{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:53:46Z","timestamp":1790916826949,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T00:00:00Z","timestamp":1633305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["ES026561"],"award-info":[{"award-number":["ES026561"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["ES023515"],"award-info":[{"award-number":["ES023515"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["ES019776"],"award-info":[{"award-number":["ES019776"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["ES028903"],"award-info":[{"award-number":["ES028903"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["OD018006"],"award-info":[{"award-number":["OD018006"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EU-H2020"],"award-info":[{"award-number":["EU-H2020"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["874627"],"award-info":[{"award-number":["874627"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["024.004.017"],"award-info":[{"award-number":["024.004.017"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 profiling of plasma collected from a cross-sectional study of 33 healthy workers exposed to benzene (median 8-h 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 false discovery rate &amp;lt; 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.<\/jats:p>","DOI":"10.1093\/carcin\/bgab089","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T16:33:13Z","timestamp":1633019593000},"page":"1326-1336","source":"Crossref","is-referenced-by-count":40,"title":["Metabolome-wide association study of occupational exposure to benzene"],"prefix":"10.1093","volume":"42","author":[{"given":"Nathaniel","family":"Rothman","sequence":"first","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-8163","authenticated-orcid":false,"given":"Roel","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luoping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Environmental Health Sciences, School of Public Health, University of California at Berkeley, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songnian","family":"Yin","sequence":"additional","affiliation":[{"name":"Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M","family":"Rappaport","sequence":"additional","affiliation":[{"name":"Division of Environmental Health Sciences, School of Public Health, University of California at Berkeley, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martyn T","family":"Smith","sequence":"additional","affiliation":[{"name":"Division of Environmental Health Sciences, School of Public Health, University of California at Berkeley, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean P","family":"Jones","sequence":"additional","affiliation":[{"name":"Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8322-0495","authenticated-orcid":false,"given":"Mohammad","family":"Rahman","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Lan","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2912-398X","authenticated-orcid":false,"given":"Douglas I","family":"Walker","sequence":"additional","affiliation":[{"name":"Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,4]]},"reference":[{"key":"2021111800100704100_CIT0001","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1016\/S1470-2045(17)30832-X","article-title":"Carcinogenicity of benzene","volume":"18","author":"Loomis","year":"2017","journal-title":"Lancet. Oncol.,"},{"key":"2021111800100704100_CIT0002","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1093\/carcin\/bgi297","article-title":"Using urinary biomarkers to elucidate dose-related patterns of human benzene metabolism","volume":"27","author":"Kim","year":"2006","journal-title":"Carcinogenesis,"},{"key":"2021111800100704100_CIT0003","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1289\/ehp.0800510","article-title":"Evidence that humans metabolize benzene via two pathways","volume":"117","author":"Rappaport","year":"2009","journal-title":"Environ. Health Perspect.,"},{"key":"2021111800100704100_CIT0004","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1093\/carcin\/bgy042","article-title":"Adductomic signatures of benzene exposure provide insights into cancer induction","volume":"39","author":"Grigoryan","year":"2018","journal-title":"Carcinogenesis,"},{"key":"2021111800100704100_CIT0005","article-title":"Benzene","volume-title":"IARC Monographs on the Evaluation of Carcinogenic Risks to Humans","author":"IARC","year":"2018"},{"key":"2021111800100704100_CIT0006","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1177\/0748233717750983","article-title":"Benzoquinone induces ROS-dependent mitochondria-mediated apoptosis in HL-60 cells","volume":"34","author":"Sun","year":"2018","journal-title":"Toxicol. Ind. Health,"},{"key":"2021111800100704100_CIT0007","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1021\/tx3001169","article-title":"Stem cell and benzene-induced malignancy and hematotoxicity","volume":"25","author":"Wang","year":"2012","journal-title":"Chem. Res. Toxicol.,"},{"key":"2021111800100704100_CIT0008","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1093\/carcin\/bgr297","article-title":"Current understanding of the mechanism of benzene-induced leukemia in humans: implications for risk assessment","volume":"33","author":"McHale","year":"2012","journal-title":"Carcinogenesis,"},{"key":"2021111800100704100_CIT0009","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.cbi.2009.12.011","article-title":"Systems biology of human benzene exposure","volume":"184","author":"Zhang","year":"2010","journal-title":"Chem. Biol. 