Pathological analysis of cadmium and its microenvironment in patients with itai-itai disease

• Project/Area Number: 25670175
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: The University of Tokushima (2014); University of Toyama (2013)
• Principal Investigator: TSUNEYAMA Koichi 徳島大学, ヘルスバイオサイエンス研究部, 教授 (10293341)
• Co-Investigator(Kenkyū-buntansha): IMURA Johji 富山大学, 大学院医学薬学研究部(医学), 教授 (80316554)
• Co-Investigator(Renkei-kenkyūsha): KOBAYASHI Masayoshi 新潟大学, 機器分析センター, 技術専門員 (60377215)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 重金属 / カドミウム / X線マイクロアナライザー / イタイイタイ病 / 病理標本

Outline of Final Research Achievements

Cadmium (Cd) is a highly toxic heavy metal, which is widely dispersed in the environment. Itai-itai disease is well known as the most severe form of chronic Cd poisoning. We have examined the pathological findings of human samples in itai-itai disease, and reported the mechanism of kidney and bone failure. However it is not easy to detect cadmium localization on the tissue specimen. In present study, we performed EPMA (Electron Probe MicroAnalyser) analysis and succeeded to make clarify the cadmium toxicity in cellular level. Cadmium was accumulated in the hepatocytes, portal connective tissue in the liver, and residual proximal tubules and connective tissue in the kidney. In addition, cadmium was accumulated selectively in Langerhans islets of pancreas, surprisingly. Double immunostaining of insulin and glucagon suggested that marked deletion of beta cells in patients of itai-itai disease. we hypothesized that high dose cadmium exposure may be a risk of diabetes.

