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Marumure J, Gwenzi W, Makuvara Z, Simbanegavi TT, Alufasi R, Goredema M, Gufe C, Karidzagundi R, Rzymski P, Halabowski D. Global Occurrence of Cyanotoxins in Drinking Water Systems: Recent Advances, Human Health Risks, Mitigation, and Future Directions. Life (Basel) 2025; 15:825. [PMID: 40430251 PMCID: PMC12112831 DOI: 10.3390/life15050825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2025] [Revised: 05/15/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
This paper applies a semi-quantitative approach to review the diversity, environmental controls, detection methods, human health risks, and mitigation of cyanotoxins in drinking water systems (DWSs). It discusses the environmental factors controlling the occurrence of cyanotoxins, presents the merits and limitations of emerging methods of their detection (qPCR, liquid chromatography-mass spectrometry, and electrochemical biosensors), and outlines the human exposure pathways and health outcomes with identification of high-risk groups and settings. High-risk groups include (1) communities relying on untreated drinking water from unsafe, polluted water sources and (2) low-income countries where cyanotoxins are not routinely monitored in DWSs. The fate and behavior processes are discussed, including removing cyanotoxins in DWSs based on conventional and advanced treatment processes. The available methods for cyanotoxin removal presented in this paper include (1) polymer-based adsorbents, (2) coagulation/flocculation, (3) advanced oxidation processes, (4) ultra- and nanofiltration, and (5) multi-soil layer systems. Future research should address (1) detection and fate in storage and conveyance facilities and at the point of consumption, (2) degradation pathways and toxicity of by-products or metabolites, (3) interactive health effects of cyanotoxins with legacy and emerging contaminants, (4) removal by low-cost treatment techniques (e.g., solar disinfection, boiling, bio-sand filtration, and chlorination), (5) quantitative health risk profiling of high-risk groups, and (6) epidemiological studies to link the prevalence of human health outcomes (e.g., cancer) to cyanotoxins in DWSs.
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Affiliation(s)
- Jerikias Marumure
- Department of Physics, Geography and Environmental Science, School of Natural Sciences, Great Zimbabwe University, Masvingo, Zimbabwe; (J.M.); (Z.M.)
- Department of Life and Consumer Sciences, School of Agriculture and Life Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Pretoria 0002, South Africa
| | - Willis Gwenzi
- Formerly Alexander von Humboldt Fellow, Leibniz-Institut für Agrartechnik und Bioökonomie e.V. (ATB), Max-Eyth-Allee 100, D-14469 Potsdam, Germany;
- Formerly Alexander von Humboldt Fellow, Grassland Science and Renewable Plant Resources, Faculty of Organic Agricultural Sciences, Universität Kassel, Steinstraße 19, D-37213 Witzenhausen, Germany
- Independent Researcher, Biosystems & Environmental Engineering Research Group, 380 New Adylin, Westgate, Harare, Zimbabwe
| | - Zakio Makuvara
- Department of Physics, Geography and Environmental Science, School of Natural Sciences, Great Zimbabwe University, Masvingo, Zimbabwe; (J.M.); (Z.M.)
- Department of Life and Consumer Sciences, School of Agriculture and Life Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Pretoria 0002, South Africa
| | - Tinoziva T. Simbanegavi
- Department of Soil Science and Environment, Faculty of Agriculture, Environment, and Food Systems, University of Zimbabwe, P.O. Box MP 167, Mount Pleasant, Harare, Zimbabwe;
| | - Richwell Alufasi
- Biological Sciences Department, Bindura University of Science Education, 741 Chimurenga Road, Off Trojan Road, Bindura, Zimbabwe; (R.A.); (M.G.)
| | - Marvelous Goredema
- Biological Sciences Department, Bindura University of Science Education, 741 Chimurenga Road, Off Trojan Road, Bindura, Zimbabwe; (R.A.); (M.G.)
