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Open AccessArticle

Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease

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Department of Medicine, University of Toledo, Toledo, OH 43614, USA
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Institute of Environmental Health Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
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Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
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Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA
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Department of Pediatrics, University of Toledo, Toledo, OH 43614, USA
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Department of Physiology and Pharmacology, University of Toledo, Toledo, OH 43614, USA
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Department of Pathology, University of Toledo, Toledo, OH 43614, USA
*
Authors to whom correspondence should be addressed.
Toxins 2019, 11(9), 486; https://doi.org/10.3390/toxins11090486
Received: 2 July 2019 / Revised: 15 August 2019 / Accepted: 19 August 2019 / Published: 23 August 2019
(This article belongs to the Special Issue Freshwater Algal Toxins: Monitoring and Toxicity Profile)
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 μg/kg, 100 μg/kg MC-LR or vehicle every 48 h for 4 weeks (n = 15–17 mice/group). Early mortality was observed in both the 50 μg/kg (1/17, 6%), and 100 μg/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. View Full-Text
Keywords: Microcystin-LR; Non-alcoholic Fatty Liver Disease; No Observed Adverse Effect Level; Leprdb/J mice; hepatotoxicity; oxidative stress; TiO2 enriched phosphopeptides Microcystin-LR; Non-alcoholic Fatty Liver Disease; No Observed Adverse Effect Level; Leprdb/J mice; hepatotoxicity; oxidative stress; TiO2 enriched phosphopeptides
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Lad, A.; Su, R.C.; Breidenbach, J.D.; Stemmer, P.M.; Carruthers, N.J.; Sanchez, N.K.; Khalaf, F.K.; Zhang, S.; Kleinhenz, A.L.; Dube, P.; Mohammed, C.J.; Westrick, J.A.; Crawford, E.L.; Palagama, D.; Baliu-Rodriguez, D.; Isailovic, D.; Levison, B.; Modyanov, N.; Gohara, A.F.; Malhotra, D.; Haller, S.T.; Kennedy, D.J. Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease. Toxins 2019, 11, 486.

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