Aryl hydrocarbon receptor biology and xenobiotic responses in hematopoietic progenitor cells

Studying the biological functions of the aryl hydrocarbon receptor (AhR) other than its function in xenobiotic drug metabolism may answer the questions as to why AhR orthologues have long been conserved phylogenically widely in the animal kingdom, and why homologues have diverged from nonvertebrate species such as nematodes and drosophila to all the vertebrate species. In this review, we focused on the mechanism of longevity possibly derived from evolution of AhRs and compared the functional difference of hematopoietic progenitors between wild-type (AhR+/+) mice and AhR-deficiencies (AhR+/−, AhR−/−). Particular advantages found in wild-type mice compared with AhR-deficiencies were as follows: first, higher antioxidative function in the hematopoietic microenvironment with low oxidative tension seemed to have developed with the evolution of AhR; second, primitive hematopoietic progenitor-cell-specific deceleration and dormancy of cell-cycle regulation may have developed also with AhR evolution, which keeps hematopoietic progenitor cell compartment dormant without extinction by continuous differentiation; third, the consequent evolution of genomic stabilization with a longer lifespan in wild-type mice developed with the evolution of AhR. Experimentally, mice showed a significant extension of lifespan in a gene-dosage-dependent manner with a delayed onset of leukemogenicity. Another possible additional advantage observed in wild-type mice, the mechanism of which is not yet clarified, is an improved efficiency of fertilization in wild-type mice as compared with AhR-deficiencies, which seems to have developed with the evolution of AhR. Four advantages altogether, including the anti-aging feature mentioned above may have induced the AhR molecule to diverge various of species in the animal kingdom.