title: Prolonged exposure to low-dose microcystin induces nonalcoholic steatohepatitis in mice: a systems toxicology study.
abstract: Microcystin-LR (MCLR), a cyanotoxin widely present in freshwater, has been shown to have potent acute hepatotoxicity. However, the chronic toxicity of low-dose MCLR remains confusing by traditional measurements of toxicity. This has impeded understanding of the chronic liver damage of low-dose MCLR and corresponding safety risks of the human exposure guideline value. Here, iTRAQ-based proteomics and NMR-based metabonomics were used to decipher the molecular toxicological signatures of low doses of MCLR in mice exposed to this agent for 90 days. Low levels of MCLR, even under the reported no observed adverse effect level, significantly altered hepatic protein expression, especially of proteins associated with lipid metabolism, transport, immune and proteolysis. Coherently, MCLR induced marked perturbations in lipid metabolites in both liver and serum. Integrated analysis of proteomic, metabolic, histological and cytokine profiles revealed that MCLR significantly inhibited fatty acid β-oxidation and hepatic lipoprotein secretion and promoted hepatic inflammation, resulting in nonalcoholic steatohepatitis disease (NASH). These findings for the first time provide compelling evidence that chronic exposure to low-level MCLR can induce NASH. These results also indicate that current guidelines for MCs in drinking water may be inadequate and associated with risks to human health.
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, Chinese Academy of Sciences, Donghu South Road 7, Wuhan, 430072, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Li
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, Chinese Academy of Sciences, Donghu South Road 7, Wuhan, 430072, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, Chinese Academy of Sciences, Donghu South Road 7, Wuhan, 430072, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Lin
authors.affiliation: College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, Chinese Academy of Sciences, Donghu South Road 7, Wuhan, 430072, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Shanghai Biotree Biotech Co., Ltd, Shanghai, 200433, People's Republic of China.
authors.forename: Junliang
authors.initials: J
authors.lastname: Deng
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, Chinese Academy of Sciences, Donghu South Road 7, Wuhan, 430072, People's Republic of China. xieping@ihb.ac.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage* / Q000633:toxicity; D002277:Carcinoma / Q000209:etiology; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D050356:Lipid Metabolism / Q000187:drug effects; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology; D008297:Male; D008387:Marine Toxins / Q000008:administration & dosage* / Q000633:toxicity; D008807:Mice, Inbred BALB C; D052998:Microcystins / Q000008:administration & dosage* / Q000633:toxicity; D008954:Models, Biological; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011897:Random Allocation; D013047:Specific Pathogen-Free Organisms; D036401:Toxicity Tests, Chronic
chemical_list: D001427:Bacterial Toxins; D016207:Cytokines; D008074:Lipoproteins; D008387:Marine Toxins; D052998:Microcystins; C057862:cyanoginosin LR
keywords: Hepatotoxicity; Metabonomics; Microcystin-LR; Nonalcoholic steatohepatitis; Proteomics