Chronic Exposure to Environmentally Relevant Concentrations of Microcystin-Leucine Arginine Causes Lung Barrier Damage through PP2A Activity Inhibition and Claudin1 Ubiquitination

  • J Agric Food Chem. 2022 Sep 7;70(35):10907-10918. doi: 10.1021/acs.jafc.2c05207.
Haohao Liu  1 ,  Xin Zeng  1 ,  Yueqin Wang  1 ,  Michael D Losiewicz  2 ,  Xinghai Chen  2 ,  Xingde Du  1 ,  Yongshui Wang  1 ,  Bingyu Zhang  1 ,  Xing Guo  1 ,  Shumeng Yuan  1 ,  Fei Yang  3  4 ,  Huizhen Zhang  1
Affiliations
  • 1. College of Public Health, Zhengzhou University, Zhengzhou450001, Henan, China.
  • 2. Department of Chemistry and Biochemistry, St Mary's University, San Antonio78228, Texas, United States.
  • 3. Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang421001, Hunan, China.
  • 4. Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha410008, Hunan, China.
PMID: 36026589 DOI: 10.1021/acs.jafc.2c05207
Abstract

Microcystin-leucine arginine (MC-LR), ubiquitous in water and food, is a threat to public health. In the present study, after C57BL/6J mice were fed with environmental concentrations of MC-LR (0, 1, 30, 60, 90, and 120 μg/L) for 6, 9, and 12 months, it was found that MC-LR could enter into mouse lung tissues and cause microstructural damage, as shown by western blotting and HE staining. Electron microscopy examination showed that MC-LR could damage the lung barrier by disruption of the tight junctions, which was confirmed by the decreased expression of tight junction markers, including Occludin, Claudin1, and ZO-1. In addition, MC-LR also increased the ubiquitination of Claudin1, indicating that MC-LR could disrupt tight junctions by promoting the degradation of Claudin1. Furthermore, MC-LR increased the levels of TNF-α and IL-6 in mouse lung tissues, leading to pneumonia. Importantly, pretreatment with PP2A activator D-erythro-sphingosine (DES) was found to significantly alleviate MC-LR-induced decrease of Occludin and Claudin1 by inhibiting the P-AKT/Snail pathway in vitro. Together, this study revealed that chronic exposure to MC-LR causes lung barrier damage, which involves PP2A activity inhibition and enhancement of Claudin1 ubiquitination. This study broadens the awareness of the toxic effects of MC-LR on the respiratory system, which has deep implications for public health.

Keywords
MC-LR; PP2A; lung barrier; pneumonia; tight junction; ubiquitination.
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