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

ABSTRACT: 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.

SUBMITTER: Lad A

PROVIDER: S-EPMC6783870 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Lad Apurva A Su Robin C RC Breidenbach Joshua D JD Stemmer Paul M PM Carruthers Nicholas J NJ Sanchez Nayeli K NK Khalaf Fatimah K FK Zhang Shungang S Kleinhenz Andrew L AL Dube Prabhatchandra P Mohammed Chrysan J CJ Westrick Judy A JA Crawford Erin L EL Palagama Dilrukshika D Baliu-Rodriguez David D Isailovic Dragan D Levison Bruce B Modyanov Nikolai N Gohara Amira F AF Malhotra Deepak D Haller Steven T ST Kennedy David J DJ

Toxins 20190823 9

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 (Lepr<sup>db</sup>/J) of Non-alcoholic Fatty Liver Disease (NAFLD). Ten-week-old male Lepr<sup>db</sup>/J mice were gavaged with 50 μg ...[more]

PMID: 31450746

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Project description:BackgroundMicrocystins (MCs), potent hepatotoxins pose a significant health risk to humans, particularly children, who are more vulnerable due to higher water intake and increased exposure during recreational activities.MethodsHere, we investigated the role of host microbiome-linked acetate in modulating inflammation caused by early-life exposure to the cyanotoxin Microcystin-LR (MC-LR) in a juvenile mice model.ResultsOur study revealed that early-life MC-LR exposure disrupted the gut microbiome, leading to a depletion of key acetate-producing bacteria and decreased luminal acetate concentration. Consequently, the dysbiosis hindered the establishment of a gut homeostatic microenvironment and disrupted gut barrier function. The NOD-like receptor family pyrin domain - containing 3 (NLRP3) inflammasome, a key player in MC-induced hepatoxicity emerged as a central player in this process, with acetate supplementation effectively preventing NLRP3 inflammasome activation, attenuating hepatic inflammation, and decreasing pro-inflammatory cytokine production. To elucidate the mechanism underlying the association between early-life MC-LR exposure and the progression of metabolic dysfunction associated steatotic liver disease (MASLD), we investigated the role of acetate binding to its receptor -G-protein coupled receptor 43 (GPR43) on NLRP3 inflammasome activation. Our results demonstrated that acetate-GPR43 signaling was crucial for decreasing NLRP3 protein levels and inhibiting NLRP3 inflammasome assembly. Further, acetate-induced decrease in NLRP3 protein levels was likely mediated through proteasomal degradation rather than autophagy. Overall, our findings underscore the significance of a healthy gut microbiome and its metabolites, particularly acetate, in the progression of hepatotoxicity induced by early life toxin exposure, crucial for MASLD progression.ConclusionsThis study highlights potential therapeutic targets in gut dysbiosis and NLRP3 inflammasome activation for mitigating toxin-associated inflammatory liver diseases.

Dataset Information

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

Publications

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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