title: Benzene-induced hematopoietic neoplasms including myeloid leukemia in Trp53-deficient C57BL/6 and C3H/He mice.
abstract: 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 in epidemiology? Second, why is there no linear increase in incidence at high-dose exposure despite a lower acute toxicity (LD(50) > 1000 mg/kg body weight; WHO, 2003, Benzene in drinking-water. Background document for development of WHO Guidelines for Drinking-Water Quality)? Third, why are particular acute myeloid leukemias (AMLs) not commonly observed in mice, although 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 nonthreshold response of the incidence of HPNs at the lower dose, whereas both strains showed an increasing HPN incidence up to 100% with increasing 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.
authors.affiliation: Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hirabayashi
authors.forename: Toyozo
authors.initials: T
authors.lastname: Kaneko
authors.forename: Jun
authors.initials: J
authors.lastname: Kanno
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kodama
authors.forename: Yuuko
authors.initials: Y
authors.lastname: Matsushima
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Minoru
authors.initials: M
authors.lastname: Saitoh
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sekita
authors.forename: Osayuki
authors.initials: O
authors.lastname: Uchida
authors.forename: Takashi
authors.initials: T
authors.lastname: Umemura
authors.forename: Byung-Il
authors.initials: BI
authors.lastname: Yoon
authors.forename: Tohru
authors.initials: T
authors.lastname: Inoue
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001554:Benzene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D019570:Inhalation Exposure; D007928:Lethal Dose 50; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013045:Species Specificity; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D001554:Benzene