Acute disruption of bone marrow hematopoiesis by benzo(a)pyrene is selectively reversed by aryl hydrocarbon receptor-mediated processes.
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 (AhR(d)). 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 AhR(d) 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.
Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA.
Alhaji U
AU
N'jai
Michele C
MC
Larsen
Justin R
JR
Bushkofsky
Charles J
CJ
Czuprynski
Colin R
CR
Jefcoate
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D006410:Hematopoiesis / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D013997:Time Factors
D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene
Mol Pharmacol. 2004 May;65(5):1225-37
15102951
Toxicol Sci. 2003 Dec;76(2):357-65
14514961
Biochem Pharmacol. 2009 Feb 15;77(4):508-20
18848820
Toxicology. 2010 Apr 30;271(1-2):27-35
20171256
J Biol Chem. 2005 Mar 4;280(9):8117-24
15598659
Toxicol Appl Pharmacol. 2004 Jul 1;198(1):21-8
15207645
Toxicol Appl Pharmacol. 2003 Nov 15;193(1):84-96
14613719
Toxicol Sci. 2009 Oct;111(2):238-46
19474220
Biochem Pharmacol. 2009 Feb 15;77(4):577-87
18983985
Mol Cell Biol. 2005 Jul;25(13):5687-98
15964823
Liver Transpl. 2005 Jun;11(6):635-43
15915498
Blood. 2006 Mar 1;107(5):1878-87
16282345
Br J Cancer. 1998 Mar;77(5):709-19
9514048
Biochim Biophys Acta. 2004 Nov 24;1681(1):38-46
15566942
J Cell Biochem. 1999 Mar 15;72(4):570-85
10022616
Toxicol Appl Pharmacol. 2003 Feb 15;187(1):1-10
12628579
Toxicology. 1998 Apr 3;126(3):155-62
9674963
Mol Pharmacol. 2008 Jan;73(1):137-46
17925458
Adv Exp Med Biol. 2007;602:69-75
17966390
Biochem Pharmacol. 2009 Feb 15;77(4):734-45
18955032
Cancer Res. 2008 Sep 15;68(18):7394-402
18794127
Carcinogenesis. 2009 Jan;30(1):11-9
18820284
Toxicol Sci. 2008 Jun;103(2):285-97
18343893
Mol Pharmacol. 2006 Apr;69(4):1103-14
16377763
Toxicol Sci. 2003 Mar;72(1):84-91
12604837
Toxicol Appl Pharmacol. 2005 Feb 1;202(3):244-57
15667830
Mol Pharmacol. 1983 May;23(3):735-42
6306433
Int Immunol. 2006 May;18(5):653-9
16571606
Cancer Res. 1974 Oct;34(10):2663-8
4607071
Science. 2010 Sep 10;329(5997):1345-8
20688981
Toxicol Sci. 2000 Nov;58(1):88-95
11053544
Toxicol Sci. 2005 Jul;86(1):68-74
15843505
Toxicol Appl Pharmacol. 1984 Sep 15;75(2):299-308
6433512
Mol Pharmacol. 1998 Dec;54(6):1000-6
9855628
Toxicol Sci. 2007 Jul;98(1):137-44
17442664
Toxicol Appl Pharmacol. 2006 Jun 1;213(2):105-16
16307768
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1977-82
10051580
Cancer Res. 2000 Jul 1;60(13):3454-60
10910056
Mol Pharmacol. 2001 Feb;59(2):302-9
11160867