title: New Insights into the Cytotoxic Mechanism of Hexabromocyclododecane from a Metabolomic Approach.
abstract: The toxic effects of hexabromocyclododecane (HBCD) are complex, and the underlying toxicological mechanisms are still not completely understood. In this study, a pseudotargeted metabolomic approach based on the UHPLC/Q-Trap MS system was developed to assess the HBCD-intervention-related metabolic alteration in HepG2 cells. In addition, some physiologic indicators and relevant enzyme activities were measured. HBCD exposure obviously impaired metabolic homeostasis and induced oxidative stress, even at an environmentally relevant dose (0.05 mg/L). Metabolic profiling and multivariate analysis indicated that the main metabolic pathways perturbed by HBCD included amino acid metabolism, protein biosynthesis, fatty acid metabolism, and phospholipid metabolism. HBCD suppressed the cell uptake of amino acids, mainly through inhibition of the activity of membrane transport protein Na(+)/K(+)-ATPase. HBCD down-regulated glycolysis and β-oxidation of long-chain fatty acids, causing a large decrease of ATP production. As a result, the across-membrane transport of amino acids was further inhibited. Meanwhile, HBCD induced a significant increase of total phospholipids, mainly through the remodeling of phospholipids from the increased free fatty acids. The obtained metabolomic results also provided some new evidence and clues regarding the toxicological mechanisms of HBCD that contribute to obesity, diabetes, nervous system damage, and developmental disorders.
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Feidi
authors.initials: F
authors.lastname: Wang
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Ningbo
authors.initials: N
authors.lastname: Geng
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023, China.
authors.forename: Baoqin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Ren
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023, China.
authors.forename: Jiping
authors.initials: J
authors.lastname: Chen
mesh_terms: D002851:Chromatography, High Pressure Liquid; D005227:Fatty Acids / Q000378:metabolism; D005411:Flame Retardants / Q000633:toxicity; D056945:Hep G2 Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D050356:Lipid Metabolism / Q000187:drug effects; D013058:Mass Spectrometry / Q000379:methods; D053858:Metabolic Networks and Pathways; D055432:Metabolomics / Q000295:instrumentation / Q000379:methods*; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D005411:Flame Retardants; D006842:Hydrocarbons, Brominated; D010743:Phospholipids; C089796:hexabromocyclododecane