Mechanism of Benzene-Induced Hematotoxicity and Leukemogenicity: Current Review with Implication of Microarray Analyses

Abstract

Benzene is a potent human leukemogen but the mechanism underlying benzene-induced leukemia remains an enigma due to a number of questions regarding the requirement of extraordinarily long exposure, a relatively low incidence of leukemia for genotoxicity of metabolites and a narrow dose range for leukemogenicity over marrow aplasia (overdoses tend to result in marrow aplasia). Moreover, there were previous controversies as to whether the cell cycle is upregulated or suppressed by the benzene exposure. Subsequently, it was found that the cell cycle is suppressed, but how leukemia develops under such suppression of hemopoiesis remains to be clarified. These questions were fortunately resolved with much effort. Benzene exposure was found to induce the expression of p21, an interlocking counterdevice for cell cycle: due to p53 upregulation, thereby inducing the immediate suppression of the kinetics of hemopoietic progenitors followed by the prominent suppression of hemopoiesis. Intermittent benzene exposure (i.e., cessation of exposure during weekends, for example) allowed an immediate recovery from marrow suppression after terminating exposure, which induced continuous oscillatory changes in marrow hemopoiesis. Benzene-induced leukemia was chiefly due to such an oscillatory change in hemopoiesis, which epigenetically developed leukemia more than 1 year later. The mechanisms of benzene-induced leukemogenicity seem to differ between wild-type mice and mice lacking p53. For p53 knockout mice, DNA damage such as weak mutagenicity or chromosomal damage was retained, and such damage induced consequent activation of proto-oncogenes and related genes, which led cells to undergo further neoplastic changes. In contrast, for wild-type mice carrying the p53 gene, a marked oscillatory change in the cell cycle of the stem cell compartment seems to be important. Compatible and discriminative gene expression profiling between the p53 knockout mice and wild-type mice was observed after benzene exposure by microarray analyses.

Keywords

Benzene hematotoxicity leukemogenicity gene chip array BUUV method p53-KO AhR-KO hemopoietic progenitor cells.

References

Boley, S.E.

Wong, V.A.

French, J.E.

, and

Recio, L.

(2002). p53 heterozygosity alters the mRNA expression of p53 target genes in the bone marrow in response to inhaled benzene. Toxicol Sci66, 209—15.

Cronkite, E.P.

Bullis, J.

Inoue, T.

, and

Drew, R.T.

(1984). Benzene inhalation produces leukemia in mice. Toxicol Appl Pharmacol75, 358—61.

Cronkite, E.P.

Drew, R.T.

Inoue, T.

Hirabayashi, Y.

, and

Bullis, E.

(1989). Hematotoxicity and carcinogenicity of inhaled benzene. Environ Health Perspect82, 97—108.

Cronkite, E.P.

Inoue, T.

Carsten, A.L.

Miller, M.E.

Bullis, J.E.

, and

Drew, R.T.

(1982). Effects of benzene inhalation on murine pluripotent stem cells. J Toxicol Environ Health9, 411—21.

Farris, G.M.

Robinson, S.N.

Gaido, K.W.

Wong, B.A.

Wong, V.A.

Hahn, W.P.

, and

Shah, R.S.

(1997). Benzene-induced hematotoxicity and bone marrow compensation in B6C3F1 mice. Fundam Appl Toxicol36, 119—29.

French, J.E.

Lacks, G.D.

Trempus, C.

Dunnick, J.K.

Foley, J.

Mahler, J.

Tice, R.R.

, and

Tennant, R.W.

(2001). Loss of heterozygosity frequency at the Trp53 locus in p53-deficient () mouse tumors is carcinogen-and tissue-dependent . Carcinogenesis22, 99—106.

Hirabayashi, Y.

Matsumura, T.

Matsuda, M.

Kuramoto, K.

Motoyoshi, K.

Yoshida, K.

Sasaki, H.

, and

Inoue, T.

(1998). Cell kinetics of hemopoietic colony-forming units in spleen (CFU-S) in young and old mice. Mech Ageing Dev101, 221—31.

Hirabayashi, Y.

Yoon, B.I.

Kawasaki, Y.

Li, G.X.

Kanno, J.

, and

Inoue, T.

(2002). On the mechanistic differences of benzene-induced leukemogenesis between wild type and p53 knockout mice. Molecular Mechanisms for Radiation-Induced Cellular Response and Cancer Development (

K. Tanaka

T. Takabatake

K. Fujikawa

T. Matsumoto

, and

F. Sado

, eds.), pp. 110—16. Aomori, Institute for Environmental Sciences , Japan.

Ho, T.Y.

, and

Witz, G.

