Mechanism of benzene toxicity and leukemo-genicity: Cell cycle suppression in hemopoietic progenitor cells (Cfu-gms)

Although benzene is known to induce myelotoxicity and leukemia in humans and mice, the underlying mechanisms are still controversial due to the discrepancy in reports on the effect of benzene on the cell cycle of hemopoietic stem cells. This study evaluates the cell kinetics of hemopoietic progenitor cells (CFU-GMs) in normal and p53 knock out (KO) mice after the animals had inhaled 300 ppm of benzene. Using the bromodeoxyuridine UV cytocidal (BUUV) assay, we found that the cell cycle of hemopoietic progenitor cells is not stimulated, but rather is suppressed during benzene exposure. CFU-GMs in S phase were significantly suppressed from 37.1 % in controls down to 16.3 %. Formulations of BrdUrd-incorporation in both groups revealed dramatically different slopes in the non-treated control and the benzene exposed group in normal mice. However, an inhibition in cell cycling of CFU-GMs was not observed in p53 KO mice. The suppression of the cell cycle of CFU-GMs in benzene-exposed normal mice was induced by over-expression of p21 mediated by p53. p21 was highly up-regulated to values14-fold above the controls after the two-week exposure. The suppression of the cell cycle was ceased and was accelerated 2 days after the removal of benzene, concurrent with the down-regulation of p21 to the control value; this resulted in the recovery of bone-marrow cellularity which showed a dramatic oscillation depending on the dynamics of the exposure. Taken together, our present data strongly suggest that the inhibition of the cell cycle may be a crucial mechanism in the hemopoietic toxicity of benzene. In addition, leukemogenicity caused by inhalation of benzene may not be due to its direct toxicity but probably due to a continuous oscillation which encourages a kind of promoting effect for leukemogenic-spontaneous candidate cells.