PT - JOURNAL ARTICLE AU - Alhaji U N'jai AU - Michele C Larsen AU - Justin R Bushkofsky AU - Charles J Czuprynski AU - Colin R Jefcoate TI - Acute Disruption of Bone Marrow Hematopoiesis by Benzo(a)pyrene is Selectively Reversed by Ah Receptor Mediated Processes AID - 10.1124/mol.110.070631 DP - 2011 Jan 20 TA - Molecular Pharmacology PG - mol.110.070631 4099 - http://molpharm.aspetjournals.org/content/early/2011/01/20/mol.110.070631.short 4100 - http://molpharm.aspetjournals.org/content/early/2011/01/20/mol.110.070631.full AB - 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 AhR-mediated recovery. Colony forming unit assays show suppression of lymphoid progenitors by each PAH within 6h, but a subsequent recovery, exclusively after BP treatment. Suppression of myeloid progenitors (6h) occurs only for DMBA. Each progenitor responded equally to DMBA and BP in congenic mice expressing the PAH-resistant Ah Receptor (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 (TCDD), but were absent in AhRd mice. A group of 12 such AhR responses were sustained from 6-24 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 6-24 h. A third cluster exhibited BP-induced increases in protective genes (Nqo1, GST-mu) that appeared only after 12h. 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.