title: An integrated metabonomics and transcriptomics approach to understanding metabolic pathway disturbance induced by perfluorooctanoic acid.
abstract: Perfluorooctanoic acid (PFOA) is one of the most representative perfluorinated compounds and liver is the major organ where PFOA is accumulated. Although the multiple toxicities had been reported, its toxicological profile remained unclear. In this study, a systems toxicology strategy integrating liquid chromatography/mass spectrometry-based metabonomics and transcriptomics analyses was applied for the first time to investigate the effects of PFOA on a representative Chinese normal human liver cell line L-02, with focusing on the metabolic disturbance. Fifteen potential biomarkers were identified on metabolic level and most observations were consistent with the altered levels of gene expression. Our results showed that PFOA induced the perturbations in various metabolic processes in L-02 cells, especially lipid metabolism-related pathways. The up-stream mitochondrial carnitine metabolism was proved to be influenced by PFOA treatment. The specific transformation from carnitine to acylcarnitines, which showed a dose-dependent effect, and the expression level of key genes involved in this pathway were observed to be altered correspondingly. Furthermore, the down-stream cholesterol biosynthesis was directly confirmed to be up-regulated by both increased cholesterol content and elevated expression level of key genes. The PFOA-induced lipid metabolism-related effects in L-02 cells started from the fatty acid catabolism in cytosol, fluctuated to the processes in mitochondria, extended to the cholesterol biosynthesis. Many other metabolic pathways like amino acid metabolism and tricarboxylic acid cycle might also be disturbed. The findings obtained from the systems biological research provide more details about metabolic disorders induced by PFOA in human liver.
authors: Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China.
authors: Siyuan
authors: S
authors: Peng
authors: Lijuan
authors: L
authors: Yan
authors: Jie
authors: J
authors: Zhang
authors: Zhanlin
authors: Z
authors: Wang
authors: Meiping
authors: M
authors: Tian
authors: Heqing
authors: H
authors: Shen
mesh_terms: D002210:Caprylates / Q000633:toxicity*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005466:Fluorocarbons / Q000633:toxicity*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects* / Q000502:physiology*; D055432:Metabolomics / Q000379:methods*; D010865:Pilot Projects; D059467:Transcriptome / Q000187:drug effects* / Q000502:physiology*
chemical_list: D002210:Caprylates; D005466:Fluorocarbons; C023036:perfluorooctanoic acid
keywords: Biomarker; Hepatotoxicity; Metabonomics; Perfluorooctanoic acid; Transcriptomics