(1997). Increased gene expression in human promyeloid leukemia cells exposed to trans, trans-muconaldehyde, a hematotoxic benzene metabolite. Carcinogenesis18, 739—44.

10.

Irons, R.D.

Heck, H.

Moore, B.J.

, and

Muirhead, K.A.

(1979). Effects of short-term benzene administration on bone marrow cell cycle kinetics in the rat. Toxicol Appl Pharmacol51, 399—409.

11.

Kawasaki, Y.

Hirabayashi, Y.

Yoon, B.I.

Huo, Y.

Kaneko, T.

Kurokawa, Y.

, and

Inoue, T.

(2001). Benzene inhalation induced an early onset and a high incidence of leukemias in the p53 deficient C57BL/6 mice. Jpn J Cancer Res92(Suppl), 71.

12.

Lee, E.W.

Garner, C.D.

, and

Johnson, J.T.

(1988). A proposed role played by benzene itself in the induction of acute cytopenia: inhibition of DNA synthesis. Res Commun Chem Pathol Pharmacol60, 27— 46.

13.

Le Noir

and

Claude

(1897). Sur un cas de purpura atribué a l'intoxication par la benzine. Bull Med Soc Hop Paris14, 1251—60.

14.

Li, G.X.

Hirabayashi, Y.

Yoon, B.I.

Kawasaki, Y.

Kurokawa, Y.

Yodoi, J.

Kanno, J.

, and

Inoue, T.

(2003). Benzene-induced leukemia is prevented by over-expression of Trx/ADF, along with increase in Trx/ADF-expression, increase in SOD-activity, and decrease in micronuclei. Cancer Science94(suppl), 265.

15.

Mimura, J.

Yamashita, K.

Nakamura, K.

Morita, M.

Takagi, T.N.

Nakao, K.

Ema, M.

Sogawa, K.

Yasuda, M.

Katsuki, M.

, and

Fujii-Kuriyama, Y.

(1997). Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells2, 645—54.

16.

Moeschlin, S.

, and

Speck, B.

(1967). Experimental studies on the mechanism of action of benzene on the bone marrow (radioautographic studies using 3H-thymidine) . Acta Haematol38, 104—11.

17.

Schattenberg, D.G.

Stillman, W.S.

Gruntmeir, J.J.

Helm, K.M.

Irons, R.D.

, and

Ross, D.

(1994). Peroxidase activity in murine and human hematopoietic progenitor cells: potential relevance to benzene-induced toxicity. Mol Pharmacol46, 346—51.

18.

Snyder, C.A.

Goldstein, B.D.

Sellakumar, A.R.

Bromberg, I.

Laskin, S.

, and

Albert, R.E.

(1980). The inhalation toxicology of benzene: incidence of hematopoietic neoplasms and hematotoxicity in ARK/J and C57BL/6J mice. Toxicol Appl Pharmacol54, 323—31.

19.

Tsukada, T.

Tomooka, Y.

Takai, S.

Ueda, Y.

Nishikawa, S.

Yagi, T.

Tokunaga, T.

Takeda, N.

Suda, Y.

Abe, S.

Matsuo, I.

Ikawa, Y.

, and

Aizawa, S.

(1993). Enhanced proliferative potential in culture of cells from p53-deficient mice. Oncogene8, 3313—22.

20.

Yoon, B.I.

Hirabayashi, Y.

Kawasaki, Y.

Kodama, Y.

Kaneko, T.

Kim, D.Y.

, and

Inoue, T.

(2001). Mechanism of action of benzene toxicity: cell cycle suppression in hemopoietic progenitor cells (CFU-GM). Exp Hematol29, 278—85.

21.

Yoon, B.I.

Hirabayashi, Y.

Kawasaki, Y.

Kodama, Y.

Kaneko, T.

Kanno, J.

Kim, D.Y.

Fujii-Kuriyama, Y.

, and

Inoue, T.

(2002). Aryl hydrocarbon receptor mediates benzene-induced hematotoxicity. Toxicol Sci70, 150—6.

22.

Yoon, B.I.

Li, G.X.

Kitada, K.

Kawasaki, Y.

Igarashi, K.

Kodama, Y.

Inoue, T.

Kobayashi, K.

Kanno, J.

Kim, D.Y.

, and

Hirabayashi, Y.

(2003). Mechanisms of benzene-induced hematotoxicity and leukemogenicity: cDNA microarray analyses using mouse bone marrow tissue. Environ Health Perspect111, 1411—20.

23.

Zhang, S.

Cawley, G.F.

Eyer, C.S.

, and

Backes, W.L.

(2002). Altered ethylbenzene-mediated hepatic CYP2E1 expression in growth hormonedeficient dwarf rats. Toxicol Appl Pharmacol179, 74—82.