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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzene is a potent human leukemogen but the mechanism underlying benzene-induced leukemia remains an enigma due to a number of questions regarding the requirement of extraordinarily long exposure, a relatively low incidence of leukemia for genotoxicity of metabolites and a narrow dose range for leukemogenicity over marrow aplasia (overdoses tend to result in marrow aplasia). Moreover, there were previous controversies as to whether the cell cycle is upregulated or suppressed by the benzene exposure. Subsequently, it was found that the cell cycle is suppressed, but how leukemia develops under such suppression of hemopoiesis remains to be clarified. These questions were fortunately resolved with much effort. Benzene exposure was found to induce the expression of p21, an interlocking counterdevice for cell cycle: due to p53 upregulation, thereby inducing the immediate suppression of the kinetics of hemopoietic progenitors followed by the prominent suppression of hemopoiesis. Intermittent benzene exposure (i.e., cessation of exposure during weekends, for example) allowed an immediate recovery from marrow suppression after terminating exposure, which induced continuous oscillatory changes in marrow hemopoiesis. Benzene-induced leukemia was chiefly due to such an oscillatory change in hemopoiesis, which epigenetically developed leukemia more than 1 year later. The mechanisms of benzene-induced leukemogenicity seem to differ between wild-type mice and mice lacking p53. For p53 knockout mice, DNA damage such as weak mutagenicity or chromosomal damage was retained, and such damage induced consequent activation of proto-oncogenes and related genes, which led cells to undergo further neoplastic changes. In contrast, for wild-type mice carrying the p53 gene, a marked oscillatory change in the cell cycle of the stem cell compartment seems to be important. Compatible and discriminative gene expression profiling between the p53 knockout mice and wild-type mice was observed after benzene exposure by microarray analyses.
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PMID:Mechanism of benzene-induced hematotoxicity and leukemogenicity: current review with implication of microarray analyses. 1550 59

Benzene toxicity is considered to be elicited by its metabolites and phenolic metabolites of benzene are known to induce apoptosis in leukemia cells in culture and in human bone marrow progenitor cells. One potential mechanism of apoptosis induced by benzene metabolites that has not been examined is the production of pro-apoptotic cytokines such as endothelial IL-8 from endothelial cells in bone marrow stroma. In this study, we utilized HL-60 cells which are known to produce the endothelial form of IL-8 (elL-8) and human bone marrow endothelial cells (HBMEC) as model systems. Hydroquinone (HQ), Catechol (Cat) and benzenetriol (BT) all induced eIL-8 production and apoptosis in HL-60 cells. HQ induced a marked 50-70-fold stimulation of eIL-8 levels and HL-60 cells were shown to have the eIL-8 receptor, CXCR I thus enabling an autocrine pathway of apoptosis. However, treatment with recombinant elL-8 failed to induce apoptosis in HL-60 cells as previously reported and antibodies to either IL-8 or CXCRI did not significantly abrogate benzene metabolite-induced apoptosis. HQ and Cat but not BT also induced stimulation of elL-8 production in HBMEC. These data demonstrate that although metabolites of benzene induce marked stimulation of eIL-8, this is unlikely to be responsible for apoptosis induced in HL-60 cells. Our data also demonstrates that phenolic metabolites of benzene stimulate the production of eIL-8 from HBMEC suggesting that higher levels of endothelial-derived cytokines may occur in bone marrow after benzene exposure.
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PMID:Stimulation of endothelial IL-8 (eIL-8) production and apoptosis by phenolic metabolites of benzene in HL-60 cells and human bone marrow endothelial cells. 1535 18