| | - Claudious Gufe
- Department of Veterinary Technical Services, Central Veterinary Laboratories, P.O. Box CY55, 18A Borrowdale Road, Harare, Zimbabwe;
| | - Rangarirayi Karidzagundi
- Materials Development Unit, Zimbabwe Open University, P.O. Box MP1119, Mount Pleasant, Harare, Zimbabwe;
| | - Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, 60-806 Poznań, Poland;
| | - Dariusz Halabowski
- University of Lodz, Faculty of Biology and Environmental Protection, Department of Ecology and Vertebrate Zoology, 90-237 Lodz, Poland
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Long S, Wen C, Zeng W, Yang Y, Yang F. Effect of chronic low-dose microcystin-LR exposure on jejunum apoptosis via RAF/ERK signaling pathway in mouse. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2025; 88:291-300. [PMID: 39668503 DOI: 10.1080/15287394.2024.2435631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2024]
Abstract
Microcystin-LR (MC-LR), a class of cyclic heptapeptide compounds synthesized by cyanobacterial species, presents a significant risk to ecological systems and public health. Exposure to MC-LR was found to induce damage to various organs. One of the target organ systems affected by MC-LR is the gastrointestinal tract (GIT). However, the majority of studies regarding GIT focused on colorectal toxicity, with little attention paid to small intestinal toxic injuries, in particular jejunum. Thus, the aim of this study was to investigate the effects attributed to MC-LR exposure on apoptosis and underlying mechanisms utilizing a mouse jejunum injury model following chronic low-dose MC-LR treatment. A total of 40 C57BL/6 male mice were randomly divided into 4 groups with each group receiving drinking water containing 0, 1, 60, or 120 µg/L MC-LR for a duration of 12 months. Results indicated that exposure to MC-LR induced pathological alterations in jejunal tissue as evidenced by abnormal villous serration, crypt disorganization, and lymphocyte infiltration. TUNEL assays demonstrated a significant increase in apoptotic cell count in the 60 and 120 µg/L groups. The 60 and 120 µg/L MC-LR treatment groups exhibited elevated mRNA expression of Bax accompanied by significant reduction in mRNA expression of Bcl-2. The protein levels of cleaved caspase-3 were markedly elevated in the 60 and 120 µg/L MC-LR groups. The protein expression levels of p-RAF and p-ERK were significantly increased in the 60 and 120 µg/L MC-LR treatment groups. Data demonstrated suggest that the RAF/ERK signaling pathway may be involved in MC-LR- induced jejunal apoptosis.
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Affiliation(s)
- Sihong Long
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| | - Cong Wen
- Changsha Yuhua District Center for Disease Control and Prevention, Changsha, China
| | - Wen Zeng
- The Department of Public Health, The Central Hospital of Shaoyang, Shaoyang, China
| | - Yue Yang
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
- The Department of Public Health, The Central Hospital of Shaoyang, Shaoyang, China
| | - Fei Yang
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
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Ou-Yang K, He Y, Yang H, Wang L, Zhang Q, Li D, Li L. Microcystin-LR induces fatty liver metabolic disease in zebrafish through the PPARα-NOD1 pathway: In vivo, in vitro, and in silico investigations. JOURNAL OF HAZARDOUS MATERIALS 2025; 485:136813. [PMID: 39657491 DOI: 10.1016/j.jhazmat.2024.136813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 12/01/2024] [Accepted: 12/05/2024] [Indexed: 12/12/2024]
Abstract
Hepatic lipid metabolism dysfunction caused by cyanobacteria bloom-released microcystin-LR (MC-LR) contributes to the development of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH), thereby severely impacting the health and safety of animals and humans. In this study, the effects and mechanisms of different environmental concentrations of MC-LR (0, 0.1, 1, and 10 μg/L) on fatty liver metabolic disease in zebrafish were investigated using in vivo, in vitro, and in silico models. Exposure to 10 μg/L of MC-LR-induced NASH in zebrafish, characterized by hepatic steatosis, toxic saturated fatty acid (SFA) accumulation, and inflammation. Analyses of the liver transcriptome, molecular docking, molecular dynamics simulation, and in vitro experiments indicated that PPARα might be a key molecular target in MC-LR-induced steatosis and in toxic-SFA accumulation. The results obtained from molecular docking, molecular dynamics simulation, and NOD1-inhibitor experiments further revealed that MC-LR-derived SFAs, such as palmitic acid, could target the NOD1 protein to initiate hepatitis in zebrafish. The benchmark dose model identified palmitic acid as a sensitive indicator of MC-LR-induced NASH, and the point of departure value was estimated to be 1.634 μg/L. In conclusion, our findings offer new insights into the mechanism of MC-LR-induced NASH and aid in the prognosis and treatment of MC-LR-related liver metabolic diseases, as well as in assessing the health risks associated with cyanobacterial blooms.
