Toxicity mechanism in hematopoietic stem/progenitor-derived signaling via aryl hydrocarbon receptors induced by benzene exposure

2011 Fiscal Year Final Research Report

• Project/Area Number: 21510074
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Risk sciences of radiation/Chemicals
• Research Institution: National Institute of Health Sciences
• Principal Investigator: INOUE Tohru 国立医薬品食品衛生研究所, 安全性生物試験研究センター, 客員研究員 (50100110)
• Co-Investigator(Kenkyū-buntansha): HIRABAYASHI Yoko 国立医薬品食品衛生研究所, 安全性生物試験研究センター毒性部, 室長 (30291115)
• Project Period (FY): 2009 – 2011
• Keywords: 造血幹細胞 / 幹細胞ニッチ / 生体異物相互作用 / 細胞周期 / 酸化的ストレス

Research Abstract

We have discovered that, first, the simplest and fundamental aromatic hydrocarbon, benzene, can induce xenobiotic responses through the activation of the aryl hydrocarbon receptor(AhR) and that, second, the functional localization of AhRs affects niche function related to the developmental biological maintenance of undifferentiated progenitor cells. The benzene-induced xenobiotic responses through AhR activation at the primitive hematopoietic/progenitor level can be classified on the basis of the pattern of gene expression profile : benzene-induced common gene expression profiles(BICGEP), which are the specifically and commonly expressed profiles among the test mice in the same group, and benzene-induced stochastic gene expression profiles(BISGEP), which are the stochastic gene expression profiles that are probabilistically different in each of the test mice in the same group.

