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
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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.
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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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