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Byung-IL Yoon,¹ Guang-Xun Li,¹ Kunio Kitada,² Yasushi Kawasaki,¹ Katsuhide Igarashi,¹ Yukio Kodama,¹ Tomoaki Inoue,² Kazuko Kobayashi,² Jun Kanno,¹ Dae-Yong Kim,³ Tohru Inoue,⁴ and Yoko Hirabayashi¹

¹Division of Cellular and Molecular Toxicology, National Institute of Health Sciences, Tokyo, Japan; ²Kamakura Research Labs, Chugai Pharmaceutical, Co., Ltd., Kamakura, Japan; ³Department of Veterinary Pathology, College of Veterinary Medicine and Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea; ⁴Biological Safety and Research Center, National Institute of Health Sciences, Tokyo, Japan

Abstract
Although the mechanisms underlying benzene-induced toxicity and leukemogenicity are not yet fully understood, they are likely to be complicated by various pathways, including those of metabolism, growth factor regulation, oxidative stress, DNA damage, cell cycle regulation, and programmed cell death. With this as a background, we performed cDNA microarray analyses on mouse bone marrow tissue during and after a 2-week benzene exposure by inhalation. Our goal was to clarify the mechanisms underlying the hematotoxicity and leukemogenicity induced by benzene at the level of altered multigene expression. Because a few researchers have postulated that the cell cycle regulation mediated by p53 is a critical event for benzene-induced hematotoxicity, the present study was carried out using p53-knockout (KO) mice and C57BL/6 mice. On the basis of the results of large-scale gene expression studies, we conclude the following: a) Benzene induces DNA damage in cells at any phase of the cell cycle through myeloperoxidase and in the redox cycle, resulting in p53 expression through Raf-1 and cyclin D-interacting myb-like protein 1. b) For G1/S cell cycle arrest, the p53-mediated pathway through p21 is involved, as well as the pRb gene-mediated pathway. c) Alteration of cyclin G1 and Wee-1 kinase genes may be related to the G2/M arrest induced by benzene exposure. d) DNA repair genes such as Rad50 and Rad51 are markedly downregulated in p53-KO mice. e) p53-mediated caspase 11 activation, aside from p53-mediated Bax gene induction, may be an important pathway for cellular apoptosis after benzene exposure. Our results strongly suggest that the dysfunction of the p53 gene, possibly caused by strong and repeated genetic and epigenetic effects of benzene on candidate leukemia cells, may induce fatal problems such as those of cell cycle checkpoint, apoptosis, and the DNA repair system, finally resulting in hemopoietic malignancies. Our cDNA microarray data provide valuable information for future investigations of the mechanisms underlying the toxicity and leukemogenicity of benzene. Key words: apoptosis, benzene, cDNA microarray, cell cycle, DNA damage, DNA repair, hematotoxicity, leukemia, oxidative stress, p53-knockout mice. Environ Health Perspect 111:1411-1420 (2003) . doi:10.1289/txg.6164 available via http://dx.doi.org/ doi:doi:10.1289/txg.6164 available via http://dx.doi.org/ [Online 5 August 2003]