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.
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Acknowledgments
This work was funded by the National Natural Science Foundation of China (Grant No. 31322013) and State Key Laboratory of Freshwater Ecology and Biotechnology (Grant No. 2014FBZ02). The authors thank the Wuhan Institute of Physics and Mathematics, Chinese Academy of Science, for the use of their Bruker NMR spectrometers. The authors thank Hongbing Liu and Sizhe Chen for help with the NMR experiment and data processing. The authors also thank Shangchun Li, Wei Li, Xiaochun Guo, Huihui Fan, Dezhao Yu, Lijuan Xie and Sujuan Zhao for assistance with the animal experiments.
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Jun He, Jun Chen and Guangyu Li have contributed equally to this work.
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He, J., Li, G., Chen, J. et al. Prolonged exposure to low-dose microcystin induces nonalcoholic steatohepatitis in mice: a systems toxicology study. Arch Toxicol 91, 465–480 (2017). https://doi.org/10.1007/s00204-016-1681-3
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DOI: https://doi.org/10.1007/s00204-016-1681-3