Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzene was previously detected as a heat-induced contaminant in infant carrot juices. This study shows that carrot juice contains substances such as beta-carotene, phenylalanine or terpenes that may act as precursors for benzene formation during food processing. As benzene exposure has been associated with childhood leukaemia and other cancers, this study aimed to provide a quantitative risk assessment. To accomplish this, we used measured food consumption data from the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study, along with survey data on benzene in different juice categories. The calculated exposures for infants between 3 and 12 months were low, with averages between 1 and 10 ng/kg bw/day, resulting in a margin of exposure above 100,000. The exposures were judged as unlikely to pose a health risk for infants. Nevertheless, carcinogenic contaminants should be reduced to levels as low as reasonably achievable. The focus should be set on improving the sterilization conditions.
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PMID:Benzene in infant carrot juice: further insight into formation mechanism and risk assessment including consumption data from the DONALD study. 1983 26

Aberrant regulation of gap junction intercellular communication (GJIC) has been linked to several human diseases, including cancer and abnormal hematopoietic development. Benzene exposure has been shown to cause hematotoxicity and leukemia, but the underlying mechanisms involved remain unclear. We have observed that several metabolites of benzene have the ability to block gap junction intercellular communication. The ring-opened trans,trans-muconaldehyde (MUC) was found to be the most potent inhibitor of gap junction channels. MUC was found to induce cross-linking of the gap junction protein connexin43, which seemed to be responsible for the induced inhibition of GJIC. Glutaraldehyde, which has a similar molecular structure as MUC, was found to possess similar effects on gap junctions as MUC, while the mono-aldehyde formaldehyde shows lower potency, both as a connexin cross-linker, and as an inhibitor of GJIC. Both glutaraldehyde and formaldehyde have previously been associated with induction of leukemia and disturbance of hematopoiesis. Taken together, the data support a possible link between the effect of MUC on gap junctions, and the toxic effects of benzene.
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PMID:Gap junction intercellular communication and benzene toxicity. 1993 93

Benzene causes hematotoxicity and leukemia in humans. To analyze benzene-caused aberrant gene expression, we examined differential gene expression by microarray analysis of peripheral mononuclear blood cells from seven workers diagnosed with benzene poisoning and seven matched controls. Twenty-two genes were found up-regulated and 18 down-regulated in benzene patients compared with controls. Here we report the characterization of two benzene-regulated genes. CYP4F3A, which encodes the leukotriene B(4) (LTB(4)) omega-hydroxylase, is important for inactivation of LTB(4) in neutrophils. CYP4F3A mRNA was found elevated in all patients; moreover, CYP4F3A mRNA and protein were induced by benzene metabolite phenol in HL-60 and K562 cells as well as ex vivo in human peripheral neutrophils. Silencing of CYP4F3A in HL-60 cells by lentiviral delivery of CYP4F3A-specific siRNA reduced cell survival to 56%, 44%, 22%, 14%, and 3% at 3, 4, 5, 6, and 7 days, respectively; the results suggest that CYP4F3A is a critical positive regulator of HL-60 proliferation. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) regulates non-homologous end joining (NHEJ) in DNA double strand break (DSB) repair. DNA-PKcs mRNA was found consistently increased in the patients and DNA-PKcs mRNA and protein were induced by hydroquinone in HL-60 cells. In a DSB model, hydroquinone induced the formation of gamma-H2AX foci, a marker of DSBs, in HL-60 cells. The findings indicate that hydroquinone induces DSBs and induction correlates with elevated levels of DNA-PKcs and NHEJ. Similar results were obtained in K562 cells treated with phenol. Since NHEJ is error-prone, induction of DNA-PKcs and NHEJ may contribute to mutagenesis and leukemia by benzene. To our knowledge, the study demonstrated for the first time that benzene and metabolites induce CYP4F3A and DNA-PKcs both in vivo and in vitro. Induction of the genes may play a role in the pathogenesis of benzene hematotoxicity and serve as biomarkers of benzene exposure.
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PMID:Gene expression in benzene-exposed workers by microarray analysis of peripheral mononuclear blood cells: induction and silencing of CYP4F3A and regulation of DNA-dependent protein kinase catalytic subunit in DNA double strand break repair. 2003 48

