ToxSci Advance Access published online on May 28, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp107
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Benzene-induced hematopoietic neoplasms including myeloid leukemia in Trp53-deficient C57BL/6 and C3H/He mice
* Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Tokyo, Japan
Laboratory of Histology and Molecular Pathogenesis, School of Veterinary Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea
Center for Biological Safety and Research, National Institute of Health Sciences, Tokyo, Japan
2 Corresponding author. Address all correspondence to Yoko Hirabayashi, MD, PhD. at Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, 1-18-1 Kamiyohga, Setagayaku, Tokyo 158-8501, Japan. Fax: +81-3-3700-9647. E-mail: yokohira{at}nihs.go.jp.
Received December 7, 2008; revision received May 8, 2009; accepted May 11, 2009
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Abstract |
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This research focused on three major questions regarding benzene-induced hematopoietic neoplasms (HPNs). First, why are HPNs induced equivocally and at only threshold level with low-dose benzene exposure despite the significant genotoxicity of benzene even at low-doses both in experiments and epidemiology? Second, why is there no linear increase in incidence at high-dose exposure despite a lower acute toxicity (LD50 > 1000 mg/kg body weight; WHO, 2003) ? Third, why are particular myeloid leukemias (AMLs) not commonly observed in mice even though AMLs are frequently observed in human cases of occupational exposure to benzene? In this study, we hypothesized that the threshold-like equivocal induction of HPNs at low-dose benzene exposure is based on DNA-repair potential in wild-type mice, and that the limited increase in HPNs at a high-dose exposure is due to excessive apoptosis in wild-type mice. To determine whether Trp53-deficiency satisfies the above hypotheses by eliminating or reducing DNA repair and by allowing cells to escape apoptosis, we evaluated the incidence of benzene-induced HPNs in Trp53-deficient C57BL/6 mice with specific regard to AMLs. We also used C3H/He mice, AML-prone, with Trp53-deficiency, to explore whether a higher incidence of AMLs on benzene exposure might explain the above human-murine differences. As a result, heterozygous Trp53-deficient mice of both strains showed a non-threshold response of the incidence of HPNs at the lower dose, whereas both strains showed an increasing HPN incidence up to 100% with increasing in benzene exposure dose; including AMLs, that developed 38% of heterozygous Trp53-deficient C3H/He mice compared to only 9% of wild-type mice exposed to the high dose. The detection of AMLs in heterozygous Trp53-deficient mice, even in the C57BL/6 strain, implies that benzene may be a potent inducer of AMLs also in mice with some strain differences.
Key Words: benzene; myeloid leukemia (AML); hematopoietic neoplasms (HPNs); C57BL/6; C3H/He; Trp53-deficient mice.
1 Deceased of apoplectic second cerebral attack on August 6, 2008 during follow-up study.