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Toxicologic Pathology
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Subchronic Exposure to Arsenic Through Drinking Water Alters Expression of Cancer-Related Genes in Rat Liver

Xing Cui

Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan, xing.cui{at}nies.go.jp

Song Li

Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan

Amjad Shraim

Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan

Yayoi Kobayashi

Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan

Toru Hayakawa

Graduate School of Pharmaceutical Sciences, Chiba University, Inage, Chiba 263-8522, Japan

Sanae Kanno

Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan

Megumi Yamamoto

Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan

Seishiro Hirano

Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan, Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan

Although arsenic exposure causes liver disease and/or hepatoma, little is known about molecular mechanisms of arsenic-induced liver toxicity or carcinogenesis. We investigated the effects of arsenic on expression of cancer-related genes in a rat liver following subchronic exposure to sodium arsenate (1, 10, 100 ppm in drinking water), by using real-time quantitative RT-PCR and immunohistochemical analyses. Arsenic accumulated in the rat liver dose-dependently and caused hepatic histopathological changes, such as disruption of hepatic cords, sinusoidal dilation, and fatty infiltration. A 1-month exposure to arsenic significantly increased hepatic mRNA levels of cyclin D1 (10 ppm), ILK (1 ppm), and p27Kip1 (10 ppm), whereas it reduced mRNA levels of PTEN (1 ppm) and β-catenin (100 ppm). In contrast, a 4-month arsenic exposure showed increased mRNA expression of cyclin D1 (100 ppm), ILK (1 ppm), and p27Kip1 (1 and 10 ppm), and decreased expression of both PTEN and β-catenin at all 3 doses. An immunohistochemical study revealed that each protein expression accords closely with each gene expression of mRNA level. In conclusion, subchronic exposure to inorganic arsenate caused pathological changes and altered expression of cyclin D1, p27Kip1, ILK, PTEN, and β-catenin in the liver. This implies that arsenic liver toxicity involves disturbances of some cancer-related molecules.

Key Words: Arsenate • liver toxicity • cyclin D1 • p27Kip1 • ILK • PTEN • β-catenin.

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Toxicologic Pathology, Vol. 32, No. 1, 64-72 (2004)
DOI: 10.1080/01926230490261348
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