Research Products

• [Journal Article] Effect of keishibukuryogan on genetic and dietary obesity models. (2015)
  • Author(s): Gao F, Yokoyama S, Fujimoto M, Tsuneyama K, Saiki I, Shimada Y, Hayakawa Y.
  • Journal Title: Evid Based Complement Alternat Med. Volume: in press Pages: 801291-801298
  • DOI: 10.1155/2015/801291
  • NAID: 120006389608
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Immunologic potential of CTLA-4 Ig in murine autoimmune cholangitis. (2015)
  • Author(s): Tanaka H, Yang GX, Tomiyama T, Tsuneyama K, Zhang W, Leung PS, Coppel RL, Joh T, Nadler SG, Ansari AA, Bowlus C, Gershwin ME.
  • Journal Title: Clin Exp Immunol. Volume: in press Issue: 3 Pages: 371-382
  • DOI: 10.1111/cei.12581
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Induction of insulin secretion by apolipoprotein M, a carrier for sphingosine 1-phosphate. (2014)
  • Author(s): Kurano M, Hara M, Tsuneyama K, Sakoda H, Shimizu T, Tsukamoto K, Ikeda H, Yatomi Y.
  • Journal Title: Biochim Biophys Acta. Volume: 1841 Issue: 9 Pages: 1217-1226
  • DOI: 10.1016/j.bbalip.2014.05.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Neonatal monosodium glutamate treatment causes obesity, diabetes, and macrovesicular steatohepatitis with liver nodules in DIAR mice. (2014)
  • Author(s): Tsuneyama K, Nishida T, Baba H, Taira S, Fujimoto M, Nomoto K, Hayashi S, Miwa S, Nakajima T, Sutoh M, Oda E, Hokao R, Imura J.
  • Journal Title: J Gastroenterol Hepatol. Volume: 29 Issue: 9 Pages: 1736-1743
  • DOI: 10.1111/jgh.12610
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Molecular mechanisms of hyperthermia-induced apoptosis enhanced by docosahexaenoic acid: Implication for cancer therapy. (2014)
  • Author(s): Cui ZG, Piao JL, Kondo T, Ogawa R, Tsuneyama K, Zhao QL, Feril LB Jr, Inadera H.
  • Journal Title: Chem Biol Interact Volume: in press Pages: 46-53
  • DOI: 10.1016/j.cbi.2014.03.005
  • Peer Reviewed
• [Journal Article] CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages. (2014)
  • Author(s): Kee JY, Ito A, Hojo S, Hashimoto I, Igarashi Y, Tsuneyama K, Tsukada K, Irimura T, Shibahara N, Takasaki I, Inujima A, Nakayama T, Yoshie O, Sakurai H, Saiki I, Koizumi K.
  • Journal Title: BMC Cancer. Volume: 14 Issue: 1 Pages: 949-949
  • DOI: 10.1186/1471-2407-14-949
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of cytochrome P450-mediated metabolism and identification of novel thiol-conjugated metabolites in mice with phenytoin-induced liver injury. (2014)
  • Author(s): Sasaki E, Iwamura A, Tsuneyama K, Fukami T, Nakajima M, Kume T, Yokoi T.
  • Journal Title: Toxicol Lett. Volume: 232 Issue: 1 Pages: 79-88
  • DOI: 10.1016/j.toxlet.2014.10.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation. (2014)
  • Author(s): Honda H., Nagai Y., Matsunaga T., Okamoto N., Watanabe Y., Tsuneyama K., Hayashi H., Fujii I., Ikutani M., Hirai Y., Muraguchi A., Takatsu K.
  • Journal Title: Journal of Leukocyte Biology Volume: 96 Issue: 6 Pages: 1087-1100
  • DOI: 10.1189/jlb.3a0114-005rr
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Histopathological analysis for osteomalacia and tubulopathy in itai-itai disease. (2014)
  • Author(s): Baba H, Tsuneyama K, Kumada T, Aoshima K, Imura J.
  • Journal Title: J Toxicol Sci. Volume: 39(1) Pages: 91-6
  • NAID: 130004447119
  • Peer Reviewed
• [Journal Article] The liver in itai-itai disease (chronic cadmium poisoning) : Pathological features and metallothionein expression. (2013)
  • Author(s): Baba H, Tsuneyama K, et al.
  • Journal Title: Mod Pathol Volume: (In press) Issue: 9 Pages: 1228-34
  • DOI: 10.1038/modpathol.2013.62
  • Peer Reviewed
• [Presentation] Daily moderate coffee intake inhibits pancreatic beta-cell damage and nonalcoholic steatohepatitis without improving obesity in a mouse model of spontaneous metabolic syndrome (2015)
  • Author(s): Koichi Tsuneyama, Hayato Baba, Takeshi Nishida, Hideki Hatta, Johji Imura
  • Organizer: The 24th Conference of the APASL
  • Place of Presentation: Istanbul (Turkey)
  • Year and Date: 2015-03-12 – 2015-03-15
• [Presentation] 見えないものを“見る”技術～メタボリックシンドロームからイタイイタイ病まで～ (2015)
  • Author(s): 常山幸一
  • Organizer: 徳島臨床細胞学会
  • Place of Presentation: とくしま未来健康づくり機構（徳島県・徳島市）
  • Year and Date: 2015-03-05
  • Invited
• [Presentation] Establishment of repeated liver biopsy technique in experimental mice (2014)
  • Author(s): Tsuneyama K, Baba H, Nakajima T, Nishida T, Imura J.
  • Organizer: 65th Annual meeting of the AASLD
  • Place of Presentation: Boston（ USA）
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Nano-PALDIイメージング質量分析を用いた低分子Xenobiotics（２オクチン酸）検出法の開発 (2014)
  • Author(s): 常山幸一、菊池健太郎、守時由起、井村穣二、平修
  • Organizer: JDDW 2014 神戸
  • Place of Presentation: 神戸国際展示場（兵庫県・神戸市）
  • Year and Date: 2014-10-23 – 2014-10-26
• [Presentation] イメージングMSの病理診断学への応用と展開 (2014)
  • Author(s): 常山 幸一、井村 穣二
  • Organizer: 第４１回BMSコンファレンス
  • Place of Presentation: 能登ロイヤルホテル（石川県・羽咋郡）
  • Year and Date: 2014-07-07 – 2014-07-09
  • Invited
• [Presentation] イタイイタイ病における腎病変の新たな病理学的検討 (2014)
  • Author(s): 数見友里恵、常山幸一、井村穣二
  • Organizer: 第１０３回日本病理学会総会
  • Place of Presentation: 広島国際会議場（広島県・広島市）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] イタイイタイ病では骨軟化症とともに骨粗鬆症も高度に生じている (2014)
  • Author(s): 皆川千尋、常山幸一、井村穣二
  • Organizer: 第１０３回日本病理学会総会
  • Place of Presentation: 広島国際会議場（広島県・広島市）
  • Year and Date: 2014-04-24 – 2014-04-26