The aryl hydrocarbon receptor has an important role in the regulation of hematopoiesis: implications for benzene-induced hematopoietic toxicity

Abstract

The aryl hydrocarbon receptor (AhR) belongs to the basic helix-loop-helix (bHLH) Per-Arnt-Sim (PAS) family of transcription factors. Many of these proteins are involved in regulating responses to signals in the tissue environment such as hypoxia, oxidation-reduction status, and circadian rhythms. Although the AhR is well studied as a mediator of the toxicity of certain xenobiotics, the normal physiological function remains unknown. However, accumulating data support a hypothesis that the AhR has an important function in the regulation of hematopoietic stem cells (HSCs). Persistent AhR activation by dioxin, a potent xenobiotic AhR agonist, results in altered numbers and function of HSCs in mouse bone marrow. Analysis of HSCs from AhR null-allele mice also indicates that lack of AhR expression results in altered characteristics and function of these cells. HSCs from these animals are hyperproliferative and have altered cell cycle. In addition, aging AhR-KO mice show characteristics consistent with premature bone marrow senescence and are prone to hematopoietic disease. Finally, some data suggest that the expression of the Ahr gene is regulated under conditions that control HSC proliferation. The presence of a normal functioning AhR may provide an important advantage to organisms by regulating the balance between quiescence and proliferation and preventing the premature exhaustion of HSCs and sensitivity to genetic alterations. This function assists in the preservation of HSC function and long-term multi-lineage generation over the lifespan of the organism. This also implicates a role for the AhR in the aging process. Furthermore, these functions may affect the sensitivity of HSCs to certain xenobiotics, including benzene. Defining the molecular mechanisms by which these events occur may lead to the identification of previously undefined roles of this transcription factor in human diseases, particularly those caused or affected by xenobiotics.