Impact of Benzene Metabolites on Differentiation of Bone Marrow Progenitor Cells

Irons, Richard D.; Stillman, Wayne S.

doi:10.2307/3433170

Cited by 9 publications

(13 citation statements)

References 17 publications

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“…The survival and proliferation of stem and progenitor cells are controlled by multiple growth factors, or cytokines, with overlapping functions that act individually or in combination to regulate hematopoiesis. A series of studies carried out in mice and in human bone marrow cultures have shown that benzene alters cytokine production or response to cytokines in the bone marrow (27)(28)(29)(30)(31)(32)(33)(34)(35). To determine if benzene exposure affects cytokine levels measured in peripheral blood, a more accessible and acceptable tissue source than bone marrow, we evaluated a panel of cytokines in the most heavily exposed workers and a subset of controls.…”

Section: Discussionmentioning

confidence: 99%

An epidemiologic study of early biologic effects of benzene in Chinese workers.

Rothman

Smith

Hayes

et al. 1996

Environ Health Perspect

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Benzene is a recognized hematotoxin and leukemogen, but its mechanisms of action in humans are still uncertain. To provide insight into these processes, we carried out a cross-sectional study of 44 healthy workers currently exposed to benzene (median 8-hr time-weighted average; 31 ppm), and unexposed controls in Shanghai, China. Here we provide an overview of the study results on peripheral blood cell levels and somatic cell mutation frequency measured by the glycophorin A (GPA) gene loss assay and report on peripheral cytokine levels. All peripheral blood cell levels (i.e., total white blood cells, absolute lymphocyte count, platelets, red blood cells, and hemoglobin) were decreased among exposed workers compared to controls, with the exception of the red blood cell mean corpuscular volume, which was higher among exposed subjects. In contrast, peripheral cytokine levels (interleukin-3, interleukin-6, erythropoietin, granulocyte colonystimulating factor, tissue necrosis factor-a) in a subset of the most highly exposed workers (n = 11) were similar to values in controls (n = 11), suggesting that benzene does not affect these growth factor levels in peripheral blood. The GPA assay measures stem cell or precursor erythroid cell mutations expressed in peripheral red blood cells of MN heterozygous subjects, identifying NN variants, which result from loss of the GPA M allele and duplication of the N allele, and No variants, which arise from gene inactivation. The NN (but not NO) GPA variant cell frequency was elevated in the exposed workers compared with controls (mean ± SD, 13.9 ± 8.4 mutants per million cells versus 7.4 ± 5.2 per million cells, respectively; p=0.0002), suggesting that benzene produces gene-duplicating but not gene-inactivating mutations at the GPA locus in bone marrow cells of exposed humans. These findings, combined with ongoing analyses of benzene macromolecular adducts and chromosomal aberrations, will provide an opportunity to comprehensively evaluate a wide range of early biologic effects associated with benzene exposure in humans.

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Section: Discussionmentioning

confidence: 99%

An epidemiologic study of early biologic effects of benzene in Chinese workers.

Rothman

Smith

Hayes

et al. 1996

Environ Health Perspect

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“…Our results show that HQ stimulates proliferation of TF-1 cells via activation of the ERK/AP-1 signalling pathway together with concomitant increases in GM-CSF production and clonogenic response. In contrast, HQ enhancement of CFU response in human CD34 þ BM cells is dependent on the addition of exogenous rhGM-CSF, 7,8 but similarly is accompanied by AP-1 activation and an increase in GM-CSF production. Taken collectively, these studies suggest that HQ exerts many of its hematopoietic effects via alterations in the GM-CSF signaling pathway.…”

Section: Introductionmentioning

confidence: 87%

“…[4][5][6] We have also observed clonogenic enhancement in human CD34 þ BM cells treated in vitro with the BZ metabolite, hydroquinone (HQ), and then cultured in the presence of exogenous rhGM-CSF. 7,8 Cell proliferation is a wellrecognized risk factor in carcinogenesis; cell division resulting in a number of chemical and mechanical stresses that increase the likelihood of acquiring structural genomic changes. Individual malignancies, particularly hematopoietic and lymphoid cancers, often exhibit unique patterns or signatures of clonal lesions that are thought to play important roles in either the initiation or pathogenesis of these individual diseases.…”

