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Inorganic Arsenic–Induced Intramitochondrial Granules in Mouse Urothelium

¹ Department of Pathology and Microbiology and the Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
² Department of Environmental Health Sciences, University of Alberta, Edmonton, Alberta, Canada
³ Biochemistry & Molecular Biology, University of Minnesota Medical School, Duluth, Minnesota, USA
⁴ Pathology Division, Nishi-Kobe Medical Center, Kobe, Hyogo, Japan
⁵ Havlik-Wall Professor of Oncology, University of Nebraska, Omaha, Nebraska, USA

Correspondence: Address correspondence to: Shugo Suzuki, MD, PhD, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-3135, USA; fax: (402) 559-8330; e-mail:ssuzuki{at}unmc.edu.

Based on epidemiological data, chronic exposure to high levels of inorganic arsenic in the drinking water is carcinogenic to the urinary bladder of humans. Recently, models have been developed involving transplacental administration of inorganic arsenic and subsequent administration of another substance that produces a low incidence of urogenital neoplasms. Administration of arsenite or arsenate in the diet or drinking water to five-to eight-week-old mice or rats rapidly induces urothelial cytotoxicity and regenerative hyperplasia. In mice administered arsenite, we observed eosinophilic intracytoplasmic granules present in the urothelial cells. These granules were not present in urothelial cells of untreated mice or in treated or untreated rats. By transmission electron microscopy, the granules were located within the mitochondrial matrix, that is, mitochondrial inclusions. Arsenic, primarily as arsenite, was present in partially purified mitochondria containing these granules. Cells containing the granules were not usually associated with degenerative changes. Lack of these granules in rats suggests that they are not necessary for inorganic arsenic–induced urothelial cytotoxicity or hyperplasia. These granules have also been observed with exposures to other metals in other tissues and other species, suggesting that they represent a protective mechanism against metal-induced toxicity.

Key Words: mitochondrial granules • urinary bladder • arsenite • cytotoxicity • hyperplasia

Abbreviations: As^III, arsenite • As^V, arsenate • DMA^III, dimethylarsinous acid • DMA^V, dimethylarsinic acid • EM, electron microscopy • MG, mitochondrial granules • MMA^III, monomethylarsonous acid • MMA^V, monomethylarsonic acid • NaAs^III, sodium arsenite • PBS, phosphate buffered saline • TEM, transmission electron microscopy

Toxicologic Pathology, Vol. 36, No. 7, 999-1005 (2008)
DOI: 10.1177/0192623308327408


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