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

Toxins (Basel). 2019 Aug 23;11(9):486. doi: 10.3390/toxins11090486.


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.

Keywords: Leprdb/J mice; Microcystin-LR; No Observed Adverse Effect Level; Non-alcoholic Fatty Liver Disease; TiO2 enriched phosphopeptides; hepatotoxicity; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Marine Toxins
  • Mice
  • Mice, Inbred Strains
  • Microcystins / blood
  • Microcystins / toxicity*
  • Microcystins / urine
  • Non-alcoholic Fatty Liver Disease / chemically induced*
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Organ Size / drug effects
  • Oxidative Stress / drug effects*
  • Oxidative Stress / genetics
  • Proteomics
  • Survival Analysis
  • Water Pollutants, Chemical / blood
  • Water Pollutants, Chemical / toxicity*
  • Water Pollutants, Chemical / urine


  • Marine Toxins
  • Microcystins
  • Water Pollutants, Chemical
  • cyanoginosin LR