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Int.,"},{"key":"2021111800100704100_CIT0012","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1146\/annurev-nutr-072610-145159","article-title":"Nutritional metabolomics: progress in addressing complexity in diet and health","volume":"32","author":"Jones","year":"2012","journal-title":"Annu. Rev. Nutr.,"},{"key":"2021111800100704100_CIT0013","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1016\/j.tips.2020.09.012","article-title":"Drug-exposome interactions: the next frontier in precision medicine","volume":"41","author":"Pristner","year":"2020","journal-title":"Trends Pharmacol. Sci.,"},{"issue":"suppl. 6","key":"2021111800100704100_CIT0014","first-page":"1365","article-title":"An epidemiologic study of early biologic effects of benzene in Chinese workers","volume":"104","author":"Rothman","year":"1996","journal-title":"Environ. 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Interact.,"},{"key":"2021111800100704100_CIT0030","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/em.20402","article-title":"Association between mitochondrial DNA copy number, blood cell counts, and occupational benzene exposure","volume":"49","author":"Shen","year":"2008","journal-title":"Environ. Mol. Mutagen.,"},{"key":"2021111800100704100_CIT0031","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/nrm3772","article-title":"Metabolic requirements for the maintenance of self-renewing stem cells","volume":"15","author":"Ito","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol.,"},{"key":"2021111800100704100_CIT0032","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1289\/ehp.1002546","article-title":"Global gene expression profiling of a population exposed to a range of benzene levels","volume":"119","author":"McHale","year":"2011","journal-title":"Environ. 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Med.,"},{"key":"2021111800100704100_CIT0036","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nature05862","article-title":"Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age","volume":"447","author":"Rossi","year":"2007","journal-title":"Nature,"},{"key":"2021111800100704100_CIT0037","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1182\/blood-2011-01-330050","article-title":"Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells","volume":"118","author":"Yahata","year":"2011","journal-title":"Blood,"},{"key":"2021111800100704100_CIT0038","doi-asserted-by":"crossref","first-page":"5944","DOI":"10.1021\/cr200084z","article-title":"Free radical lipid peroxidation: mechanisms and analysis","volume":"111","author":"Yin","year":"2011","journal-title":"Chem. 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Sci.,"},{"key":"2021111800100704100_CIT0042","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.etap.2017.02.013","article-title":"Acetyl-l-carnitine partially prevents benzene-induced hematotoxicity and oxidative stress in C3H\/He mice","volume":"51","author":"Sun","year":"2017","journal-title":"Environ. Toxicol. Pharmacol.,"},{"key":"2021111800100704100_CIT0043","doi-asserted-by":"crossref","first-page":"32506","DOI":"10.1007\/s11356-018-3160-2","article-title":"Plasma metabonomics investigation reveals involvement of fatty acid oxidation in hematotoxicity in Chinese benzene-exposed workers with low white blood cell count","volume":"25","author":"Sun","year":"2018","journal-title":"Environ. Sci. Pollut. Res. Int.,"},{"key":"2021111800100704100_CIT0044","doi-asserted-by":"crossref","first-page":"100962","DOI":"10.1016\/j.molmet.2020.02.005","article-title":"A non-proliferative role of pyrimidine metabolism in cancer","volume":"35","author":"Siddiqui","year":"2020","journal-title":"Mol. Metab.,"},{"key":"2021111800100704100_CIT0045","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1093\/carcin\/bgu229","article-title":"Chromosome-wide aneuploidy study of cultured circulating myeloid progenitor cells from workers occupationally exposed to formaldehyde","volume":"36","author":"Lan","year":"2015","journal-title":"Carcinogenesis,"},{"key":"2021111800100704100_CIT0046","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1101\/gad.278820.116","article-title":"Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo","volume":"30","author":"Pfau","year":"2016","journal-title":"Genes Dev.,"},{"key":"2021111800100704100_CIT0047","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S1476-5586(03)80027-1","article-title":"Induction of chromosomal instability by chronic oxidative stress","volume":"5","author":"Limoli","year":"2003","journal-title":"Neoplasia,"}],"container-title":["Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/carcin\/advance-article-pdf\/doi\/10.1093\/carcin\/bgab089\/40787761\/bgab089.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/42\/11\/1326\/41138075\/bgab089.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/42\/11\/1326\/41138075\/bgab089.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,8]],"date-time":"2024-09-08T23:12:32Z","timestamp":1725837152000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/carcin\/article\/42\/11\/1326\/6380831"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,4]]},"references-count":47,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,10,4]]},"published-print":{"date-parts":[[2021,11,12]]}},"URL":"https:\/\/doi.org\/10.1093\/carcin\/bgab089","relation":{},"ISSN":["0143-3334","1460-2180"],"issn-type":[{"value":"0143-3334","type":"print"},{"value":"1460-2180","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,11,1]]},"published":{"date-parts":[[2021,10,4]]}}}