Inhaled microcystin-LR may induce acute liver failure through hepatic congestion

As cyanobacteria growth increases due to climate change, health issues resulting from exposure to microcystin-leucine-arginine (MC-LR), a toxin produced by cyanobacteria, are becoming a pressing public health concern. In this study, we found that the diameter of water droplets containing MC-LR was about 5 μm, indicating they are inhalable. When instilled intranasally to male mice at doses of 30, 150, and 300 μg/kg, death occurred in the groups exposed to 150 and 300 μg/kg (on Day 8 and Day 2 after a single dose, respectively). Additionally, when doses of 10, 50, and 100 μg/kg were given intranasally four times (weekly) to both male and female mice, sudden death occurred approximately 2 h after the second dose (100 μg/kg), and female mice showed a more sensitive response to MC-LR than male mice. Although pulmonary inflammation was minimal, the pulmonary CRP level increased significantly after MC-LR exposure, and MC-LR was detected within a 3D reconstructed human airway model 3 h after treatment, suggesting potential translocation across the airway epithelium. Notably, severe hepatic congestion was observed in all mice that died or were near death, and liver toxicity-related biochemical indicators were affected by MC-LR exposure. Infiltration of mononuclear cells into the kidneys was notable even at a dose of 10 μg/kg, and necrotic cell damage, lamellar body-like structures, lipid droplets, and collagen fibers were observed in the liver tissues of mice exposed to the highest dose. More importantly, 2 h after the second injection, MC-LR was detected in the liver tissues of mice, and MC-LR-induced gene changes were very similar in the liver tissues of male and female mice. Activating transcription factor 3 and nuclear receptor subfamily 4 (group A, member 1) were the most upregulated in the liver tissues of male and female mice, respectively, while microRNA 122 was the most downregulated. Overall, we suggest that inhaled MC-LR causes liver-specific toxicity through hepatic congestion, and the acceptable inhalation dose of MC-LR may be below 10 μg/kg. Given the increasing global water pollution caused by blue-green algal blooms, we emphasize the need for systematic studies on the health effects of chronic exposure to environmental concentrations of MC-LR.