{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:08:13Z","timestamp":1792789693247,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T00:00:00Z","timestamp":1719964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Open Project of Key Laboratory of Environmental Medicine Engineering of Ministry of Education","award":["2022EME001"],"award-info":[{"award-number":["2022EME001"]}]},{"name":"the Open Project of Key Laboratory of Environmental Medicine Engineering of Ministry of Education","award":["M2022083"],"award-info":[{"award-number":["M2022083"]}]},{"name":"the Open Project of Key Laboratory of Environmental Medicine Engineering of Ministry of Education","award":["ZDXK202249"],"award-info":[{"award-number":["ZDXK202249"]}]},{"name":"the Scientific Research Project of Jiangsu Health Committee","award":["2022EME001"],"award-info":[{"award-number":["2022EME001"]}]},{"name":"the Scientific Research Project of Jiangsu Health Committee","award":["M2022083"],"award-info":[{"award-number":["M2022083"]}]},{"name":"the Scientific Research Project of Jiangsu Health Committee","award":["ZDXK202249"],"award-info":[{"award-number":["ZDXK202249"]}]},{"name":"Jiangsu Provincial Key Medical Discipline","award":["2022EME001"],"award-info":[{"award-number":["2022EME001"]}]},{"name":"Jiangsu Provincial Key Medical Discipline","award":["M2022083"],"award-info":[{"award-number":["M2022083"]}]},{"name":"Jiangsu Provincial Key Medical Discipline","award":["ZDXK202249"],"award-info":[{"award-number":["ZDXK202249"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Benzene, a common industrial solvent, poses significant health risks including poisoning and hematopoietic diseases. However, its precise toxicity mechanisms remain unclear. To assess the health impact of prolonged benzene exposure through metabolomic analyses of exposed workers and benzene-poisoned mice, aiming to identify biomarkers and minimize occupational hazards. This study compared 18 benzene-exposed workers with 18 non-exposed workers, matching for age, lifestyle, and BMI. The metabolites in the workers\u2019 samples were analyzed using ultra-high-performance liquid chromatography and mass spectrometry. A larger study included 118 exposed and 158 non-exposed workers, incorporating surveys and routine blood and urine tests with differential metabolites targeted via an enzyme-linked immunosorbent assay. The animal studies consisted of two 15- and 60-day benzene staining and control experiments on 28 C57BL\/6J mice, followed by sample collection and organ analysis. The data analysis employed eXtensible Computational Mass Spectrometry (XCMS), Python, MetaboAnalyst 6.0, and SPSS24.0. The exposed workers exhibited altered metabolites indicating external benzene exposure, lower glucose levels, and changes in white blood cell counts and urinary ketone bodies. The plasma metabolomics revealed disturbances in energy and lipid metabolism. The benzene-exposed mice displayed reduced weight gain, behavioral changes, and organ damage. Oxidative stress and abnormal purine and lipid metabolism were observed in both the long-term benzene-exposed workers and benzene-exposed mice. Metabolic markers for the early detection of benzene exposure hazards were identified, underscoring the need to mitigate occupational risks.<\/jats:p>","DOI":"10.3390\/metabo14070377","type":"journal-article","created":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T08:45:34Z","timestamp":1719996334000},"page":"377","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Metabolomics of Benzene Exposure and Development of Biomarkers for Exposure Hazard Assessment"],"prefix":"10.3390","volume":"14","author":[{"given":"Hao","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianyu","family":"Sun","sequence":"additional","affiliation":[{"name":"Nanjing Jiangning District Center for Disease Prevention and Control, Nanjing 211100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2366-2168","authenticated-orcid":false,"given":"Boshen","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210000, China"},{"name":"Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoli","family":"Zhu","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210000, China"},{"name":"Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing 210009, China"},{"name":"Jiangsu Preventive Medical Association, Nanjing 210000, China"},{"name":"Center for Global Health, Nanjing Medical University, Nanjing 210000, China"},{"name":"Jiangsu Province Engineering Research Center of Public Health Emergency, Nanjing 210000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,3]]},"reference":[{"key":"ref_1","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":"ref_2","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1080\/10408444.2017.1401581","article-title":"Shanghai Health Study (2001\u20132009): What was learned about benzene health effects?","volume":"48","author":"Gross","year":"2018","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_3","first-page":"1211","article-title":"Cytochromes P450 in benzene metabolism and involvement of their metabolites and reactive oxygen species in toxicity","volume":"104","author":"Gut","year":"1996","journal-title":"Environ. Health Perspect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1093\/toxsci\/kfg008","article-title":"Winn, Homologous Recombination Initiated by Benzene Metabolites: A Potential Role of Oxidative Stress","volume":"72","author":"Louise","year":"2003","journal-title":"Toxicol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cordiano, R., Papa, V., Cicero, N., Spatari, G., Allegra, A., and Gangemi, S. (2022). Effects of Benzene: Hematological and Hypersensitivity Manifestations in Resident Living in Oil Refinery Areas. Toxics, 10.","DOI":"10.3390\/toxics10110678"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s00204-009-0420-4","article-title":"Benzene activates caspase-4 and -12 at the transcription level, without an association with apoptosis, in mouse bone marrow cells lacking the p53 gene","volume":"83","author":"Yi","year":"2009","journal-title":"Arch. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.cbi.2009.12.029","article-title":"The role of DNA repair in benzene-induced carcinogenesis","volume":"184","author":"Hartwig","year":"2010","journal-title":"Chem.-Biol. Interact."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e154999","DOI":"10.1172\/jci.insight.154999","article-title":"Plasma metabolomics study reveals the critical metabolic signatures for benzene-induced hematotoxicity","volume":"7","author":"Guo","year":"2022","journal-title":"JCI Insight"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/978-1-62703-613-9_19","article-title":"Plant metabolomics: From experimental design to knowledge extraction","volume":"1069","author":"Rai","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.aca.2012.05.049","article-title":"NMR and pattern recognition methods in metabolomics: From data acquisition to biomarker discovery: A review","volume":"750","author":"Smolinska","year":"2012","journal-title":"Anal. Chim. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1080\/01616412.2020.1726588","article-title":"Use of high-sensitivity digital ELISA improves the diagnostic performance of circulating brain-specific proteins for detection of traumatic brain injury during triage","volume":"42","author":"Alder","year":"2020","journal-title":"Neurol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bla\u017eenovi\u0107, I., Kind, T., Ji, J., and Fiehn, O. (2018). Software Tools and Approaches for Compound Identification of LC-MS\/MS Data in Metabolomics. Metabolites, 8.","DOI":"10.3390\/metabo8020031"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Luo, D., Deng, T., Yuan, W., Deng, H., and Jin, M. (2017). Plasma metabolomic study in Chinese patients with wet age-related macular degeneration. BMC Ophthalmol., 17.","DOI":"10.1186\/s12886-017-0555-7"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12889","DOI":"10.1021\/acs.jafc.8b02862","article-title":"Metabolomics Reveals that Crossbred Dairy Buffaloes are more Thermotolerant than Holstein cows under Chronic Heat Stress","volume":"66","author":"Gu","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1152\/physrev.00035.2018","article-title":"Metabolomics for Investigating Physiological and Pathophysiological Processes","volume":"99","author":"Wishart","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_16","first-page":"1","article-title":"Metabolomics techniques: A brief update","volume":"28","author":"Tyagi","year":"2021","journal-title":"Epigenetics Metabolomics"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Goldansaz, S., Guo, A., Sajed, T., Steele, M., Plastow, G., and Wishart, D. (2017). Livestock metabolomics and the livestock metabolome: A systematic review. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0177675"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Gieger, C., Geistlinger, L., Altmaier, E., Angelis, M., Kronenberg, F., Meitinger, T., Mewes, H., Wichmann, H., Weinberger, K., and Adamski, J. (2008). Genetics Meets Metabolomics: A Genome-Wide Association Study of Metabolite Profiles in Human Serum. PLoS Genet., 4.","DOI":"10.1371\/journal.pgen.1000282"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1097\/MCO.0000000000000200","article-title":"Serum metabolomics in animal models and human disease","volume":"18","author":"James","year":"2015","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/978-1-61779-594-7_11","article-title":"Fourier Transform Ion Cyclotron Resonance mass spectrometry for plant metabolite profiling and metabolite identification","volume":"860","author":"Allwood","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Liu, M., Liu, H., Mei, F., Yang, N., Zhao, D., Ai, G., Xiang, H., and Zheng, Y. (2022). Identification of the Biosynthetic Pathway of Glycine Betaine That Is Responsible for Salinity Tolerance in Halophilic Thioalkalivibrio versutus D301. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.875843"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1593\/neo.13314","article-title":"The role of sarcosine metabolism in prostate cancer progression","volume":"15","author":"Khan","year":"2013","journal-title":"Neoplasia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"115682","DOI":"10.1016\/j.taap.2021.115682","article-title":"Glycine\/glycine N-methyltransferase\/sarcosine axis mediates benzene-induced hematotoxicity","volume":"428","author":"Zhang","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5964","DOI":"10.1021\/bi00141a003","article-title":"Purine nucleoside phosphorylase. Inosine hydrolysis, tight binding of the hypoxanthine intermediate, and third-the-sites reactivity","volume":"31","author":"Kline","year":"1992","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1172\/JCI109058","article-title":"Deoxyguanosine triphosphate as a possible toxic metabolite in the immunodeficiency associated with purine nucleoside phosphorylase deficiency","volume":"61","author":"Cohen","year":"1978","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0889-8561(05)70139-9","article-title":"Immunodeficiency Caused by Purine Nucleoside Phosphorylase Deficiency","volume":"20","author":"Cohen","year":"2000","journal-title":"Radiol. Clin. N. Am."