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Affiliation(s)
- Kang Ou-Yang
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Ya He
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Hui Yang
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Liangmou Wang
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Qian Zhang
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Dapeng Li
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, PR China; Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan 430070, PR China; Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan 430070, PR China; Freshwater Aquaculture Collaborative Innovation Center of Hubei Province, Wuhan 430070, PR China
| | - Li Li
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, PR China; Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan 430070, PR China; Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan 430070, PR China; Freshwater Aquaculture Collaborative Innovation Center of Hubei Province, Wuhan 430070, PR China.
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Yang M, Zheng S, Zeng W, Zhan C, Yang Y, Yang F. Chronic exposure to low-dose MC-LR induces ileal inflammation in mice through the PI3K/AKT/mTOR pathway. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2025:1-9. [PMID: 39790025 DOI: 10.1080/15287394.2024.2441294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
The global phenomenon of cyanobacterial bloom pollution is spreading globally due to climate change and eutrophication. It is well established that harmful cyanobacteria produce a wide range of toxins including microcystin-LR (MC-LR), a cyclic heptapeptide toxin known to damage various organs. The intestinal tract is the main site of MC-LR absorption and one of the targets susceptible to toxicity. Currently, studies on the enterotoxic effects of MC-LR predominantly focused on the colorectum, with limited investigations addressing the impact of microcystins on the small intestine. Therefore, the aim of our study was to examine the impact of chronic 9-month exposure of mice to low-dose 120 μg/L MC-LR in drinking water on ileal inflammation and potential mechanisms underlying these effects. Our findings showed that in mice chronically administered with low-dose MC-LR disorganized intestinal epithelial cells, lymphocytic infiltration and disturbed crypt arrangement were detected. The results of qPCR and Western blot demonstrated that, in comparison to control, the mRNA expression levels of pro-inflammatory factors IL-6, IL-17, IL-18, and IFN-γ were markedly elevated in the ileal tissue of mice treated with MC-LR, associated with significant increases in protein expression levels of p-PI3K, p-AKT, and p-mTOR. Taken together, evidence indicates that MC-LR induces ileal inflammation and histopathological damage involved activation of the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Mingjie Yang
- School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| | - Shuilin Zheng
- Changsha Center for Disease Control and Prevention, Changsha, China
| | - Wen Zeng
- The Department of Public Health, The Central Hospital of Shaoyang, Shaoyang, China
| | - Chunhua Zhan
- School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| | - Yue Yang
- School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
- The Department of Public Health, The Central Hospital of Shaoyang, Shaoyang, China
| | - Fei Yang
- School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
- Nuclear Medicine Department, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
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Song Y, Wang X, Lu X, Wang T. Exposure to microcystin-LR promotes the progression of colitis-associated colorectal cancer by inducing barrier disruption and gut microbiota dysbiosis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 282:116750. [PMID: 39053045 DOI: 10.1016/j.ecoenv.2024.116750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 07/08/2024] [Accepted: 07/15/2024] [Indexed: 07/27/2024]
Abstract