Benzene is a ubiquitous chemical in our environment that causes acute leukemia and probably other hematological cancers. Evidence for an association with childhood leukemia is growing. Exposure to benzene can lead to multiple alterations that contribute to the leukemogenic process, indicating a multimodal mechanism of action. Research is needed to elucidate the different roles of multiple metabolites in benzene toxicity and the pathways that lead to their formation. Studies to date have identified a number of polymorphisms in candidate genes that confer susceptibility to benzene hematotoxicity. However, a genome-wide study is needed to truly assess the role of genetic variation in susceptibility. Benzene affects the blood-forming system at low levels of occupational exposure, and there is no evidence of a threshold. There is probably no safe level of exposure to benzene, and all exposures constitute some risk in a linear, if not supralinear, and additive fashion.
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PMID:Advances in understanding benzene health effects and susceptibility. 2007 Feb 8

Benzene is a ubiquitous occupational and environmental toxicant. Exposures to benzene both prenatally and during adulthood are associated with the development of disorders such as aplastic anemia and leukemia. Mechanisms of benzene toxicity are unknown; however, generation of reactive oxygen species (ROS) by benzene metabolites may play a role. Little is known regarding the effects of benzene metabolites on erythropoiesis. Therefore, to determine the effects of in utero exposure to benzene on the growth and differentiation of fetal erythroid progenitor cells (CFU-E), pregnant CD-1 mice were exposed to benzene and CFU-E numbers were assessed in fetal liver (hematopoietic) tissue. In addition, to determine the effect of benzene metabolite-induced ROS generation on erythropoiesis, HD3 chicken erythroblast cells were exposed to benzene, phenol, or hydroquinone followed by stimulation of erythrocyte differentiation. Our results show that in utero exposure to benzene caused significant alterations in female offspring CFU-E numbers. In addition, exposure to hydroquinone, but not benzene or phenol, significantly reduced the percentage of differentiated HD3 cells, which was associated with an increase in ROS. Pretreatment of HD3 cells with polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) prevented hydroquinone-induced inhibition of erythropoiesis, supporting the hypothesis that ROS generation is involved in the development of benzene erythrotoxicity. In conclusion, this study provided evidence that ROS generated as a result of benzene metabolism may significantly alter erythroid differentiation, potentially leading to the development of Blood Disorders.
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PMID:In utero and in vitro effects of benzene and its metabolites on erythroid differentiation and the role of reactive oxygen species. 2008 30

Benzene is an established hematotoxic carcinogen which can cause leukemia. DNA damage and disorder of repair capacity are the crucial mechanisms in leukemogenesis of benzene. DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-aza) and histone deacetylase inhibitor, trichostatin A (TSA) are two kinds of key epigenetic modification reagents. The mRNA expression of poly(ADP-ribose) polymerases-1 (PARP-1), a pivotal repair gene, has been decreased by benzene. However, the effect of epigenetic modification on benzene-induced low PARP-1 expression has not been reported. In this study, lymphoblastoid cell line F32 was incubated by benzene and then further treated with 5-aza and TSA, alone or in combination. The reverse transcription-polymerase chain reaction and methylation-specific PCR were performed to examine the mRNA expression and methylation status of PARP-1, respectively. Results showed a dramatic decrease of PARP-1 mRNA expression and a simultaneously obvious increase in the level of PARP-1 methylation in benzene-treated cells compared to the control. Further, the PARP-1 mRNA expression was restored and the level of PARP-1 methylation was also reduced following epigenetic inhibitors, 5-aza and TSA, alone or in combination treatments. Taken together, methylation of PARP-1 promoter might be involved in the regulation of benzene-induced decrease of PARP-1 mRNA expression.
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PMID:Methylation of PARP-1 promoter involved in the regulation of benzene-induced decrease of PARP-1 mRNA expression. 2023 Aug 82

Specific cytogenetic alterations and changes in DNA methylation are involved in leukemogenesis. Benzene, an established human leukemogen, is known to induce cytogenetic changes through its active metabolites including hydroquinone (HQ), but the specific alterations have not been fully characterized. Global DNA hypomethylation was reported in a population exposed to benzene, but has not been confirmed in vitro. In this study, we examined cytogenetic changes in chromosomes 5, 7, 8, 11 and 21, and global DNA methylation in human TK6 lymphoblastoid cells treated with HQ for 48 h, and compared the HQ-induced alterations with those induced by two well-known leukemogens, melphalan, an alkylating agent, and etoposide, a DNA topoisomerase II inhibitor. We found that rather than inducing cytogenetic alterations distinct from those induced by melphalan and etoposide, HQ induced alterations characteristic of each agent. HQ induced global DNA hypomethylation at a level intermediate to melphalan (no effect) and etoposide (potent effect). These results suggest that HQ may act similar to an alkylating agent and also similar to a DNA topoisomerase II inhibitor in living cells, both of which may be potential mechanisms of benzene toxicity. In addition to cytogenetic changes, global DNA hypomethylation may be another mechanism underlying the leukemogenicity of benzene.
Leukemia 2010 May
PMID:A comparison of the cytogenetic alterations and global DNA hypomethylation induced by the benzene metabolite, hydroquinone, with those induced by melphalan and etoposide. 2033 39

