title: Cyp1b1-mediated suppression of lymphoid progenitors in bone marrow by polycyclic aromatic hydrocarbons coordinately impacts spleen and thymus: a selective role for the Ah Receptor.
abstract: Bone marrow (BM) hematopoietic stem cells differentiate to common lymphoid progenitors (CLP) that emigrate to the thymus to form T cells or differentiate into immature B cells that then migrate to the spleen for maturation. Rapid in vivo suppression of BM progenitor cells by a single oral or intraperitoneal dose of 7,12-dimethylbenz(a)anthracene (DMBA) subsequently decreased mature lymphoid populations in BM, spleen, and thymus. These suppressions depended on BM CYP1B1, but not on aryl hydrocarbon receptor (AhR) activity. Suppression of pre-B colony formation at 6 h, correlated with subsequent decreases in mature BM, spleen, and thymus populations (48-168 h). Thymus T-cell ratios were unaffected, suggesting low local toxicity. DMBA treatment suppressed progenitor cells 24-h post treatment in wild type (WT), AhRb mice, but not in Cyp1b1-ko mice. The stem cell populations were sustained. Benzo(a)pyrene (BP) mediated a similar progenitor suppression up to 6 h, but reversal rapidly ensued. This recovery was absent in mice with a polycyclic aromatic hydrocarbon (PAH)-resistant, AhRd genotype. This AhR-dependent progenitor recovery with BP induction accounts for the absence of suppression of B220+ BM and spleen populations at 48-168 h. However, DMBA and BP produced similar profiles for thymus cell suppression, independent of AhR genotype. Thus, lymphoid progenitors may exit the BM to the thymus prior to the BP reversal. This progenitor recovery is associated with elevated chemokines and cytokines that depend on AhR-mediated induction of CYP1A1. This response increased constitutively in Cyp1b1-ko BM, demonstrating that CYP1B1 metabolizes local stimulants that impact a basal progenitor protection process.
authors.affiliation: Department of Cell and Regenerative Biology University of Wisconsin Madison Wisconsin.
authors.forename: Michele Campaigne
authors.initials: MC
authors.lastname: Larsen
authors.affiliation: Molecular and Environmental Toxicology Center University of Wisconsin Madison Wisconsin 53706; Department of Pathobiological Sciences University of Wisconsin Madison Wisconsin 53706.
authors.forename: Alhaji U
authors.initials: AU
authors.lastname: N'Jai
authors.affiliation: Department of Biomolecular Engineering Institute for the Biology of Stem Cells, University of California Santa Cruz California 95064.
authors.forename: David L
authors.initials: DL
authors.lastname: Alexander
authors.affiliation: Molecular and Environmental Toxicology Center University of Wisconsin Madison Wisconsin 53706.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Rondelli
authors.affiliation: Department of Biomolecular Engineering Institute for the Biology of Stem Cells, University of California Santa Cruz California 95064.
authors.forename: E C
authors.initials: EC
authors.lastname: Forsberg
authors.affiliation: Molecular and Environmental Toxicology Center University of Wisconsin Madison Wisconsin 53706; Department of Pathobiological Sciences University of Wisconsin Madison Wisconsin 53706; Food Research Institute University of Wisconsin Madison Wisconsin 53706.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Czuprynski
authors.affiliation: Department of Cell and Regenerative Biology University of Wisconsin Madison Wisconsin; Molecular and Environmental Toxicology Center University of Wisconsin Madison Wisconsin 53706.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Jefcoate
keywords: 7, 12‐dimethylbenz(a)anthracene; Ah receptor; benzo(a)pyrene; cytochrome P450 1b1; lymphoid progenitors; polycyclic aromatic hydrocarbons; spleen; thymus