Microcystins (MCs) are secondary metabolites generated by cyanobacterial blooms, among which microcystin-LR (MC-LR) stands out as the most widely distributed variant in aquatic environments. However, the effects of MC-LR on the colorectum and its role in promoting colorectal tumor progression remain unclear. Therefore, this study aims to scrutinize the impact of MC-LR on a mice model of colitis-associated colorectal cancer and elucidate the potential underlying molecular mechanisms. In this study, we used AOM/DSS mice and orally administered MC-LR at doses of 40 µg/kg or 200 µg/kg. Exposure to MC-LR increased tumor burden, promoted tumor growth, shortened colon size, and decreased goblet cell numbers and tight junction protein levels in intestinal tissues. Additionally, exposure to MC-LR induced alterations in the structure of gut microbiota in the mouse colon, characterized by an increase in the relative abundance of Escherichia_coli and Shigella_sonnei, and a decline in the relative abundance of Akkermansia_muciniphila. Transcriptomic analysis revealed that MC-LR exposure activated the IL-17 signaling pathway in mouse colorectal tissues and participated in inflammation regulation and immune response. Immunofluorescence results demonstrated an increase in T-helper 17 (Th17) cell levels in mouse colorectal tumors following MC-LR exposure. The results from RT-qPCR revealed that MC-LR induced the upregulation of IL-6, IL-1β, IL-10, IL-17A, TNF-α, CXCL1, CXCL2, CXCL5 and CCL20. The novelty of this study lies in its comprehensive approach to understanding the mechanisms by which MC-LR may contribute to CRC progression, offering new perspectives and valuable reference points for establishing guidance standards regarding MC-LR in drinking water. Our findings suggest that even at guideline value, MC-LR can have profound effects on susceptible mice, emphasizing the need for a reevaluation of guideline value and a deeper understanding of the role of environmental toxins in cancer progression.
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Affiliation(s)
- Yuechi Song
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, China
| | - Xiaochang Wang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, China
| | - Xiaohui Lu
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, China
| | - Ting Wang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, China.
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Song Y, Wang X, Lu X, Wang T. Exposure to Microcystin-LR Promotes Colorectal Cancer Progression by Altering Gut Microbiota and Associated Metabolites in APC min/+ Mice. Toxins (Basel) 2024; 16:212. [PMID: 38787064 PMCID: PMC11125743 DOI: 10.3390/toxins16050212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 04/27/2024] [Accepted: 04/29/2024] [Indexed: 05/25/2024] Open
Abstract
Microcystins (MCs), toxins generated by cyanobacteria, feature microcystin-LR (MC-LR) as one of the most prevalent and toxic variants in aquatic environments. MC-LR not only causes environmental problems but also presents a substantial risk to human health. This study aimed to investigate the impact of MC-LR on APCmin/+ mice, considered as an ideal animal model for intestinal tumors. We administered 40 µg/kg MC-LR to mice by gavage for 8 weeks, followed by histopathological examination, microbial diversity and metabolomics analysis. The mice exposed to MC-LR exhibited a significant promotion in colorectal cancer progression and impaired intestinal barrier function in the APCmin/+ mice compared with the control. Gut microbial dysbiosis was observed in the MC-LR-exposed mice, manifesting a notable alteration in the structure of the gut microbiota. This included the enrichment of Marvinbryantia, Gordonibacter and Family_XIII_AD3011_group and reductions in Faecalibaculum and Lachnoclostridium. Metabolomics analysis revealed increased bile acid (BA) metabolites in the intestinal contents of the mice exposed to MC-LR, particularly taurocholic acid (TCA), alpha-muricholic acid (α-MCA), 3-dehydrocholic acid (3-DHCA), 7-ketodeoxycholic acid (7-KDCA) and 12-ketodeoxycholic acid (12-KDCA). Moreover, we found that Marvinbryantia and Family_XIII_AD3011_group showed the strongest positive correlation with taurocholic acid (TCA) in the mice exposed to MC-LR. These findings provide new insights into the roles and mechanisms of MC-LR in susceptible populations, providing a basis for guiding values of MC-LR in drinking water.
