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Evaluation of the alcohol-related cancer using aldehyde dehydrogenase 2 knock-out mice exposed to acetaldehyde or ethanol.

Research Project

Project/Area Number 16310047
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Risk sciences of radiation/Chemicals
Research InstitutionUniversity of Occupational and Environmental Health

Principal Investigator

KUNUGITA Naoki  University of Occupational and Environmental Health, School of Health Sciences, Associate Professor, 産業保健学部, 助教授 (90178020)

Co-Investigator(Kenkyū-buntansha) KAWAMOTO Toshihiro  University of Occupational and Environmental Health, School of Medicine, Professor, 医学部, 教授 (60177748)
OYAMA Tsunehiro  University of Occupational and Environmental Health, School of Medicine, Associate Professor, 医学部, 助教授 (00309965)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 2005: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2004: ¥3,400,000 (Direct Cost: ¥3,400,000)
KeywordsAldehyde dehydrogenase-2 / knockout mice / alcohol / micronucleus assay / acetaldehyde / mutation / cancer / Aldh2 / 小核試験 / アセトアルデヒド脱水素酵素 / 吸入曝露
Research Abstract

Introduction : Aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde produced from ethanol into acetate and plays a major role in the oxidation of acetaldehyde in vivo. Half of Japanese have inactive ALDH2. We generated Aldh2 null (Aldh2 KO) mice by gene targeting knockout. In order to investigate the mutagenicity of acetaldehyde, micronucleus (MN) assay and T cell receptor (TCR) gene mutation assay were performed in Aldh2 KO mice and wild type (Aldh2 WT) mice exposed to acetaldehyde or ethanol in vivo.
Methods : Acetaldehyde vapor, obtained by a diffusion tube, was introduced into the top of an exposure chamber (volume 100 l) made of stainless steel. The mice were exposed to 500ppm acetaldehyde vapour or 100mg/kg po for two weeks continuously. Just after exposure, mice were sacrificed and the frequency of micronucleated reticulocytes was measured by flowcytometry. We also observed the incidence of TCR gene mutation in T-lymphocytes evaluated by measuring the variant CD3^-4^+ expression by flowcytometry.
Results : Frequencies of micronuclei in reticulocytes significantly increased by acetaldehyde exposure in Aldh2 KO mice, but not in Aldh2 WT mice. In addition, frequencies of micronuclei, TCR mutation, and 8-hydroxy-2'-deoxyguanosine (8OHdG) levels in urine were significantly high in Aldh2 KO mice than in Aldh2 WT mice even in control groups. We also observed the increase of TCR mutation in Aldh2 KO mice administered acetaldehyde at the dose of 100mg/kg.
Discussion : In the MN assay, Aldh2 KO mice showed the high sensitivity compared to Aldh2 WT mice, when exposed to acetaldehyde. It means that alcohol drinkers, who have no ALDH activity, increase the risk of carcinogenesis. Aldh2 KO mice also showed significantly high in MN and TCR gene mutation compared to Aldh2 WT mice even in control. These results indicate that Aldh2 plays a major role not only in acetaldehyde detoxification but also in oxidative stress in mice.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (15 results)

All 2006 2005 2004

All Journal Article (15 results)

  • [Journal Article] Urinary 8-Hydoxydeoxyguanosine (8-OHdG) and Plasma Malondialdehyde (MDA) Levels in ALdh2 Knock-out Mice under Acetaldehyde Exposure.2006

    • Author(s)
      Ogawa, M
    • Journal Title

      Industrial Health 44

      Pages: 179-183

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Urinary 8-Hydoxydeoxyguanosine (8-OHdG) and Plasma Malondialdehyde (MDA) Levels in Aldh2 Knock-out Mice under Acetaldehyde Exposure.2006

    • Author(s)
      Ogawa, M et al.
    • Journal Title

      Industrial Health 44

      Pages: 179-183

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Urinary 8-Hydoxydeoxyguanosine (8-OHdG) and Plasma Malondialdehyde (MDA) Levels in Aldh2 Knock-out Mice under Acetaldehyde Exposure2006

    • Author(s)
      Ogawa M
    • Journal Title

      Industrial Health 44

      Pages: 179-183

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Hypothalamo-pituitary-adrenal gland axis in mice inhaling toluene prior to low-level long-term exposure to formaldehyde2005

    • Author(s)
      Sari, DK
    • Journal Title

      J Vet Med Sci. 67

      Pages: 303-309

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Hypothalamo-pituitary-adrenal gland axis in mice inhaling toluene prior to low-level long-term exposure to formaldehyde.2005

    • Author(s)
      Sari, DK et al.
    • Journal Title

      J Vet Med Sci. 67

      Pages: 303-309

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Expression of cytochrome P450 in tumor tissues and its association with cancer development.2004

    • Author(s)
      Oyama, T
    • Journal Title

      Front Biasci. 9

      Pages: 1967-1976

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Differential immunogenic and neurogenic inflammatory responses in an allergic mouse model exposed to low levels of formaldehyde.2004

    • Author(s)
      Fujimaki, H
    • Journal Title

      Toxicology 197

      Pages: 1-13

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] パラニトロフェノール2004

    • Author(s)
      欅田 尚樹
    • Journal Title

      日本臨床 62・Suppl 12

      Pages: 495-497

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 解剖学実習室における気中ホルムアルデヒド濃度評価と自覚症状調査2004

    • Author(s)
      欅田 尚樹
    • Journal Title

      産業医科大学雑誌 26・3

      Pages: 337-348

    • NAID

      110001259699

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Expression of cytochrome P450 in tumor tissues and its association with cancer development.2004

    • Author(s)
      Oyama, T et al.
    • Journal Title

      Front Biosci. 9

      Pages: 1967-1976

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Differential immunogenic and neurogenic inflammatory responses in an allergic mouse model exposed to low levels of formaldehyde.2004

    • Author(s)
      Fujimaki, H et al.
    • Journal Title

      Toxicology 197

      Pages: 1-13

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Long-term exposure to low levels of formaldehyde increases the number of tyrosine hydroxylase-immunopositive periglomerular cells in mouse main olfactory bulb.2004

    • Author(s)
      Hayashi, H et al.
    • Journal Title

      Brain Res. 1007(1-2)

      Pages: 192-197

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] p-Nitrophenol2004

    • Author(s)
      Kunugita, N et al.
    • Journal Title

      Nippon Rinsho 62 Suppl 12

      Pages: 495-497

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Exposure to formaldehyde during an anatomy dissecting course.2004

    • Author(s)
      Kunugita, N et al.
    • Journal Title

      J UOEH 26

      Pages: 337-348

    • NAID

      110001259699

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Expression of cytochrome P450 in tumor tissues and its association with cancer development.2004

    • Author(s)
      Oyama, T
    • Journal Title

      Frontiers in Bioscience 9

      Pages: 1967-1976

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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