Research Products

• [Journal Article] Hematopoietic neoplastic diseases develop in C3H/He and C57BL/6 mice after benzene exposure : strain differences in bone marrow tissue responses observed using microarrays (2010)
  • Author(s): Inoue T, Hirabayashi Y
  • Journal Title: Chem Biol Interact Volume: 184(1-2) Pages: 240-5
  • Peer Reviewed
• [Journal Article] Benzene-induced bone-marrow toxicity : a hemato-poietic stem-cell-specific, aryl hydrocarbon receptor-mediated adverse effect (2010)
  • Author(s): Hirabayashi Y, Inoue T
  • Journal Title: Chem Biol Interact Volume: 184(1-2) Pages: 252-258
  • Peer Reviewed
• [Journal Article] Aryl hydrocarbon receptor biology and xenobiotic responses in hematopoietic progenitor cells (2009)
  • Author(s): Hirabayashi Y, Inoue T
  • Journal Title: Biochem Pharmacol Volume: 77(4) Pages: 521-535
  • Peer Reviewed
• [Journal Article] Benzene-induced hematopoietic neoplasms including myeloid leukemia in Trp53-deficient C57BL/6 and C3H/He mice (2009)
  • Author(s): Kawasaki Y, Hirabayashi Y, Kaneko T, Kanno J, Kodama Y, Matsushima Y, Ogawa Y, Saitoh M, Sekita K, Uchida O, Umemura T, Yoon BI, Inoue T
  • Journal Title: Toxicol Sci Volume: 110(2) Pages: 293-306
  • Peer Reviewed
• [Journal Article] Comparison of murine gene expression profiles between spontaneous and radiation-induced myelogenous leukemias : stochastic and probabilistic expression variances in the former vs. radiation-specific expression commonalities in the latter (2009)
  • Author(s): Hirabayashi Y, Tsuboi I, Kitada K, Igarashi K, Kodama Y, Kanno J, Yoshida K, Dainiak N. Inoue T
  • Journal Title: Exp Hematol Volume: 37(2) Pages: 195-205
  • Peer Reviewed
• [Presentation] Comparison of microarray gene expression profiles corresponding to xenobiotic responses to oxidative stresses induced by ionizing radiation and benzene treatment (2012)
  • Author(s): Hirabayashi1 Y, Li GX, Igarashi1 K, Kanno J, Yodoi J, Inoue T
  • Organizer: Society of Toxicology 51^<st> Annual Meeting & ToxExpo
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2012-03-14
• [Presentation] Hematopoietic stroma and niches form a generation-age structure, based on the stem/progenitor cell differentiation, separated by heterogeneous functional compartment (2012)
  • Author(s): Inoue T, Otsuka K, Tsuboi I, Aizawa S, Hirabayashi Y
  • Organizer: Society of Toxicology 51^<st> Annual Meeting & ToxExpo
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2012-03-12
• [Presentation] A comparison of microarray gene expressions at leukemogenic doses between ionizing radiation and benzene exposure (2011)
  • Author(s): Hirabayashi Y, Yoon B-I, Li G-X, Igarashi K, Ogawa Y, Kanno J, Yodoi J, Inoue T
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] A hematopoietic stem-cell-specific aryl hydrocarbon receptor(AhR)-mediated benzene-induced adverse effect (2011)
  • Author(s): Hirabayashi Y, Yoon B-I, Li G-X, Igarashi K, Fujii-Kuriyama Y, Kanno J
  • Organizer: 第70回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] Commonality and stochasticity in gene expression profiles during aging process (2011)
  • Author(s): Inoue T, Hirabayashi Y
  • Organizer: Society of Toxicology 50^<th> Annual Meeting & ToxExpo
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2011-03-07
• [Presentation] Commonality and stochasticity in gene expression profiles during aging (2010)
  • Author(s): Inoue T, Hirabayashi Y
  • Organizer: BMB2010(第33回日本分子生物学会年会・第83回日本生化学会大会合同大会)
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-10
• [Presentation] Strain differences of the effect of benzene exposure : microarray study of the bone marrow in C57BL/6 and C3H/He mice (2010)
  • Author(s): Hirabayashi Y, Yoon BI, Igarashi K, Kodama Y, Sekita K, Kaneko T, Kanno J, Inoue T
  • Organizer: IUTOX 2010-XII International Congress of Toxicology
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2010-07-21
• [Presentation] Biological Safety Testing in the 21^<st> Century : Overview of the past and prospects for the future (2009)
  • Author(s): Inoue T
  • Organizer: The 10^<th> Annual Commemorative Drug Nonclinical Safety Academic Conference, National Center for Safety Evaluation of Drugs Foundation(NCSEDF)
  • Place of Presentation: Beijing, China
  • Year and Date: 2009-12-02
• [Presentation] Benzene Induced Myeloid leukemia Revisited, Based on Induction of Thioredoxin (2009)
  • Author(s): Inoue T
  • Organizer: 2009 Autumn Symposium, Korean Society of Toxicology/Korean Society of Environ-mental Mutagens and Carcinogens/Korean Society of Environmental Toxicology
  • Place of Presentation: Seoul, South Korea
  • Year and Date: 2009-11-13
• [Presentation] Thioredoxin-over-expression mice prevent benzene-induced lymphoma/leukemias : Experimental model for possible beneficial role in anti-oxidative stress by broccoli(Sulforaphan) (2009)
  • Author(s): Inoue T, Hirabayashi Y
  • Organizer: Asia Pacific Symposium on Food Safety 2009
  • Place of Presentation: Seoul, South Korea
  • Year and Date: 2009-11-13
• [Presentation] Gene expression profile of the bone marrow after benzene exposure in C57BL/6 and C3H/He mice : the common gene expression and the stochastic gene expression (2009)
  • Author(s): Inoue T
  • Organizer: FDA-China International Forum and Workshop Microarray-Bioinformatics-Next-Generation Sequencing in Safety Assessment and Biomarker discovery
  • Place of Presentation: Shanghai, China
  • Year and Date: 2009-09-26
• [Presentation] Hematopoietic neoplastic diseases in C3H/He and C57BL/6 mice after benzene exposure. Differences observed using microarrays (2009)
  • Author(s): Inoue T
  • Organizer: Benzene 2009 : Health Effects and Mechanisms of Bone Marrow Toxicity, Implication for t-AML and the Mode of Action Framework
  • Place of Presentation: Munich, Germany
  • Year and Date: 2009-09-10
• [Book] Commonality and Stochasticity in Systems Toxicology. In : Handbook of Systems Toxicology (2011)
  • Author(s): Hirabayashi Y, Inoue T
  • Total Pages: 432-460
• [Book] Aryl hydrocarbon receptor suppresses spontaneous neoplasms thereby extends life span. In : Morita M, edPersistent Organic Pollutants(POPs) Research in Asia (2008)
  • Author(s): Hirabayashi Y, Yoon BI, Li GX, Kaneko T, Kanno J, Fujii-Kuriyama Y, Inoue T
  • Total Pages: 326-31