Chronic exposure to benzene has been shown to lead to bone marrow depression and the development of leukemia. The mechanism underlying the carcinogenicity of benzene is unknown, although a number of genetic changes including chromosomal aberrations have been associated with benzene toxicity. Metabolism of benzene is required for the induced toxicological effects. We have investigated the effect of trans,trans-muconaldehyde (MUC), hydroquinone (HQ), and four MUC metabolites on gap-junction intercellular communication (GJIC). Inhibition of GJIC has been considered a possible predictor of tumor promoters and non-genotoxic carcinogens, and shown to result in perturbation of hematopoiesis. MUC was found to be a strong inhibitor of GJIC (EC50=12 micromol L(-1)) in rat liver epithelial cells IAR20, with potency similar to that of chlordane (EC50=7 micromol L(-1)). HQ inhibited GJIC with an EC50 of 25 micromolmol L(-1), and the metabolite OH/CHO with an EC50 of 58 micromol L(-1). The other MUC metabolites tested, CHO/COOH and OH/COOH were weak inhibitors of GJIC whereas COOH/COOH had no effect. Benzene itself had no effect on GJIC when tested in concentrations up to 20 micromol L(-1). The relative potency observed for the metabolites on GJIC is similar to their hematotoxic effects. The effect of MUC on GJIC was observed to take place concordant with a dramatic loss of connexin 43 (Cx43) from the cells as visualized by Western blotting. Substances with the ability to inhibit Cx43-dependent GJIC have previously been observed to interfere with normal hematopoietic development. The ability of benzene metabolites to interfere with gap-junction functionality, and especially the dramatic loss of Cx43 induced by MUC, should therefore be considered as a possible mechanism for benzene-induced hematotoxicity and development of leukemia.
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PMID:Metabolites of benzene are potent inhibitors of gap-junction intercellular communication. 1569 Jan 52

Benzene is an industrial chemical and component of gasoline that is an established cause of leukemia. To better understand the risk benzene poses, we examined the effect of benzene exposure on peripheral blood mononuclear cell (PBMC) gene expression in a population of shoe-factory workers with well-characterized occupational exposures using microarrays and real-time polymerase chain reaction (PCR). PBMC RNA was stabilized in the field and analyzed using a comprehensive human array, the U133A/B Affymetrix GeneChip set. A matched analysis of six exposed-control pairs was performed. A combination of robust multiarray analysis and ordering of genes using paired t-statistics, along with bootstrapping to control for a 5% familywise error rate, was used to identify differentially expressed genes in a global analysis. This resulted in a set of 29 known genes being identified that were highly likely to be differentially expressed. We also repeated these analyses on a smaller subset of 508 cytokine probe sets and found that the expression of 19 known cytokine genes was significantly different between the exposed and the control subjects. Six genes were selected for confirmation by real-time PCR, and of these, CXCL16, ZNF331, JUN, and PF4 were the most significantly affected by benzene exposure, a finding that was confirmed in a larger data set from 28 subjects. The altered expression was not caused by changes in the makeup of the PBMC fraction. Thus, microarray analysis along with real-time PCR confirmation reveals that altered expressions of CXCL16, ZNF331, JUN, and PF4 are potential biomarkers of benzene exposure.
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PMID:Discovery of novel biomarkers by microarray analysis of peripheral blood mononuclear cell gene expression in benzene-exposed workers. 1592 7

A nested case-control study found that the excess of leukemia, identified among the male members of the Health Watch cohort, was associated with benzene exposure. Exposure had been retrospectively estimated for each individual occupational history using an algorithm in a relational database. Benzene exposure measurements, supplied by Australian petroleum companies, were used to estimate exposure for specific tasks. The tasks carried out within each job, the products handled, and the technology used, were identified from structured interviews with contemporary colleagues. More than half of the subjects started work after 1965 and had an average exposure period of 20 years. Exposure was low; nearly 85% of the cumulative exposure estimates were at or below 10 ppm-years. Matched analyses showed that leukemia risk increased with increasing cumulative benzene exposures and with increasing exposure intensity of the highest-exposed job. Non-Hodgkin lymphoma and multiple myeloma were not associated with benzene exposure. A reanalysis reported here, showed that for the 7 leukemia case-sets with greater than 16 ppm-years cumulative exposure, the odds ratio was 51.9 (5.6-477) when compared to the 2 lowest exposed categories combined to form a new reference category. The addition of occasional high exposures, e.g. as a result of spillages, increased exposure for 25% of subjects but for most, the increase was less than 5% of total exposure. The addition of these exposures reduced the odds ratios. Cumulative exposures did not range as high as those in comparable studies; however, the recent nature of the cohort and local handling practices can explain these differences.
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PMID:Health Watch exposure estimates: do they underestimate benzene exposure? 1593 97

