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Molecular Pharmacology

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Research ArticleArticle

Acute Disruption of Bone Marrow Hematopoiesis by Benzo(a)pyrene Is Selectively Reversed by Aryl Hydrocarbon Receptor-Mediated Processes

Alhaji U. N′jai, Michele C. Larsen, Justin R. Bushkofsky, Charles J. Czuprynski and Colin R. Jefcoate
Molecular Pharmacology April 2011, 79 (4) 724-734; DOI: https://doi.org/10.1124/mol.110.070631
Alhaji U. N′jai
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Michele C. Larsen
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Justin R. Bushkofsky
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Charles J. Czuprynski
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Colin R. Jefcoate
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Abstract

Bone marrow (BM) hematopoietic cells are selectively sensitive to polycyclic aromatic hydrocarbons (PAH) in vivo. 7,12-Dimethylbenz(a)anthracene (DMBA), but not benzo(a)pyrene (BP), depletes BM hematopoietic cells in C57BL/6 mice. This difference is due to a BP-selective aryl hydrocarbon receptor (AhR)-mediated recovery. Colony-forming unit assays show suppression of lymphoid progenitors by each PAH within 6 h but a subsequent recovery, exclusively after BP treatment. Suppression of myeloid progenitors (6 h) occurs only for DMBA. Each progenitor responded equally to DMBA and BP in congenic mice expressing the PAH-resistant AhR (AhRd). AhR, therefore, mediates this BP recovery in each progenitor type. These PAH suppressions depend on Cyp1b1-mediated metabolism. Paradoxically, few genes responded to DMBA, whereas 12 times more responded to BP. Progenitor suppression by DMBA, therefore, occurs with minimal effects on the general BM population. Standard AhR-mediated stimulations (Cyp1a1, Cyp1b1, Ahrr) were similar for each PAH and for the specific agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin but were absent in AhRd mice. A group of 12 such AhR responses was sustained from 6 to 24 h. A second, larger set of BP responses (chemokines, cytokines, cyclooxygenase 2) differed in two respects; DMBA responses were low and BP responses declined extensively from 6 to 24 h. A third cluster exhibited BP-induced increases in protective genes (Nqo1, GST-mu) that appeared only after 12 h. Conversion of BP to quinones contributes oxidative signaling not seen with DMBA. We propose that genes in this second cluster, which share oxidative signaling and AhR activation, provide the AhR-dependent protection of hematopoietic progenitors seen for BP.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK072749]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant T32-ES007015]; and the Walter and Martha Renk Endowed Laboratory for Food Safety.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/mol.110.070631.

  • ABBREVIATIONS:

    BP
    benzo(a)pyrene
    Abc
    ATP-binding cassette
    AhR
    aryl hydrocarbon receptor
    Ahrr
    aryl hydrocarbon receptor repressor
    B220+
    220-kDa variant of CD45, a B-lymphocyte marker
    BM
    bone marrow
    CCL
    chemokine C-C motif ligand
    CFU
    colony-forming unit
    Cxcl
    chemokine (C-X-C motif) ligand
    DBP
    dibenzo(a,l)pyrene
    DMBA
    7,12-dimethylbenz(a)anthracene
    FBS
    fetal bovine serum
    GM
    granulocyte macrophage
    Gr-1+
    granulocyte differentiation marker 1
    GST-mu
    glutathione transferase mu
    HPLC
    high-performance liquid chromatography
    HSC
    hematopoietic stem cells
    IL
    interleukin
    NFκB
    nuclear factor κB
    Nqo1
    NADPH dehydrogenase quinone 1
    Nrf2
    nuclear factor (erythroid-derived 2)-like 2
    p53
    tumor suppressor protein
    PAH
    polycyclic aromatic hydrocarbon
    PCR
    polymerase chain reaction
    PKR
    protein kinase R
    QPCR
    quantitative polymerase chain reaction
    Sca-1
    stem cell antigen 1
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    TNF
    tumor necrosis factor
    WT
    wild type.

  • Received December 15, 2010.
  • Accepted January 20, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (4)
Molecular Pharmacology
Vol. 79, Issue 4
1 Apr 2011
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Research ArticleArticle

Acute Disruption of Bone Marrow Hematopoiesis by Benzo(a)pyrene Is Selectively Reversed by Aryl Hydrocarbon Receptor-Mediated Processes

Alhaji U. N′jai, Michele C. Larsen, Justin R. Bushkofsky, Charles J. Czuprynski and Colin R. Jefcoate
Molecular Pharmacology April 1, 2011, 79 (4) 724-734; DOI: https://doi.org/10.1124/mol.110.070631

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Research ArticleArticle

Acute Disruption of Bone Marrow Hematopoiesis by Benzo(a)pyrene Is Selectively Reversed by Aryl Hydrocarbon Receptor-Mediated Processes

Alhaji U. N′jai, Michele C. Larsen, Justin R. Bushkofsky, Charles J. Czuprynski and Colin R. Jefcoate
Molecular Pharmacology April 1, 2011, 79 (4) 724-734; DOI: https://doi.org/10.1124/mol.110.070631
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