Treatment of mice with the Ah receptor agonist and human carcinogen dioxin results in altered numbers and function of hematopoietic stem cells.
The aryl hydrocarbon receptor (AhR) mediates the carcinogenicity of a family of environmental contaminants, the most potent being 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increased incidence of lymphoma and leukemia in humans is associated with TCDD exposure. Although AhR activation by TCDD has profound effects on the immune system, precise cellular and molecular mechanisms have yet to be determined. These studies tested the hypothesis that alteration of marrow populations following treatment of mice with TCDD is due to an effect on hematopoietic stem cells (HSCs). Treatment with TCDD resulted in an increased number and proliferation of bone marrow (BM) populations enriched for HSCs. There was a time-dependent decrease in B-lineage cells with a concomitant increase in myeloid populations. The decrease in the B-cell lineage colony-forming unit-preB progenitors along with a transient increase in myeloid progenitors were consistent with a skewing of lineage development from lymphoid to myeloid populations. However, HSCs from TCDD-treated mice exhibited diminished capacity to reconstitute and home to marrow of irradiated recipients. AhR messenger RNA was expressed in progenitor subsets but is downregulated during HSC proliferation. This result was consistent with the lack of response following the exposure of 5-fluorouracil-treated mice to TCDD. The direct exposure of cultured BM cells to TCDD inhibited the growth of immature hematopoietic progenitor cells, but not more mature lineage-restricted progenitors. Overall, these data are consistent with the hypothesis that TCDD, through AhR activation, alters the ability of HSCs to respond appropriately to signals within the marrow microenvironment.
Singh
Kameshwar P
KP
Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA.
Wyman
Amber
A
Casado
Fanny L
FL
Garrett
Russell W
RW
Gasiewicz
Thomas A
TA
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*
D002273:Carcinogens; D017931:DNA Primers; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon