#METABOLOMICS WORKBENCH douglas_walker_20210826_102502 DATATRACK_ID:2813 STUDY_ID:ST001918 ANALYSIS_ID:AN003117 PROJECT_ID:PR001209 VERSION 1 CREATED_ON August 26, 2021, 5:41 pm #PROJECT PR:PROJECT_TITLE Metabolome-wide association study of occupational exposure to benzene PR:PROJECT_SUMMARY Benzene is a recognized hematotoxin and leukemogen; however, its mechanism of PR:PROJECT_SUMMARY action in humans remain unclear. To provide insight into the processes PR:PROJECT_SUMMARY underlying benzene hematotoxicity, we performed high-resolution metabolomic PR:PROJECT_SUMMARY (HRM) profiling of plasma collected from a cross-sectional study of 33 healthy PR:PROJECT_SUMMARY workers exposed to benzene (median 8-hr time-weighted average exposure; 20 PR:PROJECT_SUMMARY ppma), and 25 unexposed controls in Shanghai, China. Metabolic features PR:PROJECT_SUMMARY associated with benzene were identified using a metabolome-wide association PR:PROJECT_SUMMARY study (MWAS) that tested for the relationship between feature intensity and PR:PROJECT_SUMMARY benzene exposure. MWAS identified 478 mass spectral features associated with PR:PROJECT_SUMMARY benzene exposure at FDR<20%. Comparison to a list of 13 known benzene PR:PROJECT_SUMMARY metabolites and metabolites predicted using a multi-component biotransformation PR:PROJECT_SUMMARY algorithm showed five metabolites were detected, which included the known PR:PROJECT_SUMMARY metabolites phenol and benzene diolepoxide. Metabolic pathway enrichment PR:PROJECT_SUMMARY identified 41 pathways associated with benzene exposure, with altered pathways PR:PROJECT_SUMMARY including carnitine shuttle, fatty acid metabolism, sulfur amino acid PR:PROJECT_SUMMARY metabolism, glycolysis, gluconeogenesis, and branched chain amino acid PR:PROJECT_SUMMARY metabolism. These results suggest disruption to fatty acid uptake, energy PR:PROJECT_SUMMARY metabolism and increased oxidative stress, and point towards pathways related to PR:PROJECT_SUMMARY mitochondrial dysfunction, which has previously been linked to benzene exposure PR:PROJECT_SUMMARY in animal models and human studies. Taken together, these results suggest PR:PROJECT_SUMMARY benzene exposure is associated with disruption of mitochondrial pathways, and PR:PROJECT_SUMMARY provide promising, systems biology biomarkers for risk assessment of PR:PROJECT_SUMMARY benzene-induced hematotoxicity in humans. PR:INSTITUTE Icahn School of Medicine at Mount Sinai PR:DEPARTMENT Environmental Medicine and Public Health PR:LABORATORY High Resolution Exposomics PR:LAST_NAME Walker PR:FIRST_NAME Douglas PR:ADDRESS Atran Building RM AB3-39, 1428 Madison Ave, New York, NY, 10029, USA PR:EMAIL douglas.walker@mssm.edu PR:PHONE 1-212-241-4392 PR:FUNDING_SOURCE This work was supported by funds received from the National Institute of PR:FUNDING_SOURCE Environmental Health Sciences (ES026561, ES023515, ES019776, ES028903), the PR:FUNDING_SOURCE National Institutes of Health Office of the Director (OD018006), EU-H2020 PR:FUNDING_SOURCE (874627), EXPOSOME-NL (NWO grant number 024.004.017) and intramural funds PR:FUNDING_SOURCE received from the National Cancer Institute. PR:PROJECT_COMMENTS This data was submitted in support of PR:PUBLICATIONS N Rothman, R Vermeulen, L Zhang, W Hu, S Yin, SM Rappaport, MT Smith, DP Jones, PR:PUBLICATIONS M Rahman, Qing Lan, DI Walker. (2021). Metabolome-wide association study of PR:PUBLICATIONS occupational exposure to benzene. Carcinogenesis. In Review #STUDY ST:STUDY_TITLE Metabolome-wide association study of occupational exposure to benzene ST:STUDY_SUMMARY Benzene is a recognized hematotoxin and leukemogen; however, its mechanism of ST:STUDY_SUMMARY action in humans remain unclear. To provide insight into the processes ST:STUDY_SUMMARY underlying benzene hematotoxicity, we performed high-resolution metabolomic ST:STUDY_SUMMARY (HRM) profiling of plasma collected from a cross-sectional study of 33 healthy ST:STUDY_SUMMARY workers exposed to benzene (median 8-hr time-weighted average exposure; 20 ST:STUDY_SUMMARY ppma), and 25 unexposed controls in Shanghai, China. Metabolic features ST:STUDY_SUMMARY associated with benzene were identified using a metabolome-wide association ST:STUDY_SUMMARY study (MWAS) that tested for the relationship between feature intensity and ST:STUDY_SUMMARY benzene exposure. MWAS identified 478 mass spectral features associated with ST:STUDY_SUMMARY benzene exposure at FDR<20%. Comparison to a list of 13 known benzene ST:STUDY_SUMMARY metabolites and metabolites predicted using a multi-component biotransformation ST:STUDY_SUMMARY algorithm showed five metabolites were detected, which included the known ST:STUDY_SUMMARY metabolites phenol and benzene diolepoxide. Metabolic pathway enrichment ST:STUDY_SUMMARY identified 41 pathways associated with benzene exposure, with altered pathways ST:STUDY_SUMMARY including carnitine shuttle, fatty acid metabolism, sulfur amino acid ST:STUDY_SUMMARY metabolism, glycolysis, gluconeogenesis, and branched chain amino acid ST:STUDY_SUMMARY metabolism. These results suggest disruption to fatty acid uptake, energy ST:STUDY_SUMMARY metabolism and increased oxidative stress, and point towards pathways related to ST:STUDY_SUMMARY mitochondrial dysfunction, which has previously been linked to benzene exposure ST:STUDY_SUMMARY in animal models and human studies. Taken together, these results suggest ST:STUDY_SUMMARY benzene exposure is associated with disruption of mitochondrial pathways, and ST:STUDY_SUMMARY provide promising, systems biology biomarkers for risk assessment of ST:STUDY_SUMMARY benzene-induced hematotoxicity in humans. ST:INSTITUTE Icahn School of Medicine at Mount Sinai ST:DEPARTMENT Environmental Medicine and Public Health ST:LABORATORY High Resolution Exposomics ST:LAST_NAME Walker ST:FIRST_NAME Douglas ST:ADDRESS Atran Building RM AB3-39, 1428 Madison Ave, New York, NY, 10029, USA ST:EMAIL douglas.walker@mssm.edu ST:NUM_GROUPS 3 ST:TOTAL_SUBJECTS 58 ST:NUM_MALES 28 ST:NUM_FEMALES 30 ST:PUBLICATIONS N Rothman, R Vermeulen, L Zhang, W Hu, S Yin, SM Rappaport, MT Smith, DP Jones, ST:PUBLICATIONS M Rahman, Qing Lan, DI Walker. (2021). Metabolome-wide association study of ST:PUBLICATIONS occupational exposure to benzene. Carcinogenesis. 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RAW_FILE_NAME=VT_170729_M021_038; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=2; bmi=19.67516685 SUBJECT_SAMPLE_FACTORS BEW.1029.001 BEW.1029.001_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_043; RAW_FILE_NAME=VT_170729_M021_044; Batch=2; Sample_Class=Study_QC_Sample; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS CZ.0038.006 CZ.0038.006_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_049; RAW_FILE_NAME=VT_170729_M021_050; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=-; bmi=18.04270106 SUBJECT_SAMPLE_FACTORS CZ.0010.003 CZ.0010.003_1 Sex:2 | Smoking_status:2 RAW_FILE_NAME=VT_170729_M021_055; RAW_FILE_NAME=VT_170729_M021_056; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=2; bmi=33.69493754 SUBJECT_SAMPLE_FACTORS CZ.0100.002 CZ.0100.002_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_061; RAW_FILE_NAME=VT_170729_M021_062; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=-; bmi=19.71332153 SUBJECT_SAMPLE_FACTORS CZ.0141.006 CZ.0141.006_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_067; RAW_FILE_NAME=VT_170729_M021_068; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=1; bmi=19.59183673 SUBJECT_SAMPLE_FACTORS BEW.1032.001 BEW.1032.001_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_073; RAW_FILE_NAME=VT_170729_M021_074; Batch=2; Sample_Class=Study_QC_Sample; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS CZ.0074.006 CZ.0074.006_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_079; RAW_FILE_NAME=VT_170729_M021_080; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=1; bmi=20.2812331 SUBJECT_SAMPLE_FACTORS CZ.0135.004 CZ.0135.004_1 Sex:2 | Smoking_status:2 RAW_FILE_NAME=VT_170729_M021_085; RAW_FILE_NAME=VT_170729_M021_086; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=2; bmi=19.22768787 SUBJECT_SAMPLE_FACTORS CZ.0039.004 CZ.0039.004_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_091; RAW_FILE_NAME=VT_170729_M021_092; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=-; bmi=21.46193662 SUBJECT_SAMPLE_FACTORS CZ.0131.006 CZ.0131.006_1 Sex:2 | Smoking_status:2 RAW_FILE_NAME=VT_170729_M021_097; RAW_FILE_NAME=VT_170729_M021_098; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=2; bmi=20.42941836 SUBJECT_SAMPLE_FACTORS BEW.1030.001 BEW.1030.001_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_103; RAW_FILE_NAME=VT_170729_M021_104; Batch=2; Sample_Class=Study_QC_Sample; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS CZ.0113.003 CZ.0113.003_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_109; RAW_FILE_NAME=VT_170729_M021_110; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=-; bmi=19.49317739 SUBJECT_SAMPLE_FACTORS CZ.0076.006 CZ.0076.006_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_115; RAW_FILE_NAME=VT_170729_M021_116; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=1; bmi=20.2020202 SUBJECT_SAMPLE_FACTORS CZ.0142.006 CZ.0142.006_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_121; RAW_FILE_NAME=VT_170729_M021_122; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=2; bmi=25.64891762 SUBJECT_SAMPLE_FACTORS BEW.1031.001 BEW.1031.001_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_127; RAW_FILE_NAME=VT_170729_M021_128; Batch=2; Sample_Class=Study_QC_Sample; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS q3June2014_2c q3June2014_2c_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_133; RAW_FILE_NAME=VT_170729_M021_134; Batch=2; Sample_Class=Pooled_Plasma; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS q3June2014_2d q3June2014_2d_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_139; RAW_FILE_NAME=VT_170729_M021_140; Batch=2; Sample_Class=Pooled_Plasma; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS CZ.0137.003 CZ.0137.003_1 Sex:2 | Smoking_status:2 RAW_FILE_NAME=VT_170729_M021_145; RAW_FILE_NAME=VT_170729_M021_146; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=1; bmi=22.03856749 SUBJECT_SAMPLE_FACTORS CZ.0136.005 CZ.0136.005_1 Sex:2 | Smoking_status:2 RAW_FILE_NAME=VT_170729_M021_151; RAW_FILE_NAME=VT_170729_M021_152; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=2; bmi=20.2020202 SUBJECT_SAMPLE_FACTORS BEW.1035.001 BEW.1035.001_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_157; RAW_FILE_NAME=VT_170729_M021_158; Batch=2; Sample_Class=Study_QC_Sample; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS CZ.0068.005 CZ.0068.005_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_163; RAW_FILE_NAME=VT_170729_M021_164; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=1; bmi=18.16620425 SUBJECT_SAMPLE_FACTORS CZ.0143.005 CZ.0143.005_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_169; RAW_FILE_NAME=VT_170729_M021_170; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=1; bmi=19.53125 SUBJECT_SAMPLE_FACTORS CZ.0041.003 CZ.0041.003_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_175; RAW_FILE_NAME=VT_170729_M021_176; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS CZ.0178.006 CZ.0178.006_1 Sex:2 | Smoking_status:2 RAW_FILE_NAME=VT_170729_M021_181; RAW_FILE_NAME=VT_170729_M021_182; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=-; bmi=18.42653421 SUBJECT_SAMPLE_FACTORS CZ.0069.006 CZ.0069.006_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_187; RAW_FILE_NAME=VT_170729_M021_188; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=1; bmi=20.90419501 SUBJECT_SAMPLE_FACTORS BEW.1036.001 BEW.1036.001_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_193; RAW_FILE_NAME=VT_170729_M021_194; Batch=2; Sample_Class=Study_QC_Sample; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS CZ.0165.006 CZ.0165.006_1 Sex:2 | Smoking_status:2 RAW_FILE_NAME=VT_170729_M021_199; RAW_FILE_NAME=VT_170729_M021_200; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=-; bmi=24.77679525 SUBJECT_SAMPLE_FACTORS CZ.0023.001 CZ.0023.001_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_205; RAW_FILE_NAME=VT_170729_M021_206; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=-; bmi=20.30741221 SUBJECT_SAMPLE_FACTORS CZ.0064.250 CZ.0064.250_1 Sex:1 | Smoking_status:2 RAW_FILE_NAME=VT_170729_M021_211; RAW_FILE_NAME=VT_170729_M021_212; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=1; bmi=20.24489796 SUBJECT_SAMPLE_FACTORS BEW.1033.001 BEW.1033.001_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_217; RAW_FILE_NAME=VT_170729_M021_218; Batch=2; Sample_Class=Study_QC_Sample; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS CZ.0172.001 CZ.0172.001_1 Sex:2 | Smoking_status:2 RAW_FILE_NAME=VT_170729_M021_223; RAW_FILE_NAME=VT_170729_M021_224; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=-; bmi=20.70081674 SUBJECT_SAMPLE_FACTORS BEW.1034.001 BEW.1034.001_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_229; RAW_FILE_NAME=VT_170729_M021_230; Batch=2; Sample_Class=Study_QC_Sample; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS CZ.0180.002 CZ.0180.002_1 Sex:1 | Smoking_status:2 RAW_FILE_NAME=VT_170729_M021_235; RAW_FILE_NAME=VT_170729_M021_236; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=-; bmi=22.64737696 SUBJECT_SAMPLE_FACTORS CZ.0072.004 CZ.0072.004_1 Sex:1 | Smoking_status:1 RAW_FILE_NAME=VT_170729_M021_241; RAW_FILE_NAME=VT_170729_M021_242; Batch=2; Sample_Class=Study_Sample; Benzene_Exposure_Category=1; bmi=19.71332153 SUBJECT_SAMPLE_FACTORS q3June2014_2e q3June2014_2e_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_247; RAW_FILE_NAME=VT_170729_M021_248; Batch=2; Sample_Class=Pooled_Plasma; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS q3June2014_2f q3June2014_2f_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_253; RAW_FILE_NAME=VT_170729_M021_254; Batch=2; Sample_Class=Pooled_Plasma; Benzene_Exposure_Category=NA; bmi=NA SUBJECT_SAMPLE_FACTORS nist2 nist2_1 Sex:NA | Smoking_status:NA RAW_FILE_NAME=VT_170729_M021_259; RAW_FILE_NAME=VT_170729_M021_260; Batch=2; Sample_Class=NIST1950; Benzene_Exposure_Category=NA; bmi=NA #COLLECTION CO:COLLECTION_SUMMARY Identification of factories and worker enrollment are described in detail CO:COLLECTION_SUMMARY elsewhere. [14] Study subjects were enrolled in the Fall of 1992 in Shanghai, CO:COLLECTION_SUMMARY China and evaluated at the Shanghai Hygiene and Anti-Epidemic Institute. The CO:COLLECTION_SUMMARY study protocol was explained to all potential participants, and informed consent CO:COLLECTION_SUMMARY was obtained using Institutional Review Board-approved procedures. Data CO:COLLECTION_SUMMARY collected included age, gender, tobacco use, alcohol consumption, medical CO:COLLECTION_SUMMARY history, and an occupational work history. Prior to the clinical visit, study CO:COLLECTION_SUMMARY subjects were asked to refrain from eating solid foods after dinner the night CO:COLLECTION_SUMMARY before and the morning of the clinical phase of the study. The following CO:COLLECTION_SUMMARY morning, a 27 mL sample of blood was obtained by venous phlebotomy. Plasma CO:COLLECTION_SUMMARY samples were then frozen at -80°C, shipped to the NCI on dry ice, and stored CO:COLLECTION_SUMMARY continuously at -80°C until analysis. CO:SAMPLE_TYPE Blood (plasma) CO:STORAGE_CONDITIONS -80℃ CO:ADDITIVES EDTA #TREATMENT TR:TREATMENT_SUMMARY Details of personal benzene exposure assessment have been reported previously. TR:TREATMENT_SUMMARY [14] In brief, individual exposure was monitored by organic vapor passive TR:TREATMENT_SUMMARY dosimetry badges (3M no. 3500. St.Paul. Minnesota), which were worn by each TR:TREATMENT_SUMMARY worker for a full shift on 5 separate days for a 1–2 week period prior to TR:TREATMENT_SUMMARY blood collection. Badges were analyzed by gas chromatography (GC) with flame TR:TREATMENT_SUMMARY ionization detection for benzene, toluene, and xylene. Average exposure was TR:TREATMENT_SUMMARY calculated for each compound as the geometric mean of the five air measurements. TR:TREATMENT_SUMMARY In this study, we focus on control workers with no benzene exposure, lower TR:TREATMENT_SUMMARY (relative) exposures (<20ppm) and high exposure (>20ppm) Due to benzene levels TR:TREATMENT_SUMMARY exceeding the current OSHA time-weighted exposure limit of 1 ppma for all TR:TREATMENT_SUMMARY exposed workers, the median exposure of 20 ppm was used to classify low- and TR:TREATMENT_SUMMARY high-exposed workers to identify exposure-associated metabolic changes. For each TR:TREATMENT_SUMMARY m/z feature, peak intensity was log2 transformed to test for association with TR:TREATMENT_SUMMARY benzene across the categories of exposure, which included controls, low exposed TR:TREATMENT_SUMMARY (<20 ppma) and high exposed (≥20 ppma), defined as a continuous variable TR:TREATMENT_SUMMARY (control=0; < 20 ppma= 1; ≥20 ppma= 2) #SAMPLEPREP SP:SAMPLEPREP_SUMMARY Samples are prepared for metabolomics analysis using established methods SP:SAMPLEPREP_SUMMARY (Johnson et al. (2010). Analyst; Go et al. (2015). Tox Sci). Prior to analysis, SP:SAMPLEPREP_SUMMARY plasma aliquots were removed from storage at -80°C and thawed on ice. Each SP:SAMPLEPREP_SUMMARY cryotube is then vortexed briefly to ensure homogeneity, and 50 μL transferred SP:SAMPLEPREP_SUMMARY to a clean microfuge tube. Immediately after, the plasma is treated with 100 μL SP:SAMPLEPREP_SUMMARY of ice-cold LC-MS grade acetonitrile (Sigma Aldrich) containing 2.5 μL of SP:SAMPLEPREP_SUMMARY internal standard solution with eight stable isotopic chemicals selected to SP:SAMPLEPREP_SUMMARY cover a range of chemical properties. Following addition of acetonitrile, plasma SP:SAMPLEPREP_SUMMARY is then equilibrated for 30 min on ice, upon which precipitated proteins are SP:SAMPLEPREP_SUMMARY removed by centrifuge (16.1 ×g at 4°C for 10 min). The resulting supernatant SP:SAMPLEPREP_SUMMARY (100 μL) is removed, added to a low volume autosampler vial and maintained at SP:SAMPLEPREP_SUMMARY 4°C until analysis (<22 h). SP:SAMPLEPREP_PROTOCOL_ID EmoryUniversity_HRM_SP_082016_01.pdf SP:SAMPLEPREP_PROTOCOL_FILENAME EmoryUniversity_HRM_SP_082016_01.pdf SP:EXTRACTION_METHOD 2:1 addition of acetonitrile SP:SAMPLE_SPIKING [13C6]-D-glucose, [15N,13C5]-L-methionine, [13C5]-L-glutamic acid, SP:SAMPLE_SPIKING [15N]-L-tyrosine, [3,3-13C2]-cystine, [trimethyl-13C3]-caffeine, [U-13C5, SP:SAMPLE_SPIKING U-15N2]-L-glutamine, [15N]-indole #CHROMATOGRAPHY CH:CHROMATOGRAPHY_SUMMARY C18–negative chromatography method summary The C18 column is operated parallel CH:CHROMATOGRAPHY_SUMMARY to the HILIC column for simultaneous analytical separation and