Benzene, toluene, o-xylene, ethylbenzene, trichloroethylene and dichloromethane are the most widely used volatile organic compounds (VOCs), and their toxic mechanisms are still undefined. This study analyzed the genome-wide expression profiles of human promyelocytic leukemia HL-60 cells exposed to VOCs using a 35-K whole human genome oligonucleotide microarray to ascertain potential biomarkers. Genes with a significantly increased expression levels (over 1.5-fold and p-values <0.05) with six VOCs were then classified with gene ontology and KEGG pathway annotation. At IC(20) doses identified genes were functionally categorized as being involved in cytokine-cytokine receptor interactions and the toll-like receptor signaling pathway, whereas exposure at IC(50) doses identified genes associated with the p53 signaling pathway, apoptosis, and natural killer cell-mediated cytotoxicity pathway. Functionally important immune response- and apoptosis-related genes were further validated by real-time RT-PCR. The results showed that IFIT1, IFIT2, IFIT3, USP18, INFGR2, PMAIP1, GADD45A, NFKBIA, TNFAIP3, and BIRC3 genes altered their expression profiles in a dose-dependent manner. Similar expressions profiles were also found in human erythromyeloblastoid leukemia K562 cells and in human leukemic monocyte lymphoma U937 cells. In conclusion, both gene expression profiles and gene ontology analysis have elucidated potential gene-based biomarkers and provided insights into the mechanism underlying the response of human leukemia cell lines to VOC exposure.
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PMID:Gene expression profiles of human promyelocytic leukemia cell lines exposed to volatile organic compounds. 2035 17

Benzene (C(6)H(6)) is a highly flammable, colorless liquid. Ubiquitous exposures result from its presence in gasoline vapors, cigarette smoke, and industrial processes. Benzene increases the incidence of leukemia in humans when they are exposed to high doses for extended periods; however, leukemia risks in humans subjected to low exposures are uncertain. The exposure-dose- response relationship of benzene in humans is expected to be nonlinear because benzene undergoes a series of metabolic transformations, detoxifying and activating, resulting in various metabolites that exert toxic effects on the bone marrow. Since benzene is a known human leukemogen, the toxicity of benzene in the bone marrow is of most importance. And because blood cells are produced in the bone marrow, we investigated the effects of benzene on hematopoiesis (blood cell production and development). An age-structured model was used to examine the process of erythropoiesis, the development of red blood cells. This investigation proved the existence and uniqueness of the solution of the system of coupled partial and ordinary differential equations. In addition, we formulated an optimal control problem for the control of erythropoiesis and performed numerical simulations to compare the performance of the optimal feedback law and another feedback function based on the Hill function.
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PMID:Modeling and optimal regulation of erythropoiesis subject to benzene intoxication. 2036 57

The purpose of this study was to review the existing studies on lymphohematopoietic (LHP) cancer in Korea, estimate the prevalence of workers exposed to carcinogens, and determine the population attributable fraction (PAF) of leukemia. Two case series and 4 case reports were reviewed. Using official statistics, the prevalence of benzene exposure and ionizing radiation exposure was estimated. Based on the prevalence of exposure and the relative risk, The PAF of leukemia was calculated. Between 1996 and 2005, 51 cases of LHP cancer were reported from the compensation system. Greater than 50% of occupational LHP cancer was leukemia, and the most important cause was benzene. In a cohort study, the standardized incidence ratio was 2.71 (95% CI, 0.56-7.91). The prevalence of exposure was 2.5% and 2.2% in 1995 and 2000, respectively. Using the 1995 prevalence, 3.6-4.8% and 0.1% of cases with leukemia were attributable to benzene and ionizing radiation exposure, respectively, which resulted in 39.7-51.4 cases per year. Benzene is the most important cause of occupational leukemia in Korea. Considering the estimated PAF in this study, the annual number of occupational LHP cancer (51 cases during 10-yr period), might be underreported within the compensation system.
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PMID:Occupational lymphohematopoietic cancer in Korea. 2125 98


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