Summary of Study ST001918

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001209. The data can be accessed directly via it's Project DOI: 10.21228/M8F70B This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

Show all samples  |  Perform analysis on untargeted data  
Download mwTab file (text)   |  Download mwTab file(JSON)   |  Download data files (Contains raw data)
Study IDST001918
Study TitleMetabolome-wide association study of occupational exposure to benzene
Study SummaryBenzene is a recognized hematotoxin and leukemogen; however, its mechanism of action in humans remain unclear. To provide insight into the processes underlying benzene hematotoxicity, we performed high-resolution metabolomic (HRM) profiling of plasma collected from a cross-sectional study of 33 healthy workers exposed to benzene (median 8-hr time-weighted average exposure; 20 ppma), and 25 unexposed controls in Shanghai, China. Metabolic features associated with benzene were identified using a metabolome-wide association study (MWAS) that tested for the relationship between feature intensity and benzene exposure. MWAS identified 478 mass spectral features associated with benzene exposure at FDR<20%. Comparison to a list of 13 known benzene metabolites and metabolites predicted using a multi-component biotransformation algorithm showed five metabolites were detected, which included the known metabolites phenol and benzene diolepoxide. Metabolic pathway enrichment identified 41 pathways associated with benzene exposure, with altered pathways including carnitine shuttle, fatty acid metabolism, sulfur amino acid metabolism, glycolysis, gluconeogenesis, and branched chain amino acid metabolism. These results suggest disruption to fatty acid uptake, energy metabolism and increased oxidative stress, and point towards pathways related to mitochondrial dysfunction, which has previously been linked to benzene exposure in animal models and human studies. Taken together, these results suggest benzene exposure is associated with disruption of mitochondrial pathways, and provide promising, systems biology biomarkers for risk assessment of benzene-induced hematotoxicity in humans.
Institute
Icahn School of Medicine at Mount Sinai
DepartmentEnvironmental Medicine and Public Health
LaboratoryHigh Resolution Exposomics
Last NameWalker
First NameDouglas
AddressAtran Building RM AB3-39, 1428 Madison Ave, New York, NY, 10029, USA
Emaildouglas.walker@mssm.edu
Phone1-212-241-4392
Submit Date2021-08-26
Num Groups3
Total Subjects58
Num Males28
Num Females30
PublicationsN Rothman, R Vermeulen, L Zhang, W Hu, S Yin, SM Rappaport, MT Smith, DP Jones, M Rahman, Qing Lan, DI Walker. (2021). Metabolome-wide association study of occupational exposure to benzene. Carcinogenesis. In Review
Raw Data AvailableYes
Raw Data File Type(s)mzXML, raw(Thermo)
Analysis Type DetailLC-MS
Release Date2021-10-02
Release Version1
Douglas Walker Douglas Walker
https://dx.doi.org/10.21228/M8F70B
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR001209
Project DOI:doi: 10.21228/M8F70B
Project Title:Metabolome-wide association study of occupational exposure to benzene
Project Summary:Benzene is a recognized hematotoxin and leukemogen; however, its mechanism of action in humans remain unclear. To provide insight into the processes underlying benzene hematotoxicity, we performed high-resolution metabolomic (HRM) profiling of plasma collected from a cross-sectional study of 33 healthy workers exposed to benzene (median 8-hr time-weighted average exposure; 20 ppma), and 25 unexposed controls in Shanghai, China. Metabolic features associated with benzene were identified using a metabolome-wide association study (MWAS) that tested for the relationship between feature intensity and benzene exposure. MWAS identified 478 mass spectral features associated with benzene exposure at FDR<20%. Comparison to a list of 13 known benzene metabolites and metabolites predicted using a multi-component biotransformation algorithm showed five metabolites were detected, which included the known metabolites phenol and benzene diolepoxide. Metabolic pathway enrichment identified 41 pathways associated with benzene exposure, with altered pathways including carnitine shuttle, fatty acid metabolism, sulfur amino acid metabolism, glycolysis, gluconeogenesis, and branched chain amino acid metabolism. These results suggest disruption to fatty acid uptake, energy metabolism and increased oxidative stress, and point towards pathways related to mitochondrial dysfunction, which has previously been linked to benzene exposure in animal models and human studies. Taken together, these results suggest benzene exposure is associated with disruption of mitochondrial pathways, and provide promising, systems biology biomarkers for risk assessment of benzene-induced hematotoxicity in humans.
Institute:Icahn School of Medicine at Mount Sinai
Department:Environmental Medicine and Public Health
Laboratory:High Resolution Exposomics
Last Name:Walker
First Name:Douglas
Address:Atran Building RM AB3-39, 1428 Madison Ave, New York, NY, 10029, USA
Email:douglas.walker@mssm.edu
Phone:1-212-241-4392
Funding Source:This work was supported by funds received from the National Institute of Environmental Health Sciences (ES026561, ES023515, ES019776, ES028903), the National Institutes of Health Office of the Director (OD018006), EU-H2020 (874627), EXPOSOME-NL (NWO grant number 024.004.017) and intramural funds received from the National Cancer Institute.
Project Comments:This data was submitted in support of
Publications:N Rothman, R Vermeulen, L Zhang, W Hu, S Yin, SM Rappaport, MT Smith, DP Jones, M Rahman, Qing Lan, DI Walker. (2021). Metabolome-wide association study of occupational exposure to benzene. Carcinogenesis. In Review

Subject:

Subject ID:SU001996
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Gender:Male and female

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Sex Smoking_status
SA177739CZ.0073.001_11 1
SA177740CZ.0069.006_11 1
SA177741CZ.0068.005_11 1
SA177742CZ.0065.006_11 1
SA177743CZ.0143.005_11 1
SA177744CZ.0034.003_11 1
SA177745CZ.0023.001_11 1
SA177746CZ.0150.005_11 1
SA177747CZ.0177.002_11 1
SA177748CZ.0037.001_11 1
SA177749CZ.0013.001_11 1
SA177750CZ.0113.003_11 1
SA177751CZ.0076.006_11 1
SA177752CZ.0142.006_11 1
SA177753CZ.0039.004_11 1
SA177754CZ.0074.006_11 1
SA177755CZ.0038.006_11 1
SA177756CZ.0100.002_11 1
SA177757CZ.0141.006_11 1
SA177758CZ.0033.006_11 1
SA177759CZ.0012.004_11 1
SA177760CZ.0072.004_11 1
SA177761CZ.0114.004_11 1
SA177762CZ.0014.004_11 1
SA177763CZ.0066.006_11 1
SA177764CZ.0109.005_11 1
SA177765CZ.0067.005_11 2
SA177766CZ.0160.004_11 2
SA177767CZ.0064.250_11 2
SA177768CZ.0180.002_11 2
SA177769CZ.0003.005_12 2
SA177770CZ.0006.004_12 2
SA177771CZ.0004.004_12 2
SA177772CZ.0075.003_12 2
SA177773CZ.0132.005_12 2
SA177774CZ.0005.001_12 2
SA177775CZ.0131.006_12 2
SA177776CZ.0137.003_12 2
SA177777CZ.0002.004_12 2
SA177778CZ.0135.004_12 2
SA177779CZ.0136.005_12 2
SA177780CZ.0010.003_12 2
SA177781CZ.0172.001_12 2
SA177782CZ.0169.005_12 2
SA177783CZ.0178.006_12 2
SA177784CZ.0165.006_12 2
SA177785CZ.0008.006_12 2
SA177786CZ.0153.006_12 2
SA177787CZ.0138.005_12 2
SA177788CZ.0157.005_12 2
SA177789CZ.0159.002_12 2
SA177790CZ.0179.001_12 2
SA177791CZ.0078.003_12 2
SA177792CZ.0171.006_12 2
SA177793CZ.0011.006_12 2
SA177794CZ.0154.003_12 2
SA177795CZ.0176.002_12 2
SA177796CZ.0133.005_12 2
SA177797nist2_1NA NA
SA177798q3June2014_2d_1NA NA
SA177799BEW.1033.001_1NA NA
SA177800q3June2014_2e_1NA NA
SA177801BEW.1034.001_1NA NA
SA177802BEW.1036.001_1NA NA
SA177803BEW.1035.001_1NA NA
SA177804q3June2014_2c_1NA NA
SA177805CZ.0041.003_1NA NA
SA177806q3June2014_2f_1NA NA
SA177807q3June2014_1e_1NA NA
SA177808CZ.0035.003_1NA NA
SA177809BEW.1022.001_1NA NA
SA177810q3June2014_1c_1NA NA
SA177811q3June2014_1d_1NA NA
SA177812BEW.1023.001_1NA NA
SA177813BEW.1021.001_1NA NA
SA177814q3June2014_1a_1NA NA
SA177815q3June2014_1b_1NA NA
SA177816BEW.1024.001_1NA NA
SA177817CZ.0162.005_1NA NA
SA177818BEW.1026.001_1NA NA
SA177819BEW.1025.001_1NA NA
SA177820q3June2014_2b_1NA NA
SA177821BEW.1029.001_1NA NA
SA177822BEW.1032.001_1NA NA
SA177823BEW.1030.001_1NA NA
SA177824q3June2014_2a_1NA NA
SA177825q3June2014_1f_1NA NA
SA177826BEW.1027.001_1NA NA
SA177827BEW.1028.001_1NA NA
SA177828nist1_1NA NA
SA177829BEW.1031.001_1NA NA
Showing results 1 to 91 of 91

