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Updated: Jul 2, 2026
Magnetic Resonance Imaging Assessment of Carcinogen-induced Murine Bladder Tumors
Published on: March 29, 2019
Effects of inorganic arsenic on the rat and mouse urinary bladder
Shugo Suzuki1, Lora L Arnold, Takamasa Ohnishi
1Department of Pathology and Microbiology and Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA.
Abstract:
Inorganic arsenic (arsenate and arsenite) is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. Understanding the mechanism of inorganic arsenic carcinogenesis has been hampered by a lack of animal models. To define the urothelial effects of inorganic arsenic, we administered arsenate and arsenite in the diet or drinking water to rats and mice in several short-term experiments (2-10 weeks). Treatment with arsenate or arsenite in the drinking water or diet induced cytotoxicity and necrosis of the urothelial superficial layer and hyperplasia in rats and mice. Arsenate-induced changes occurred later in mice compared with arsenite-induced changes, but not in the rat. Hyperplasia in rats was evident by light microscopy at an earlier time point (2 weeks) than previously observed after treatment with dimethylarsinic acid (DMA(V)). The bromodeoxyuridine labeling index was increased in treated rats. We were unable to determine the bromodeoxyuridine labeling index in mice. The effects of inorganic arsenicals on the bladder were greater when administered in the drinking water than in the diet in rats and mice, but so was the overall toxicity to the animal. The female rat appeared more sensitive to the effects of inorganic arsenic than the male rat, but effects were similar in female and male mice. The mode of action of inorganic arsenic in rats and mice appears to involve urothelial cytotoxicity, increased cell proliferation and ultimately tumors. Cytotoxicity is likely due to the generation of reactive trivalent arsenicals excreted in the urine.
Insights
Inorganic arsenic exposure causes urothelial cell damage and increased cell proliferation in rats and mice. These findings in new animal models help understand arsenic-induced bladder cancer mechanisms.
Area of Science:
- Toxicology
- Carcinogenesis
- Urothelial Biology
Background:
- Inorganic arsenic (arsenate and arsenite) is a known human carcinogen.
- Understanding arsenic carcinogenesis is limited by a lack of suitable animal models.
- The urothelium is a target organ for arsenic-induced tumors.
Purpose of the Study:
- To investigate the urothelial effects of inorganic arsenic in rodent models.
- To establish short-term animal models for studying inorganic arsenic carcinogenesis.
- To elucidate the mechanism of inorganic arsenic-induced urothelial toxicity and hyperplasia.
Main Methods:
- Rats and mice were administered arsenate and arsenite via diet or drinking water for 2-10 weeks.
- Urothelial cytotoxicity, necrosis, and hyperplasia were assessed.
- Bromodeoxyuridine (BrdU) labeling index was used to measure cell proliferation.
Main Results:
- Arsenate and arsenite induced urothelial cytotoxicity, necrosis, and hyperplasia in both rats and mice.
- Effects were observed earlier in rats than in mice for arsenate.
- Increased cell proliferation (BrdU labeling index) was noted in arsenic-treated rats.
- Administration via drinking water resulted in greater urothelial effects but also higher overall toxicity compared to dietary administration.
- Female rats were more sensitive than male rats, while sensitivity was similar in male and female mice.
Conclusions:
- Inorganic arsenic induces urothelial cytotoxicity and hyperplasia in rodent models.
- Increased cell proliferation is a key component of inorganic arsenic's mode of action.
- These findings provide a foundation for understanding arsenic-induced bladder cancer.
- Reactive trivalent arsenicals are implicated in arsenic-induced urothelial cytotoxicity.