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Affiliation(s)
| | | | | | - Ting Wang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China; (Y.S.); (X.W.); (X.L.)
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Li T, Fan X, Cai M, Jiang Y, Wang Y, He P, Ni J, Mo A, Peng C, Liu J. Advances in investigating microcystin-induced liver toxicity and underlying mechanisms. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 905:167167. [PMID: 37730048 DOI: 10.1016/j.scitotenv.2023.167167] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/27/2023] [Accepted: 09/15/2023] [Indexed: 09/22/2023]
Abstract
Microcystins (MCs) are a class of biologically active cyclic heptapeptide pollutants produced by the freshwater alga Microcystis aeruginosa. With increased environmental pollution, MCs have become a popular research topic. In recent years, the hepatotoxicity of MCs and associated effects and mechanisms have been studied extensively. Current epidemiological data indicate that long-term human exposure to MCs can lead to severe liver toxicity, acute toxicity, and death. In addition, current toxicological studies on the liver, a vital target organ of MCs, indicate that MC contamination is associated with the development of liver cancer, nonalcoholic fatty liver, and liver fibrosis. MCs produce hepatotoxicity that affects the metabolic homeostasis of the liver, induces apoptosis, and acts as a pro-cancer factor, leading to liver lesions. MCs mainly mediate the activation of signaling pathways, such as the ERK/JNK/p38 MAPK and IL-6-STAT3 pathways, which leads to oxidative damage and even carcinogenesis. Moreover, MCs can act synergistically with other pollutants to produce combined toxicity. However, few systematic reviews have been performed on these new findings. This review systematically summarizes the toxic effects and mechanisms of MCs on the liver and discusses the combined liver toxicity effects of MCs and other pollutants to provide reference for subsequent research. The toxicity of different MC isomers deserves further study. The detection methods and limit standards of MCs in agricultural and aquatic products will represent important research directions in the future. Standard protocols for fish sampling during harmful algal blooms or to evaluate the degree of MC toxicity in nature are lacking. In future, bioinformatics can be applied to offer insights into MC toxicology research and potential drug development for MC poisoning. Further research is essential to understand the molecular mechanisms of liver function damage in combined-exposure toxicology studies to establish treatment for MC-induced liver damage.
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Affiliation(s)
- Tong Li
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Xinting Fan
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Meihan Cai
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Yuanyuan Jiang
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Yaqi Wang
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Peishuang He
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Juan Ni
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Aili Mo
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Cuiying Peng
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China
| | - Jun Liu
- Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Hengyang City on Ecological Impedance Technology of Heavy Metal Pollution in Cultivated Soil of Nonferrous Metal Mining Area, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, China; School of Public Health, Hengyang Medical School, Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, China.