Collection:

Collection ID:CO001989
Collection Summary:Identification of factories and worker enrollment are described in detail elsewhere. [14] Study subjects were enrolled in the Fall of 1992 in Shanghai, China and evaluated at the Shanghai Hygiene and Anti-Epidemic Institute. The study protocol was explained to all potential participants, and informed consent was obtained using Institutional Review Board-approved procedures. Data collected included age, gender, tobacco use, alcohol consumption, medical history, and an occupational work history. Prior to the clinical visit, study subjects were asked to refrain from eating solid foods after dinner the night before and the morning of the clinical phase of the study. The following morning, a 27 mL sample of blood was obtained by venous phlebotomy. Plasma samples were then frozen at -80°C, shipped to the NCI on dry ice, and stored continuously at -80°C until analysis.
Sample Type:Blood (plasma)
Storage Conditions:-80℃
Additives:EDTA

Treatment:

Treatment ID:TR002008
Treatment Summary:Details of personal benzene exposure assessment have been reported previously. [14] In brief, individual exposure was monitored by organic vapor passive dosimetry badges (3M no. 3500. St.Paul. Minnesota), which were worn by each worker for a full shift on 5 separate days for a 1–2 week period prior to blood collection. Badges were analyzed by gas chromatography (GC) with flame ionization detection for benzene, toluene, and xylene. Average exposure was calculated for each compound as the geometric mean of the five air measurements. In this study, we focus on control workers with no benzene exposure, lower (relative) exposures (<20ppm) and high exposure (>20ppm) Due to benzene levels exceeding the current OSHA time-weighted exposure limit of 1 ppma for all exposed workers, the median exposure of 20 ppm was used to classify low- and high-exposed workers to identify exposure-associated metabolic changes. For each m/z feature, peak intensity was log2 transformed to test for association with benzene across the categories of exposure, which included controls, low exposed (<20 ppma) and high exposed (≥20 ppma), defined as a continuous variable (control=0; < 20 ppma= 1; ≥20 ppma= 2)

Sample Preparation:

Sampleprep ID:SP002002
Sampleprep Summary:Samples are prepared for metabolomics analysis using established methods (Johnson et al. (2010). Analyst; Go et al. (2015). Tox Sci). Prior to analysis, plasma aliquots were removed from storage at -80°C and thawed on ice. Each cryotube is then vortexed briefly to ensure homogeneity, and 50 μL transferred to a clean microfuge tube. Immediately after, the plasma is treated with 100 μL of ice-cold LC-MS grade acetonitrile (Sigma Aldrich) containing 2.5 μL of internal standard solution with eight stable isotopic chemicals selected to cover a range of chemical properties. Following addition of acetonitrile, plasma is then equilibrated for 30 min on ice, upon which precipitated proteins are removed by centrifuge (16.1 ×g at 4°C for 10 min). The resulting supernatant (100 μL) is removed, added to a low volume autosampler vial and maintained at 4°C until analysis (<22 h).
Sampleprep Protocol ID:EmoryUniversity_HRM_SP_082016_01.pdf
Sampleprep Protocol Filename:EmoryUniversity_HRM_SP_082016_01.pdf
Extraction Method:2:1 addition of acetonitrile
Sample Spiking:[13C6]-D-glucose, [15N,13C5]-L-methionine, [13C5]-L-glutamic acid, [15N]-L-tyrosine, [3,3-13C2]-cystine, [trimethyl-13C3]-caffeine, [U-13C5, U-15N2]-L-glutamine, [15N]-indole

