in urothelial hyperplasia in the rat. No significant increases in bromodeoxyuridine-labeling index were observed. The data support the hypothesis that the sequence of events in the mode of action for urothelial effects of orally administered inorganic arsenic in the rat and mouse involves superficial cytotoxicity with consequent regenerative increased cell proliferation similar to the findings associated with the administration of dimethylarsinic acid (DMA(V)) in rats.
authors.affiliation: Department of Pathology and Microbiology and the Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Lora L
authors.initials: LL
authors.lastname: Arnold
authors.affiliation: Department of Pathology and Microbiology and the Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Shugo
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Pathology and Microbiology and the Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA Department of Pathology and Host-Defence, Kagawa University Faculty of Medicine, Kagawa, Japan.
authors.forename: Masanao
authors.initials: M
authors.lastname: Yokohira
authors.affiliation: Department of Pathology and Microbiology and the Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA Compound Safety Prediction, Pfizer Inc., Groton, Connecticut, USA.
authors.forename: Satoko
authors.initials: S
authors.lastname: Kakiuchi-Kiyota
authors.affiliation: Department of Pathology and Microbiology and the Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Pennington
authors.affiliation: Department of Pathology and Microbiology and the Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA scohen@unmc.edu.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018053:Arsenites / Q000008:administration & dosage* / Q000633:toxicity*; D001835:Body Weight; D002101:Cacodylic Acid / Q000008:administration & dosage / Q000633:toxicity; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D051381:Rats; D011916:Rats, Inbred F344; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology; D019459:Urothelium / Q000187:drug effects* / Q000473:pathology
chemical_list: D018053:Arsenites; D002273:Carcinogens; D002101:Cacodylic Acid; C015001:arsenite
keywords: arsenic; cell proliferation.; cytotoxicity; hyperplasia; urinary bladder