column flushing CH:CHROMATOGRAPHY_SUMMARY through the use of a dual head HPLC pump equipped with 10-port and 6-port CH:CHROMATOGRAPHY_SUMMARY switching valves. During operation of the C18 method, the MS is operated in CH:CHROMATOGRAPHY_SUMMARY negative ion mode and 10 μL of sample is injected onto the C18 column while the CH:CHROMATOGRAPHY_SUMMARY HILIC column is flushing with wash solution. Flow rate is maintained at 0.4 CH:CHROMATOGRAPHY_SUMMARY mL/min until 1.5 min, increased to 0.5 mL/min at 2 min and held for 3 min. CH:CHROMATOGRAPHY_SUMMARY Solvent A is 100% LC-MS grade water, solvent B is 100% LC-MS grade acetonitrile CH:CHROMATOGRAPHY_SUMMARY and solvent C is 10mM ammonium acetate in LC-MS grade water. Initial mobile CH:CHROMATOGRAPHY_SUMMARY phase conditions are 60% A, 35% B, 5% C hold for 0.5 min, with linear gradient CH:CHROMATOGRAPHY_SUMMARY to 0% A, 95% B, 5% C at 1.5 min, hold for 3.5 min, resulting in a total CH:CHROMATOGRAPHY_SUMMARY analytical run time of 5 min. During the flushing phase (HILIC analytical CH:CHROMATOGRAPHY_SUMMARY separation), the C18 column is equilibrated with a wash solution of 0% A, 95% B, CH:CHROMATOGRAPHY_SUMMARY 5% C until 2.5 min, followed by an equilibration solution of 60% A, 35% B, 5% C CH:CHROMATOGRAPHY_SUMMARY for 2.5 min. CH:CHROMATOGRAPHY_TYPE Reversed phase CH:INSTRUMENT_NAME Thermo Dionex Ultimate 3000 CH:COLUMN_NAME Higgins endcapped C18 (50 x 2.1mm, 3μm) CH:METHODS_FILENAME EmoryUniversity_HRM-QEHF_DC5min_092017_v1.pdf #ANALYSIS AN:ANALYSIS_TYPE MS AN:LABORATORY_NAME Clinical Biomarkers Laboratory, Emory University AN:OPERATOR_NAME Vilinh Tran AN:ANALYSIS_PROTOCOL_FILE EmoryUniversity_HRM_QEHF-MS_092017_v1.pdf #MS MS:INSTRUMENT_NAME Thermo Q Exactive HF hybrid Orbitrap MS:INSTRUMENT_TYPE Orbitrap MS:MS_TYPE ESI MS:ION_MODE NEGATIVE MS:MS_COMMENTS The mass spectrometer was operated at a resolution of 120,000. Source tune MS:MS_COMMENTS settings were optimized using a standard mixture for both positive and negative MS:MS_COMMENTS mode, resulting in capillary temperature, vaporizer temperature, sheath gas, MS:MS_COMMENTS auxiliary gas, sweep gas and S-Lens RF level settings of 250°C, 150°C, 45 MS:MS_COMMENTS (arbitrary units), 5 (arbitrary units), 1 (arbitrary units) and 55, MS:MS_COMMENTS respectively. Negative mode ESI was operated at -4 kV. High-resolution detection MS:MS_COMMENTS of m/z features was accomplished by maximum injection time of 100 milliseconds MS:MS_COMMENTS and AGC target of 1x106. During untargeted data acquisition, no exclusion or MS:MS_COMMENTS inclusion masses were selected, and data was acquired in MS1 mode only over the MS:MS_COMMENTS scan range of 85-1250 m/z. Following instrumental analysis of all study and MS:MS_COMMENTS quality control (QC) samples, which included NIST SRM 1950 and pooled human MS:MS_COMMENTS plasma, instrument files were converted to .mzXML format and m/z features were MS:MS_COMMENTS extracted and aligned at multiple parameter settings using apLCMS. [2] The MS:MS_COMMENTS resulting feature tables were then merged with xMSanalyzer [3], which MS:MS_COMMENTS systemically evaluates sample profile quality, feature detection and technical MS:MS_COMMENTS reliability for optimal peak selection. Only features exhibiting a median MS:MS_COMMENTS triplicate coefficient of variation ≤ 100% and detected in greater than 25% of MS:MS_COMMENTS the study samples were retained. The resulting feature table was then batch MS:MS_COMMENTS corrected using ComBat [4] and triplicate injections averaged prior to analysis. MS:CAPILLARY_TEMPERATURE 250 MS:DRY_GAS_FLOW 45 MS:DRY_GAS_TEMP 150 MS:ION_SOURCE_TEMPERATURE 150 MS:MS_RESULTS_FILE ST001918_AN003117_Results.txt UNITS:Peak area Has m/z:Yes Has RT:Yes RT units:Seconds #END