Long-term environmental levels of microcystin-LR exposure induces colorectal chronic inflammation, fibrosis and barrier disruption via CSF1R/Rap1b signaling pathway

Yue Yang; Hui Wang; Xiaoyan Wang; Ling Chen; Wenya Liu; Danping Cai; Shuxiang Deng; Hanyu Chu; Ying Liu; Xiangling Feng; Jihua Chen; Mengshi Chen; Chengkun Wang; Ran Liu; Yuepu Pu; Zhen Ding; Deliang Cao; Dingxin Long; Yi Cao; Fei Yang

doi:10.1016/j.jhazmat.2022.129793

Long-term environmental levels of microcystin-LR exposure induces colorectal chronic inflammation, fibrosis and barrier disruption via CSF1R/Rap1b signaling pathway

J Hazard Mater. 2022 Oct 15:440:129793. doi: 10.1016/j.jhazmat.2022.129793. Epub 2022 Aug 18.

Authors

Yue Yang¹, Hui Wang², Xiaoyan Wang³, Ling Chen⁴, Wenya Liu¹, Danping Cai², Shuxiang Deng², Hanyu Chu², Ying Liu², Xiangling Feng¹, Jihua Chen¹, Mengshi Chen¹, Chengkun Wang⁵, Ran Liu⁶, Yuepu Pu⁶, Zhen Ding⁷, Deliang Cao², Dingxin Long², Yi Cao², Fei Yang⁸

Affiliations

¹ Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha, China.
² Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China.
³ Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, China.
⁴ First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
⁵ Department of Medical Pathology, School of Basic Medical, Hengyang Medical School, University of South China, Hengyang, China.
⁶ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
⁷ Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.
⁸ Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China; Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China. Electronic address: yangfeilong@126.com.

PMID: 36029734
DOI: 10.1016/j.jhazmat.2022.129793

Abstract

Microcystin-LR (MC-LR) is a very common toxic cyanotoxins threating ecosystems and the public health. This study aims to explore the long-term effects and potential toxicity mechanisms of MC-LR exposure at environmental levels on colorectal injury. We performed histopathological, biochemical indicator and multi-omics analyses in mice with low-dose MC-LR exposure for 12 months. Long-term environmental levels of MC-LR exposure caused epithelial barrier disruption, inflammatory cell infiltration and an increase of collagen fibers in mouse colorectum. Integrated proteotranscriptomics revealed differential expression of genes/proteins, including CSF1R, which were mainly involved in oxidative stress-induced premature senescence and inflammatory response. MC-LR induced chronic inflammation and fibrosis through oxidative stress and CSF1R/Rap1b signaling pathway were confirmed in cell models. We found for the first time that long-term environmental levels of MC-LR exposure caused colorectal chronic inflammation, fibrosis and barrier disruption via a novel CSF1R/Rap1b signaling pathway. Moreover, MC-LR changed the gut microbiota and microbial-related metabolites in a vicious cycle aggravating colorectal injury. These findings provide novel insights into the effects and toxic mechanisms of MC-LR and suggest strategies for the prevention and treatment of MC-caused intestinal diseases.

Keywords: CSF1R; Chronic inflammation; Fibrosis; Intestinal injury; MC-LR.

MeSH terms

Animals
Collagen
Colon* / pathology
Fibrosis
Inflammation* / chemically induced
Marine Toxins / toxicity
Mice
Microcystins* / toxicity
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
Signal Transduction
rap GTP-Binding Proteins / metabolism

Substances

Csf1r protein, mouse
Marine Toxins
Microcystins
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
Collagen
Rap1b protein, mouse
rap GTP-Binding Proteins
cyanoginosin LR