{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T02:38:10Z","timestamp":1792031890789,"version":"4.4.0"},"reference-count":71,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,8,23]],"date-time":"2019-08-23T00:00:00Z","timestamp":1566518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016942","name":"Ohio Department of Higher Education","doi-asserted-by":"publisher","award":["4240"],"award-info":[{"award-number":["4240"]}],"id":[{"id":"10.13039\/100016942","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Microcystins are potent hepatotoxins that have become a global health concern in recent years. Their actions in at-risk populations with pre-existing liver disease is unknown. We tested the hypothesis that the No Observed Adverse Effect Level (NOAEL) of Microcystin-LR (MC-LR) established in healthy mice would cause exacerbation of hepatic injury in a murine model (Leprdb\/J) of Non-alcoholic Fatty Liver Disease (NAFLD). Ten-week-old male Leprdb\/J mice were gavaged with 50 \u03bcg\/kg, 100 \u03bcg\/kg MC-LR or vehicle every 48 h for 4 weeks (n = 15\u201317 mice\/group). Early mortality was observed in both the 50 \u03bcg\/kg (1\/17, 6%), and 100 \u03bcg\/kg (3\/17, 18%) MC-LR exposed mice. MC-LR exposure resulted in significant increases in circulating alkaline phosphatase levels, and histopathological markers of hepatic injury as well as significant upregulation of genes associated with hepatotoxicity, necrosis, nongenotoxic hepatocarcinogenicity and oxidative stress response. In addition, we observed exposure dependent changes in protein phosphorylation sites in pathways involved in inflammation, immune function, and response to oxidative stress. These results demonstrate that exposure to MC-LR at levels that are below the NOAEL established in healthy animals results in significant exacerbation of hepatic injury that is accompanied by genetic and phosphoproteomic dysregulation in key signaling pathways in the livers of NAFLD mice.<\/jats:p>","DOI":"10.3390\/toxins11090486","type":"journal-article","created":{"date-parts":[[2019,8,26]],"date-time":"2019-08-26T04:38:23Z","timestamp":1566794303000},"page":"486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"11","author":[{"given":"Apurva","family":"Lad","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7423-0939","authenticated-orcid":false,"given":"Robin","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5892-1879","authenticated-orcid":false,"given":"Joshua","family":"Breidenbach","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Stemmer","sequence":"additional","affiliation":[{"name":"Institute of Environmental Health Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, 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Chemistry, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4447-5863","authenticated-orcid":false,"given":"Erin","family":"Crawford","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilrukshika","family":"Palagama","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Baliu-Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragan","family":"Isailovic","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, 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