Combined analysis:

Analysis ID AN003116 AN003117
Analysis type MS MS
Chromatography type HILIC Reversed phase
Chromatography system Thermo Dionex Ultimate 3000 Thermo Dionex Ultimate 3000
Column Waters XBridge BEH Amide XP HILIC (50 x 2.1mm,2.5m) Higgins endcapped C18 (50 x 2.1mm,3um)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive HF hybrid Orbitrap Thermo Q Exactive HF hybrid Orbitrap
Ion Mode POSITIVE NEGATIVE
Units Peak area Peak area

Chromatography:

Chromatography ID:CH002301
Chromatography Summary:HILIC–positive chromatography method summary The HILIC column is operated parallel to reverse phase column for simultaneous analytical separation and column flushing through the use of a dual head HPLC pump equipped with 10-port and 6-port switching valves. During operation of HILIC separation method, the MS is operated in positive ion mode and 10 μL of sample is injected onto the HILIC column while the reverse phase column is flushing with wash solution. Flow rate is maintained at 0.35 mL/min until 1.5 min, increased to 0.4 mL/min at 4 min and held for 1 min. Solvent A is 100% LC-MS grade water, solvent B is 100% LC-MS grade acetonitrile and solvent C is 2% formic acid (v/v) in LC-MS grade water. Initial mobile phase conditions are 22.5% A, 75% B, 2.5% C hold for 1.5 min, with linear gradient to 77.5% A, 20% B, 2.5% C at 4 min, hold for 1 min, resulting in a total analytical run time of 5 min. During the flushing phase (reverse phase analytical separation), the HILIC column is equilibrated with a wash solution of 77.5% A, 20% B, 2.5% C
Methods Filename:EmoryUniversity_HRM-QEHF_DC5min_092017_v1.pdf
Instrument Name:Thermo Dionex Ultimate 3000
Column Name:Waters XBridge BEH Amide XP HILIC (50 x 2.1mm,2.5m)
Flow Gradient:Initial mobile phase conditions are 22.5% A, 75% B, 2.5% C hold for 1.5 min, with linear gradient to 77.5% A, 20% B, 2.5% C at 4 min, hold for 1 min, resulting in a total analytical run time of 5 min.
Solvent A:100% water(A), 100% acetonitrile(B), 100% water; 2% formic acid(C)
Solvent B:100% water(A), 100% acetonitrile(B), 100% water; 2% formic acid(C)
Chromatography Type:HILIC
  
Chromatography ID:CH002302
Chromatography Summary:C18–negative chromatography method summary The C18 column is operated parallel to the HILIC column for simultaneous analytical separation and column flushing through the use of a dual head HPLC pump equipped with 10-port and 6-port switching valves. During operation of the C18 method, the MS is operated in negative ion mode and 10 μL of sample is injected onto the C18 column while the HILIC column is flushing with wash solution. Flow rate is maintained at 0.4 mL/min until 1.5 min, increased to 0.5 mL/min at 2 min and held for 3 min. Solvent A is 100% LC-MS grade water, solvent B is 100% LC-MS grade acetonitrile and solvent C is 10mM ammonium acetate in LC-MS grade water. Initial mobile phase conditions are 60% A, 35% B, 5% C hold for 0.5 min, with linear gradient to 0% A, 95% B, 5% C at 1.5 min, hold for 3.5 min, resulting in a total analytical run time of 5 min. During the flushing phase (HILIC analytical separation), the C18 column is equilibrated with a wash solution of 0% A, 95% B, 5% C until 2.5 min, followed by an equilibration solution of 60% A, 35% B, 5% C for 2.5 min.
Methods Filename:EmoryUniversity_HRM-QEHF_DC5min_092017_v1.pdf
Instrument Name:Thermo Dionex Ultimate 3000
Column Name:Higgins endcapped C18 (50 x 2.1mm,3um)
Flow Gradient:Initial mobile phase conditions are 60% A, 35% B, 5% C hold for 0.5 min, with linear gradient to 0% A, 95% B, 5% C at 1.5 min, hold for 3.5 min, resulting in a total analytical run time of 5 min.
Flow Rate:0.4 mL/min-0.5 mL/min
Solvent A:100% water(A), 100% acetonitrile(B), 10 mM ammonium acetate(C)
Solvent B:100% water(A), 100% acetonitrile(B), 10 mM ammonium acetate(C)
Chromatography Type:Reversed phase

