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リエゾンラボ研究会
発表内容

Title:
A Fusion of Field and Laboratory Studies in the Investigation of Environmental Chemical

Yoshito Kumagai (Environmental Biology Section, Faculty of Medicine, University of Tsukuba)

Abstract:
Arsenic is ubiquitously distributed in nature throughout Earth’s crust and thus the major source of exposure to this metalloid for the general population is naturally polluted drinking water from wells. In East Asia , more than 30 million people are chronically exposed to arsenic. Interestingly, the manifestations of vascular diseases caused by prolonged exposure to arsenic are consistent with those induced by impaired production of endothelium-derived nitric oxide (NO). However, no information has been available on the relation between NO synthesis and chronic arsenic poisoning in humans. A cross-sectional study in an endemic area of chronic arsenic poisoning in Inner Mongolia and experimental animal studies indicated that long-term exposure to arsenic by drinking water causes reduction of NO production in endothelial cells. Subsequent examinations with rabbits showed that decreased NO production during arsenic exposure is, at least in part, due to an “uncoupling” of endothelial NO synthase evoked by decreased levels of (6 R )-5,6,7,8-tetrahydro-L-biopterin (BH 4 ), a cofactor of the enzyme, leading to endothelial dysfunction. Furthermore, an intervention study in the area of chronic arsenic poisoning in Inner Mongolia suggested that decreased NO levels and peripheral vascular disease in arsenosis patients can be reversed by exposure cessation. In our cellular experiments, we found that arsenic exposure causes adaptive responses against oxidative stress and arsenic cytotoxicity through Nrf2 activation. In the seminar, I introduce the results of our studies on a fusion of field and laboratory studies on the chronic arsenic poisoning and cellular protection against the metalloid.

References:
1. Pi JB, *Kumagai Y, Sun GF, Yamauchi H, Yoshida T, Iso H, Endo A, Yu LA, Yuki K, Miyauchi T, Shimojo N. Decreased serum concentrations of nitric oxide metabolites among Chinese in an endemic area of chronic arsenic poisoning in Inner Mongolia. Free Radical Biology & Medicine 28: 1137-1142, 2000.

2. Pi JB, Yamauchi H, *Kumagai Y, Sun GF, Yoshida T, Aikawa H, Hopenhayn-Rich C, Shimojo N. Evidence for induction of oxidative stress caused by chronic exposure of Chinese residents to arsenic contained in drinking water. Environmental Health Perspective 110: 331-336, 2002.

3. Pi JB, Horiguchi S, Sun Y, Nikaido M, Shimojo N, Hayashi T, Yamauchi H, Sun GF, Itoh K, Yamamoto M, Waalkes MP, *Kumagai Y. A potential mechanism for the impairment of nitric oxide formation caused by prolonged oral exposure to arsenate in rabbits . Free Radical Biology & Medicine 35: 102-113, 2003.

4. Nikaido M, Pi JB, *Kumagai Y, Yamauchi H, Taguchi K, Horiguchi S, Sun Y, Sun GF, Shinkai Y, Sumi D, Fukami I, Ishii T, * Kumagai Y. Sulforaphane, an activator of Nrf2, suppresses cellular accumulation of arsenic and its cytotoxicity in primary mouse hepatocytes. FEBS Letters 580: 1771-1774, 2006.

5. *Kumagai Y, Sumi D. Arsenic: Signal Transduction, Transcription Factor, and Biotransformation Involved in Cellular Response and Toxicity. Annual Review of Pharmacology and Toxicology 47: 243-262, 2007.

6. Shinkai Y, Sumi D,Toyama T, Kaji T, * Kumagai Y. Role of aquaporin 9 in cellular accumulation of arsenic and its cytotoxicity in primary mouse hepatocytes. Toxicology and Applied Pharmacology237: 232-236, 2009.

*, corresponding author