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

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.

Fhit-Deficient Hematopoietic Stem Cells Survive Hydroquinone Exposure Carrying Precancerous Changes

“…Among reactions to hydroquinone exposure, we found that DNA damage repair activity and responsiveness to cell death were altered in Fhit-deficient cells, alterations that could contribute to an increase in genomic instability during hematopoiesis. Considering that the DNA damage checkpoint pathway can induce immediate suppression of cell cycling of hemopoietic progenitors and prominent suppression of hemopoiesis, it has been proposed that the process of recovery from intermittent benzeneinduced marrow suppression may be involved in benzene-induced leukemogenesis (8). Further study would include assessment of oscillatory changes in ROS, possibly associated with chromosome aberrations in hematopoietic disorders or in transplanted bone marrow cells, after exposure to genotoxin.…”

“…Comparative gene expression profiling of p53 knockout and wild-type (Wt) mice has revealed altered expression of cell cycle, apoptosis, and growth control genes in hematopoietic samples from benzene-exposed mice, indicating that benzene exposure activates checkpoint proteins such as p21 and p53 (8,9), which inhibit DNA replication and apoptosis (10,11). Recent studies indicate that p21 cooperates with Chk1 to prevent apoptosis during DNA replication fork stress, which is important for maintaining chromosome stability (11).…”

A note on myeloperoxidation index and its correlation to the biomarker, urine trans, trans-muconic acid level, in the subjects occupationally exposed to benzene

“…2 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. 3 The potential metabolic mechanisms underlying the hemopoietic toxicity of benzene include bioactivation of phenolic metabolites of benzene by myeloperoxidases in the bone marrow and ring opening reactions to generate muconate derivatives. 4 This study is aimed at the knowledge on the correlation between the urine trans, trans-muconic acid (tt-MA), a novel biomarker for accumulated uptake of benzene, 5 and myelopeozidase index (MPXI) in the subjects occupationally exposed to benzene.…”

Polymorphisms in genes involved in innate immunity and susceptibility to benzene-induced hematotoxicity

“…Epidemiological studies have shown that exposure to benzene results in an increased risk of aplastic anemia, myelodysplastic syndromes, leukemia, and other blood disorders (Goldstein, 1988). Benzene metabolites may induce toxicity and leukemogenicity by oxidative stress, DNA damage, growth factor regulation, cell cycle regulation, and/or programmed cell death (Yoon et al, 2003).…”