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To comprehensively understand the toxicity mechanism of chronic exposure to environmental levels of MC-LR on the liver of fish, juvenile Nile tilapia were exposed to 0 \u03bcg\/L (control), 1 \u03bcg\/L (M1), 3 \u03bcg\/L (M3), 10 \u03bcg\/L (M10), and 30 \u03bcg\/L (M30) MC-LR for 60 days. Then, the liver hepatotoxicity induced by MC-LR exposure was systematically evaluated via histological and biochemical determinations, and the underlying mechanisms were explored through combining analysis of biochemical parameters, multi-omics (transcriptome and metabolome), and gene expression. The results exhibited that chronic MC-LR exposure caused slight liver minor structural damage and lipid accumulation in the M10 group, while resulting in serious histological damage and lipid accumulation in the M30 group, indicating obvious hepatotoxicity, which was confirmed by increased toxicity indexes (i.e., AST, ALT, and AKP). Transcriptomic and metabolomic analysis revealed that chronic MC-LR exposure induced extensive changes in gene expression and metabolites in six typical pathways, including oxidative stress, apoptosis, autophagy, amino acid metabolism, primary bile acid biosynthesis, and lipid metabolism. Taken together, chronic MC-LR exposure induced oxidative stress, apoptosis, and autophagy, inhibited primary bile acid biosynthesis, and caused fatty deposition in the liver of Nile tilapia.<\/jats:p>","DOI":"10.3390\/toxins16030149","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T05:43:08Z","timestamp":1710394988000},"page":"149","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Integration of Multi-Omics, Histological, and Biochemical Analysis Reveals the Toxic Responses of Nile Tilapia Liver to Chronic Microcystin-LR Exposure"],"prefix":"10.3390","volume":"16","author":[{"given":"Yichao","family":"Li","sequence":"first","affiliation":[{"name":"Faculty of Fisheries and Life Sciences, Shanghai Ocean University, Shanghai 201306, China"},{"name":"Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huici","family":"Yang","sequence":"additional","affiliation":[{"name":"Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Fu","sequence":"additional","affiliation":[{"name":"College of Marine Sciences, South China Agricultural University, Guangzhou 510640, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4295-5123","authenticated-orcid":false,"given":"Gen","family":"Kaneko","sequence":"additional","affiliation":[{"name":"College of Natural and Applied Science, University of Houston-Victoria, Victoria, TX 77901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5437-9779","authenticated-orcid":false,"given":"Hongyan","family":"Li","sequence":"additional","affiliation":[{"name":"Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0948-289X","authenticated-orcid":false,"given":"Jingjing","family":"Tian","sequence":"additional","affiliation":[{"name":"Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingken","family":"Wei","sequence":"additional","affiliation":[{"name":"Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming 525000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xie","sequence":"additional","affiliation":[{"name":"Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6348-9884","authenticated-orcid":false,"given":"Ermeng","family":"Yu","sequence":"additional","affiliation":[{"name":"Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1021\/acs.est.6b03990","article-title":"Responses of the Proteome and Metabolome in Livers of Zebrafish Exposed Chronically to Environmentally Relevant Concentrations of Microcystin-LR","volume":"51","author":"Chen","year":"2017","journal-title":"Environ. 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