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

Details

• Personal Author:
  Bi Y ; He X ; Kong M ; Li Y ; Ma Q ; Xiao X ; Zhao Z
• Description:
  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 B4 (LTB4) omega-hydroxylase, is important for inactivation of LTB4 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 (DNAPKcs) 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. [Description provided by NIOSH]
• Subjects:
  Benzene Genetics Mutagens Occupational Health Poisoning Safety Solvents
• Keywords:
  Author Keywords: Benzene Benzene-poisoning Benzenes CYP4F3 DNA-PKcs DNA Double Strand Break Repair Gene-mutation Genes Genotoxic-effects Genotoxicity Microarray Mutagenesis Mutagenicity Mutation Organic-solvents

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• ISSN:
  0009-2797
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  207-211
• Volume:
  184
• Issue:
  1
• NIOSHTIC Number:
  nn:20036676
• Citation:
  Chem-Biol Interact 2010 Mar; 184(1-2):207-211
• Contact Point Address:
  Yongyi Bi, School of Public Health, Wuhan University, 185 Donghu Rd., Wuhan, Hubei 430071, China
• Email:
  yongyib@yahoo.com.cn
• CAS Registry Number:
  Benzene (CAS RN 71-43-2)
• Federal Fiscal Year:
  2010
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Chemico-Biological Interactions
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:62bd7fbdcc4d2c674c868766f4d968352b87a70e2fec716ef45f1549d2fab33a3e5ba0b59d976a52d4efbbdbe90e43c611bb2560ffc1c4611d2b82b01d66e3b7
• Download URL:
  https://stacks.cdc.gov/view/cdc/188005/cdc_188005_DS1.pdf
• File Type:
  [PDF - 349.15 KB ]