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.
Environ Sci Technol. 2016 Mar 15;50(6):3145-53. doi: 10.1021/acs.est.5b03678. Epub 2016 Feb 29.
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.
六溴环十二烷（HBCD）的毒性作用较为复杂，其潜在的毒理学机制尚不完全清楚。本研究采用基于 UHPLC/Q-Trap MS 系统的伪靶向代谢组学方法，评估了 HBCD 干预对 HepG2 细胞的代谢变化，并测定了一些生理指标和相关酶活性。HBCD 暴露明显破坏了代谢平衡，诱导了氧化应激，即使在环境相关剂量（0.05mg/L）下也是如此。代谢组学分析和多元统计分析表明，HBCD 主要干扰的代谢途径包括氨基酸代谢、蛋白质生物合成、脂肪酸代谢和磷脂代谢。HBCD 抑制了氨基酸的细胞摄取，主要是通过抑制膜转运蛋白 Na(+)/K(+)-ATP 酶的活性。HBCD 下调了糖酵解和长链脂肪酸的β氧化，导致 ATP 生成大量减少。结果，氨基酸的跨膜转运进一步受到抑制。同时，HBCD 诱导了总磷脂的显著增加，主要是通过增加的游离脂肪酸来重塑磷脂。所获得的代谢组学结果还为 HBCD 的毒性作用机制提供了一些新的证据和线索，这些机制可能导致肥胖、糖尿病、神经系统损伤和发育障碍。
