title: High-resolution metabolomics of occupational exposure to trichloroethylene.
abstract: Occupational exposure to trichloroethylene (TCE) has been linked to adverse health outcomes including non-Hodgkin's lymphoma and kidney and liver cancer; however, TCE's mode of action for development of these diseases in humans is not well understood.
  
  
  
  Non-targeted metabolomics analysis of plasma obtained from 80 TCE-exposed workers [full shift exposure range of 0.4 to 230 parts-per-million of air (ppma)] and 95 matched controls were completed by ultra-high resolution mass spectrometry. Biological response to TCE exposure was determined using a metabolome-wide association study (MWAS) framework, with metabolic changes and plasma TCE metabolites evaluated by dose-response and pathway enrichment. Biological perturbations were then linked to immunological, renal and exposure molecular markers measured in the same population.
  
  
  
  Metabolic features associated with TCE exposure included known TCE metabolites, unidentifiable chlorinated compounds and endogenous metabolites. Exposure resulted in a systemic response in endogenous metabolism, including disruption in purine catabolism and decreases in sulphur amino acid and bile acid biosynthesis pathways. Metabolite associations with TCE exposure included uric acid (β = 0.13, P-value = 3.6 × 10-5), glutamine (β = 0.08, P-value = 0.0013), cystine (β = 0.75, P-value = 0.0022), methylthioadenosine (β = -1.6, P-value = 0.0043), taurine (β = -2.4, P-value = 0.0011) and chenodeoxycholic acid (β = -1.3, P-value = 0.0039), which are consistent with known toxic effects of TCE, including immunosuppression, hepatotoxicity and nephrotoxicity. Correlation with additional exposure markers and physiological endpoints supported known disease associations.
  
  
  
  High-resolution metabolomics correlates measured occupational exposure to internal dose and metabolic response, providing insight into molecular mechanisms of exposure-related disease aetiology.
authors.affiliation: Pulmonary, Allergy and Critical Medicine, Emory University, Atlanta, GA, USA, douglas.walker@emory.edu.|Deptartment of Civil and Environmental Engineering, Tufts University, Medford, MA, USA.
authors.forename: Douglas I
authors.initials: DI
authors.lastname: Walker
authors.affiliation: Pulmonary, Allergy and Critical Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Karan
authors.initials: K
authors.lastname: Uppal
authors.affiliation: Environmental Health Sciences, University of California at Berkeley, Berkeley, CA, USA.
authors.forename: Luoping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute for Risk Assessment Sciences, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Vermeulen
authors.affiliation: Environmental Health Sciences, University of California at Berkeley, Berkeley, CA, USA.
authors.forename: Martyn
authors.initials: M
authors.lastname: Smith
authors.affiliation: Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Purdue
authors.affiliation: Guangdong Medical Laboratory Animal Center, Guangdong, China.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA and.
authors.forename: Boris
authors.initials: B
authors.lastname: Reiss
authors.affiliation: School of Public Health, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sungkyoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Guangdong Medical Laboratory Animal Center, Guangdong, China.
authors.forename: Laiyu
authors.initials: L
authors.lastname: Li
authors.affiliation: Guangdong Medical Laboratory Animal Center, Guangdong, China.
authors.forename: Hanlin
authors.initials: H
authors.lastname: Huang
authors.affiliation: Deptartment of Civil and Environmental Engineering, Tufts University, Medford, MA, USA.|Pulmonary, Allergy and Critical Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Kurt D
authors.initials: KD
authors.lastname: Pennell
authors.affiliation: Pulmonary, Allergy and Critical Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
authors.affiliation: Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.affiliation: Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lan
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002681:China; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000209:etiology; D008113:Liver Neoplasms / Q000209:etiology; D008228:Lymphoma, Non-Hodgkin / Q000209:etiology; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome; D055432:Metabolomics; D009784:Occupational Diseases / Q000209:etiology; D016273:Occupational Exposure / Q000009:adverse effects*; D012044:Regression Analysis; D014241:Trichloroethylene / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014241:Trichloroethylene
keywords: Bioeffect monitoring; Exposome; High-resolution metabolomics; Metabolic phenotype; Population screening; Trichlororoethylene; VOC exposure