Section: Introductionmentioning

confidence: 99%

Hydroquinone modulates the GM-CSF signaling pathway in TF-1 cells

Zheng

Pyatt

et al. 2004

Leukemia

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Human leukemogens, including alkylating chemotherapeutic agents and benzene, enhance granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent proliferation of human CD34 þ bone marrow (BM) cells. The extracellular signal-regulated kinase (ERK) pathway plays an important role in GM-CSF-dependent proliferation and also has been implicated in the pathogenesis of acute myelogenous leukemia. Therefore, we investigated the effects of the benzene metabolite, hydroquinone (HQ), on alterations in the GM-CSF signaling pathway in TF-1 erythroleukemia cells and human CD34 þ BM cells. HQ treatment in TF-1 cells results in a strong proliferative response that is dependent on ERK activation and GM-CSF production. HQ also induces ERK-dependent AP-1 activation with concomitant increased transcriptional activity of AP-1 reporter gene. However, the kinetics of ERK activation are different between rhGM-CSF and HQ in TF-1 cells: rhGM-CSF results in immediate activation of ERK, whereas HQ activation of ERK is delayed. Further, HQ and rhGM-CSF together produce an immediate increase in ERK phosphorylation, which is sustained for over 48 h. HQ also stimulates colony formation, AP-1 DNA binding and GM-CSF production in human CD34 þ BM cells. These results suggest that HQ stimulates proliferation via activation of ERK/AP-1 and is at least partially mediated via the production of GM-CSF.

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“…Previous studies have indicated that benzene toxicity mainly results from its intermediate reactive metabolites (Irons and Stillman 1996;Kolachana et al 1993). Benzene is initially oxidized to benzene oxide by hepatic CYP2E1 in the liver (Koop et al 1989;Valentine et al 1996).…”

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confidence: 99%

Association of genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, and GSTT1 genes with benzene poisoning.

Wan

Shi²,

Hui³

et al. 2002

Environ Health Perspect

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Metabolic enzymes involved in benzene activation or detoxification, including NAD(P)H, quinone oxidoreductase 1 (NQO1), cytochrome P450 2E1 (CYP2E1), myeloperoxidase (MPO), glutathione-S-transferase mu-1 (GSTM1), and glutathione-S-transferase theta-1 (GSTT1), were studied for their roles in human susceptibility to benzene poisoning. The potential interactions of these metabolic enzymes with lifestyle factors such as cigarette smoking and alcohol consumption were also explored. We studied 156 benzene-poisoning patients and 152 workers occupationally exposed to benzene in South China. Sequencing, denaturing HPLC, restriction fragment-length polymorphism, and polymerase chain reaction were used to detect polymorphisms on the promoters and complete coding regions of NQO1, CYP2E1, MPO, and the null genotypes of GSTM1 and GSTT1. Seventeen single nucleotide polymorphisms (SNPs) were identified in NQO1, CYP2E1, and MPO genes, including 6 novel SNPs in CYP2E1 and MPO. Of the subjects who smoked and drank alcohol, an 8.15-fold [95% confidence interval (CI), 1.43-46.50] and a 21.50-fold (95% CI, 2.79-165.79) increased risk of benzene poisoning, respectively, were observed among the subjects with two copies of NQO1 with a C-to-T substitution in cDNA at nucleotide 609 (c.609 C>T variation; i.e., NQO1 c.609 T/T) compared to those with the heterozygous or wild (NQO1 c.609 C/T and c.609 C/C) genotypes. Our data also indicated that individuals with CYP2E1 c.-1293 C/C and c.-1293 G/C, and NQO1 c.609 T/T, and GSTT1 null genotypes tended to be more susceptible to benzene toxicity. Our results suggest that the combined effect of polymorphisms in NQO1, CYP2E1, and GSTT1 genes and lifestyle factors might contribute to benzene poisoning.

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Impact of Benzene Metabolites on Differentiation of Bone Marrow Progenitor Cells

Abstract: Interleukin-3 (IL-3) and granulocyte/macrophage-colony-stimulating factor (GM-CSF) are responsible for maintaining survival and stimulating growth of early dormant hematopoietic progenitor cells (HPC

Cited by 9 publications

References 17 publications

An epidemiologic study of early biologic effects of benzene in Chinese workers.

An epidemiologic study of early biologic effects of benzene in Chinese workers.

Hydroquinone modulates the GM-CSF signaling pathway in TF-1 cells

Association of genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, and GSTT1 genes with benzene poisoning.

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