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1093\/carcin\/bgab089","article-title":"Metabolome-wide association study of occupational exposure to benzene","volume":"42","author":"Rothman","year":"2021","journal-title":"Carcinogenesis"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1006\/jmbi.1998.1675","article-title":"The structure of glutamine-binding protein complexed with glutamine at 1.94 A resolution: Comparisons with other amino acid binding proteins","volume":"278","author":"Sun","year":"1998","journal-title":"J. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1016\/j.ejca.2005.02.013","article-title":"Amino acid concentrations in cerebrospinal fluid in children with acute lymphoblastic leukemia undergoing chemotherapy","volume":"41","author":"Peng","year":"2005","journal-title":"Eur. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.1002\/elps.201300019","article-title":"Capillary electrophoresis-mass spectrometry-based metabolome analysis of serum and saliva from neurodegenerative dementia patients","volume":"34","author":"Tsuruoka","year":"2013","journal-title":"Electrophoresis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.foodchem.2019.02.126","article-title":"Effects of malondialdehyde as a byproduct of lipid oxidation on protein oxidation in rabbit meat","volume":"288","author":"Wang","year":"2019","journal-title":"Food Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"224","DOI":"10.18794\/aams\/65697","article-title":"Malondialdehyde (MDA)\u2014Product of lipid peroxidation as marker of homeostasis disorders and aging","volume":"70","author":"Walkiewicz","year":"2016","journal-title":"Ann. Acad. Medicae Silesiensis"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.aca.2020.05.053","article-title":"Large-scale targeted metabolomics method for metabolite profiling of human samples","volume":"1125","author":"Cao","year":"2020","journal-title":"Anal. Chim. Acta"},{"key":"ref_34","first-page":"7","article-title":"Use of Malondialdehyde as a Biomarker for Assessing Oxidative Stress in Different Disease Pathologies: A Review","volume":"43","author":"Singh","year":"2014","journal-title":"Iran. J. Public Health"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"34046","DOI":"10.1007\/s11356-018-3354-7","article-title":"Association of benzene exposure with insulin resistance, SOD, and MDA as markers of oxidative stress in children and adolescents","volume":"25","author":"Amin","year":"2018","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/10915810701489697","article-title":"Amifostine Protects Bone Marrow from Benzene-Induced Hematotoxicity in Mice","volume":"26","author":"Yu","year":"2007","journal-title":"Int. J. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1002\/hep.22657","article-title":"Alanine aminotransferase isoenzymes: Molecular cloning and quantitative analysis of tissue expression in rats and serum elevation in liver toxicity","volume":"49","author":"Yang","year":"2009","journal-title":"Hepatology"},{"key":"ref_38","first-page":"5821","article-title":"Lipid metabolism after autologous orthotopic liver transplantation in rat models of fatty liver","volume":"22","author":"Ding","year":"2018","journal-title":"J. Clin. Rehabil. Tissue Eng. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3109\/03602532.2011.605791","article-title":"Metabolic activation in drug-induced liver injury","volume":"44","author":"Leung","year":"2012","journal-title":"Drug Metab. Rev."},{"key":"ref_40","first-page":"34","article-title":"Effect of benzene on oxidative stress and the functions of liver and kidney in rats","volume":"4","author":"Ibrahim","year":"2015","journal-title":"J. Environ. Occup. Health"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"344","DOI":"10.2741\/2068","article-title":"Glutamine, gene expression, and cell function","volume":"12","author":"Curi","year":"2007","journal-title":"Front. Biosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1182\/blood-2015-01-621870","article-title":"Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition","volume":"126","author":"Jacque","year":"2015","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3521","DOI":"10.1182\/blood-2013-03-493163","article-title":"Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia","volume":"122","author":"Willems","year":"2013","journal-title":"Blood"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/14\/7\/377\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:09:35Z","timestamp":1760108975000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/14\/7\/377"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,3]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["metabo14070377"],"URL":"https:\/\/doi.org\/10.3390\/metabo14070377","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,3]]}}}