Benzene can result in bone marrow suppression. Chronic benzene poisoning (CBP) can be found among workers with excessive benzene exposure. CBP could give the appearance of different types of disorders such as leukopenia, agranulocytosis, anemia, pancytopenia, aplastic anemia (AA), myelodysplastic syndrome (MDS), and leukemia. This paper describes 43 CBP cases with the patients' ages ranging from 18 to 36 years (average: 23 years). Among them, 13 (30%) were male and 30 (70%) were female. Their job titles were furniture maker, shoemaker, industrial painter and metal shop worker. Their work durations ranged from 1.5 to 72 months (average: 14 months). Benzene levels in these workplaces exceeded 30 mg/m3. Ten of the 43 cases (23%) were diagnosed as mild cases of CBP, another 10 (23%) were moderate, and 23 (53%) were severe. Treatment for CBP included the following: cessation of benzene exposure, general supportive therapy, antibiotics, vitamins, corticosteroids, androgens, colony-stimulating factors (G-CSF, GM-CSF), blood component therapy, and traditional Chinese medicine. Thirty-three (77%) of the cases recovered completely, nine (21%) cases improved, and one (2%) died. In general, prognosis of CBP cases is optimistic when appropriate treatment is given. However, a few of the benzene-induced AA cases showed no response to treatment, which raises questions about the traditional view of the pathogenesis of the illness. Furthermore, only a part of the population with the same level of benzene exposure would suffer from the disease. Still, CBP cases with the same benzene exposure level exhibited different extents of severity of the illness. This evidence suggests strongly the existence of individual susceptibility. Detection of the biological markers regarding the individual susceptibility would be valuable for screening workers who are not suitable to be exposed to benzene.
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PMID:Clinical analysis of 43 cases of chronic benzene poisoning. 1593 9

Benzene is a human carcinogen that induces hematopoietic malignancies. It is believed that benzene does not initiate leukemias directly, but rather generates DNA damage through a series of phenolic and quinone-based metabolites, especially 1,4-benzoquinone. Since the DNA damage induced by 1,4-benzoquinone is consistent with that of topoisomerase II-targeted drugs, it has been proposed that the compound initiates specific types of leukemia by acting as a topoisomerase II poison. This hypothesis, however, was not supported by initial in vitro studies. While 1,4-benzoquinone inhibited topoisomerase II catalysis, increases in enzyme-mediated DNA cleavage were not observed. Because of the potential involvement of topoisomerase II in benzene-induced leukemias, we re-examined the effects of benzene metabolites (including 1,4-benzoquinone, 1,4-hydroquinone, catechol, 1,2,4-benzenetriol, 2,2'-biphenol, and 4,4'-biphenol) on DNA cleavage mediated by human topoisomerase IIalpha. In contrast to previous reports, we found that 1,4-benzoquinone was a strong topoisomerase II poison and was more potent in vitro than the anticancer drug etoposide. Other metabolites displayed considerably less activity. DNA cleavage enhancement by 1,4-benzoquinone was unseen in previous studies due to the presence of reducing agents and the incubation of 1,4-benzoquinone with the enzyme prior to the addition of DNA. Unlike anticancer drugs such as etoposide that interact with topoisomerase IIalpha in a noncovalent manner, the actions of 1,4-benzoquinone appear to involve a covalent attachment to the enzyme. Finally, 1,4-benzoquinone stimulated DNA cleavage by topoisomerase IIalpha in cultured human cells. These findings are consistent with the hypothesis that topoisomerase IIalpha plays a role in the initiation of some benzene-induced leukemias.
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PMID:Stimulation of topoisomerase II-mediated DNA cleavage by benzene metabolites. 1593 17

