title: PAHs Target Hematopoietic Linages in Bone Marrow through Cyp1b1 Primarily in Mesenchymal Stromal Cells but Not AhR: A ReconstitutedIn VitroModel.
abstract: 7,12-Dimethylbenz(a)anthracene (DMBA) rapidly suppresses hematopoietic progenitors, measured as colony forming units (CFU), in mouse bone marrow (BM) leading to mature cell losses as replenishment fails. These losses are mediated by Cyp1b1, independent of the AhR, despite induction of Cyp1b1. BM mesenchymal progenitor cells (MPC) may mediate these responses since basal Cyp1b1 is minimally induced. PreB colony forming unit activity (PreB CFU) is lost within 24 hours in isolated BM cells (BMC) unless cocultured with cells derived from primary MPC (BMS2 line). The mouse embryonic OP9 line, which provides more efficient coculture support, shares similar induction-resistant Cyp1b1 characteristics. This OP9 support is suppressed by DMBA, which is then prevented by Cyp1b1 inhibitors. OP9-enriched medium partially sustains CFU activities but loses DMBA-mediated suppression, consistent with mediation by OP9 Cyp1b1. PreB CFU activity in BMC from Cyp1b1-ko mice has enhanced sensitivity to DMBA. BMC gene expression profiles identified cytokines and developmental factors that are substantially changed in Cyp1b1-ko mice. DMBA had few effects in WT mice but systematically modified many clustered responses in Cyp1b1-ko mice. Typical BMC AhR-responsive genes were insensitive to Cyp1b1 deletion. TCDD replicated Cyp1b1 interventions, suggesting alternative AhR mediation. Cyp1b1 also diminishes oxidative stress, a key cause of stem cell instability.
authors.affiliation: Molecular and Environmental Toxicology Program, University of Wisconsin, Madison, WI, USA.
authors.forename: Catherine M
authors.identifier: 0000-0002-5264-6714
authors.initials: CM
authors.lastname: Rondelli
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin Medical School, Madison, WI 53705, USA.
authors.forename: Michele Campaigne
authors.initials: MC
authors.lastname: Larsen
authors.affiliation: Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Alhaji
authors.initials: A
authors.lastname: N'jai
authors.affiliation: Molecular and Environmental Toxicology Program, University of Wisconsin, Madison, WI, USA; Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Czuprynski
authors.affiliation: Molecular and Environmental Toxicology Program, University of Wisconsin, Madison, WI, USA; Department of Cell and Regenerative Biology, University of Wisconsin Medical School, Madison, WI 53705, USA.
authors.forename: Colin R
authors.identifier: 0000-0002-1739-6211
authors.initials: CR
authors.lastname: Jefcoate