Benzene-Induced Hematotoxicity and Bone Marrow Compensation in B6C3F1 Mice

FARRIS, GEORGIA M.; ROBINSON, SIMON N.; GAIDO, KEVIN W.; WONG, BRIAN A.; WONG, VICTORIA A.; Hahn, William P.; SHAH, REKHA S.

doi:10.1093/toxsci/36.2.119

Cited by 10 publications

(17 citation statements)

References 22 publications

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“…The animals were placed in cages (five mice per cage) where food and water were available ad libitum. Benzene-induced hematotoxicity mouse model was established according to the published methods (Farris et al 1997; Velasco Lezama et al 2001).…”

Section: Design and Methodsmentioning

confidence: 99%

Amifostine Protects Bone Marrow from Benzene-Induced Hematotoxicity in Mice

et al. 2007

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Benzene is one of the most widely used industrial chemical agents. Long-term benzene exposure causes bone marrow aplasia and leads to a wide range of hematopoietic disorders including aplastic anaemia (AA). There are currently no effective approaches to protect people from benzene-induced hematotoxicity and AA. In addition, current treatments for AA have limitations with short- and long-term risks. Protective agents and new therapeutic approaches, therefore, are needed to prevent and treat the disease. Amifostine is a well-known cytoprotective agent and has been widely used in clinical for protecting normal tissues from the toxic effects of chemotherapy and radiotherapy. The authors utilized an established mouse model to determine the protective effect of amifostine on benzene-induced bone marrow hematotoxicity. Whole-blood cell count, morphological and histopathological alterations in the bone marrow and spleen, as well as the production of inducible toxic oxidative species were examined and compared among the mouse groups. Amifostine treatment in benzene-exposed mice significantly improved blood cell counts, and morphological and histopathological signs of hematotoxicity in the bone marrow as well as in the spleen. Moreover, amifostine prevented benzene-induced bone marrow and spleen cell apoptosis and rescinded the inhibition of cell proliferation induced by benzene exposure. Finally, amifostine significantly inhibited the levels of reactive oxidative species and lipid peroxidation induced by benzene exposure. These data suggest that amifostine appears to have substantial protective effect on benzene-induced bone marrow hematotoxicity.

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Section: Design and Methodsmentioning

confidence: 99%

Amifostine Protects Bone Marrow from Benzene-Induced Hematotoxicity in Mice

et al. 2007

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“…Benzene metabolites subsequently undergo secondary activation by myeloperoxidase (MPO) that is present at high levels in the bone marrow tissue. This results in the production of genotoxic quinones and reactive oxygen species, thereby inducing not only hemopoietic cellular damage (Farris et al 1997;Kolachana et al 1993; Lee and Garner 1991;Smith et al 1989) but also the dysfunction of bone marrow stromal cells (Niculescu et al 1995).…”

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confidence: 99%

Mechanisms of benzene-induced hematotoxicity and leukemogenicity: cDNA microarray analyses using mouse bone marrow tissue.

Yoon

Kitada

et al. 2003

Environ Health Perspect

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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.

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“…Although many investigators observed suppression of peripheral blood and bone marrow cellularities, some observed a suppression of cell cycling in the bone marrow, as measured by a decrease in tritiated thymidine incorporation [57], whereas others observed a marked increase in the number of cycling stem/progenitor cells in bone marrow and peripheral blood [55,58,59]. Careful analysis of these apparently conflicting data revealed increased cell cycling occurring at least two hours after the termination of benzene exposure.…”

Section: Benzene Exposure and Cell Cycle In Hematopoietic Stem/progenmentioning

confidence: 99%