title: Low-Level Environmental Phthalate Exposure Associates with Urine Metabolome Alteration in a Chinese Male Cohort.
abstract: The general population is exposed to phthalates through various sources and routes. Integration of omics data and epidemiological data is a key step toward directly linking phthalate biomonitoring data with biological response. Urine metabolomics is a powerful tool to identify exposure biomarkers and delineate the modes of action of environmental stressors. The objectives of this study are to investigate the association between low-level environmental phthalate exposure and urine metabolome alteration in male population, and to unveil the metabolic pathways involved in the mechanisms of phthalate toxicity. In this retrospective cross-sectional study, we studied the urine metabolomic profiles of 364 male subjects exposed to low-level environmental phthalates. Di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) are the most widely used phthalates. ∑DEHP and MBP (the major metabolite of DBP) were associated with significant alteration of global urine metabolome in the male population. We observed significant increase in the levels of acetylneuraminic acid, carnitine C8:1, carnitine C18:0, cystine, phenylglycine, phenylpyruvic acid and glutamylphenylalanine; and meanwhile, decrease in the levels of carnitine C16:2, diacetylspermine, alanine, taurine, tryptophan, ornithine, methylglutaconic acid, hydroxyl-PEG2 and keto-PGE2 in high exposure group. The observations indicated that low-level environmental phthalate exposure associated with increased oxidative stress and fatty acid oxidation and decreased prostaglandin metabolism. Urea cycle, tryptophan and phenylalanine metabolism disruption was also observed. The urine metabolome disruption effects associated with ∑DEHP and MBP were similar, but not identical. The multibiomarker models presented AUC values of 0.845 and 0.834 for ∑DEHP and MBP, respectively. The predictive accuracy rates of established models were 81% for ΣDEHP and 73% for MBP. Our results suggest that low-level environmental phthalate exposure associates with urine metabolome disruption in male population, providing new insight into the early molecular events of phthalate exposure.
authors.affiliation: Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences , 1799 Jimei Road, Xiamen 361021, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences , 1799 Jimei Road, Xiamen 361021, China.
authors.forename: Liangpo
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences , 1799 Jimei Road, Xiamen 361021, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences , 1799 Jimei Road, Xiamen 361021, China.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences , 1799 Jimei Road, Xiamen 361021, China.
authors.forename: Meiping
authors.initials: M
authors.lastname: Tian
authors.affiliation: Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences , 1799 Jimei Road, Xiamen 361021, China.
authors.forename: Heqing
authors.initials: H
authors.lastname: Shen
mesh_terms: D003430:Cross-Sectional Studies; D004051:Diethylhexyl Phthalate / Q000378:metabolism; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000378:metabolism*; D006801:Humans; D008297:Male; D055442:Metabolome; D010795:Phthalic Acids / Q000652:urine; D012189:Retrospective Studies
chemical_list: D004785:Environmental Pollutants; D010795:Phthalic Acids; D004051:Diethylhexyl Phthalate