MS:

MS ID:MS002897
Analysis ID:AN003116
Instrument Name:Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:The mass spectrometer was operated at a resolution of 120,000. Source tune settings were optimized using a standard mixture for both positive and negative mode, resulting in capillary temperature, vaporizer temperature, sheath gas, auxiliary gas, sweep gas and S-Lens RF level settings of 250°C, 150°C, 45 (arbitrary units), 5 (arbitrary units), 1 (arbitrary units) and 55, respectively. Positive mode ESI was operated using a spray voltage of +3.5 kV. High-resolution detection of m/z features was accomplished by maximum injection time of 100 milliseconds and AGC target of 1x106. During untargeted data acquisition, no exclusion or inclusion masses were selected, and data was acquired in MS1 mode only over the scan range of 85-1250 m/z. Following instrumental analysis of all study and quality control (QC) samples, which included NIST SRM 1950 and pooled human plasma, instrument files were converted to .mzXML format and m/z features were extracted and aligned at multiple parameter settings using apLCMS. [2] The resulting feature tables were then merged with xMSanalyzer [3], which systemically evaluates sample profile quality, feature detection and technical reliability for optimal peak selection. Only features exhibiting a median triplicate coefficient of variation ≤ 100% and detected in greater than 25% of the study samples were retained. The resulting feature table was then batch corrected using ComBat [4] and triplicate injections averaged prior to analysis.
Ion Mode:POSITIVE
Capillary Temperature:250
Dry Gas Flow:45
Dry Gas Temp:150
Ion Source Temperature:150
Analysis Protocol File:EmoryUniversity_HRM_QEHF-MS_092017_v1.pdf
  
MS ID:MS002898
Analysis ID:AN003117
Instrument Name:Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:The mass spectrometer was operated at a resolution of 120,000. Source tune settings were optimized using a standard mixture for both positive and negative mode, resulting in capillary temperature, vaporizer temperature, sheath gas, auxiliary gas, sweep gas and S-Lens RF level settings of 250°C, 150°C, 45 (arbitrary units), 5 (arbitrary units), 1 (arbitrary units) and 55, respectively. Negative mode ESI was operated at -4 kV. High-resolution detection of m/z features was accomplished by maximum injection time of 100 milliseconds and AGC target of 1x106. During untargeted data acquisition, no exclusion or inclusion masses were selected, and data was acquired in MS1 mode only over the scan range of 85-1250 m/z. Following instrumental analysis of all study and quality control (QC) samples, which included NIST SRM 1950 and pooled human plasma, instrument files were converted to .mzXML format and m/z features were extracted and aligned at multiple parameter settings using apLCMS. [2] The resulting feature tables were then merged with xMSanalyzer [3], which systemically evaluates sample profile quality, feature detection and technical reliability for optimal peak selection. Only features exhibiting a median triplicate coefficient of variation ≤ 100% and detected in greater than 25% of the study samples were retained. The resulting feature table was then batch corrected using ComBat [4] and triplicate injections averaged prior to analysis.
Ion Mode:NEGATIVE
Capillary Temperature:250
Dry Gas Flow:45
Dry Gas Temp:150
Ion Source Temperature:150
Analysis Protocol File:EmoryUniversity_HRM_QEHF-MS_092017_v1.pdf
  logo