Benzene is an established human and animal carcinogen. While many of the key mechanisms underlying its carcinogenic effects remain unknown, there is increasing evidence that chromosomal alterations play an important role in the development of the induced leukemias. Inhibition of enzymes involved in DNA replication and maintenance such as topoisomerases by benzene metabolites represents a potential mechanism by which benzene may induce its chromosome-altering effects. Previous work from our laboratory and others has demonstrated that bioactivated benzene metabolites are capable of inhibiting topoisomerase II (topo II) in isolated enzyme and cell systems as well as in mice administered benzene in vivo. The current studies were designed to build upon this hypothesis, and show that in the presence of human myeloperoxidase and H2O2, hydroquinone can be activated to a potent topo II inhibitor. In the absence of dithiothreitol, partial inhibition can be seen at hydroquinone concentrations as low as 50 nM. The potential role of topo II inhibition in the development of benzene-induced leukemia is also discussed in the context of other known leukemia-inducing agents. Current evidence indicates that multiple mechanisms are likely to contribute to benzene-induced leukemias, and that inhibition of topo II could represent an important step in the development of certain leukemia subtypes.
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PMID:Topoisomerase II inhibition by myeloperoxidase-activated hydroquinone: a potential mechanism underlying the genotoxic and carcinogenic effects of benzene. 1593 18

Genome rearrangements, such as DNA deletions, translocations and duplications, are associated with cancer in rodents and humans, and clastogens are capable of inducing such genomic rearrangements. The clastogen benzene and several of its toxic metabolites have been shown to cause cancer in animals. Benzene is associated with leukemia and other blood related disorders in humans. Benzene and metabolites tested negative in short-term bacterial mutation assays such as the Salmonella Mutagenicity Test and the Escherichia coli Tryptophan Reversion Assay. These assays, while reliable for the detection of point-mutagenic carcinogens, are incapable of detecting DNA strand break inducing xenobiotics. The yeast DEL assay is based on intrachromosomal recombination events resulting in deletions and is very sensitive in detecting DNA strand breaks. In previous results the DEL assay detected 17 Salmonella positive as well as 25 Salmonella negative carcinogens [Bishop, Schiestl, Hum. Mol. Genet. 9 (2000) 2427-2434]. The carcinogen benzene and its metabolites including phenol, catechol, p-benzoquinone and hydroquinone induced DEL recombination. The benzene metabolite 1,2,4-benzenetriol was negative. Interestingly, p-benzoquinone induced DEL recombination at a dose 300-fold lower than any of the other metabolites, suggesting that it might be responsible for much of benzene's genotoxicity. In addition, an excision repair deficient strain was used, but no difference was detected compared to the wildtype, indicating that DNA adducts subject to excision repair were not formed by benzene or its metabolites.
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PMID:Effect of benzene and its closed ring metabolites on intrachromosomal recombination in Saccharomyces cerevisiae. 1615 1

Benzene is a human leukemia carcinogen, resulting from its cellular metabolism. A major benzene metabolite is p-benzoquinone (pBQ), which can damage DNA by forming the exocyclic base adducts pBQ-dC, pBQ-dA, and pBQ-dG in vitro. To gain insights into the role of pBQ in benzene genotoxicity, we examined in vitro translesion synthesis and in vivo mutagenesis of these pBQ adducts. Purified REV1 and Polkappa were essentially incapable of translesion synthesis in response to the pBQ adducts. Opposite pBQ-dA and pBQ-dC, purified human Poliota was capable of error-prone nucleotide insertion, but was unable to perform extension synthesis. Error-prone translesion synthesis was observed with Poleta. However, DNA synthesis largely stopped opposite the lesion. Consistent with in vitro results, replication of site-specifically damaged plasmids was strongly inhibited by pBQ adducts in yeast cells, which depended on both Polzeta and Poleta. In wild-type cells, the majority of translesion products were deletions at the site of damage, accounting for 91%, 90%, and 76% for pBQ-dA, pBQ-dG, and pBQ-dC, respectively. These results show that the pBQ-dC, pBQ-dA, and pBQ-dG adducts are strong blocking lesions, and are highly mutagenic by predominantly inducing deletion mutations. These results are consistent with the lesion structures predicted by molecular dynamics simulation. Our results led to the following model. Translesion synthesis normally occurs by directly copying the lesion site through base insertion and extension synthesis. When the lesion becomes incompatible in accommodating a base opposite the lesion in DNA, translesion synthesis occurs by a less efficient lesion loop-out mechanism, resulting in avoiding copying the damaged base and leading to deletion.
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PMID:The p-benzoquinone DNA adducts derived from benzene are highly mutagenic. 1618 13


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