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Yang Y, Wen C, Zheng S, Song F, Liu Y, Yao X, Tang Y, Feng X, Chen J, Yang F. Lactobacillus fermentum Alleviates the Colorectal Inflammation Induced by Low-Dose Sub-Chronic Microcystin-LR Exposure. Toxins (Basel) 2023; 15:579. [PMID: 37756005 PMCID: PMC10536654 DOI: 10.3390/toxins15090579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 08/30/2023] [Accepted: 09/13/2023] [Indexed: 09/28/2023] Open
Abstract
Microcystin-LR (MC-LR) contamination is a worldwide environmental problem that poses a grave threat to the water ecosystem and public health. Exposure to MC-LR has been associated with the development of intestinal injury, but there are no effective treatments for MC-LR-induced intestinal disease. Probiotics are "live microorganisms that are beneficial to the health of the host when administered in sufficient quantities". It has been demonstrated that probiotics can prevent or treat a variety of human diseases; however, their ability to mitigate MC-LR-induced intestinal harm has not yet been investigated. The objective of this study was to determine whether probiotics can mitigate MC-LR-induced intestinal toxicity and its underlying mechanisms. We first evaluated the pathological changes in colorectal tissues using an animal model with sub-chronic exposure to low-dose MC-LR, HE staining to assess colorectal histopathologic changes, qPCR to detect the expression levels of inflammatory factors in colorectal tissues, and WB to detect the alterations on CSF1R signaling pathway proteins in colorectal tissues. Microbial sequencing analysis and screening of fecal microorganisms differential to MC-LR treatment in mice. To investigate the role of microorganisms in MC-LR-induced colorectal injury, an in vitro model of MC-LR co-treatment with microorganisms was developed. Our findings demonstrated that MC-LR treatment induced an inflammatory response in mouse colorectal tissues, promoted the expression of inflammatory factors, activated the CSF1R signaling pathway, and significantly decreased the abundance of Lactobacillus. In a model of co-treatment with MC-LR and Lactobacillus fermentum (L. fermentum), it was discovered that L. fermentum substantially reduced the incidence of the colorectal inflammatory response induced by MC-LR and inhibited the protein expression of the CSF1R signaling pathway. This is the first study to suggest that L. fermentum inhibits the CSF1R signaling pathway to reduce the incidence of MC-LR-induced colorectal inflammation. This research may provide an excellent experimental foundation for the development of strategies for the prevention and treatment of intestinal diseases in MC-LR.
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Affiliation(s)
- Yue Yang
- The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, Department of Epidemiology and Health Statistics, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; (Y.Y.); (F.S.); (Y.L.); (X.Y.); (Y.T.)
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410017, China; (X.F.); (J.C.)
| | - Cong Wen
- Changsha Yuhua District Center for Disease Control and Prevention, Changsha 410014, China;
| | - Shuilin Zheng
- Changsha Center for Disease Control and Prevention, Changsha 410004, China;
| | - Fengmei Song
- The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, Department of Epidemiology and Health Statistics, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; (Y.Y.); (F.S.); (Y.L.); (X.Y.); (Y.T.)
| | - Ying Liu
- The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, Department of Epidemiology and Health Statistics, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; (Y.Y.); (F.S.); (Y.L.); (X.Y.); (Y.T.)
| | - Xueqiong Yao
- The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, Department of Epidemiology and Health Statistics, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; (Y.Y.); (F.S.); (Y.L.); (X.Y.); (Y.T.)
| | - Yan Tang
- The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, Department of Epidemiology and Health Statistics, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; (Y.Y.); (F.S.); (Y.L.); (X.Y.); (Y.T.)
| | - Xiangling Feng
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410017, China; (X.F.); (J.C.)
| | - Jihua Chen
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410017, China; (X.F.); (J.C.)
| | - Fei Yang
- The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, Department of Epidemiology and Health Statistics, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; (Y.Y.); (F.S.); (Y.L.); (X.Y.); (Y.T.)
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410017, China; (X.F.); (J.C.)
- Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang 421001, China
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9
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Yang Y, Gong P, Long X, Jiang Y, Ye M, Tao S, Su Y, Yang F, Tian L. Microcystin-LR Induces and Aggravates Colitis through NLRP3 Inflammasome-Mediated Pyroptosis in Mice. Toxins (Basel) 2023; 15:447. [PMID: 37505716 PMCID: PMC10467093 DOI: 10.3390/toxins15070447] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/13/2023] [Accepted: 06/27/2023] [Indexed: 07/29/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, lifelong gastrointestinal disease, characterized by periods of activity and remission. The etiology of IBD is closely related to environmental factors. Previous studies have shown that the cyanotoxin microcystin-LR (MC-LR) causes intestinal damage, even IBD. To explore MC-LR's effects and potential mechanisms on IBD occurrence and development, we used dextran-sulfate sodium gavage (DSS) and MC-LR together for the first time in mice. There were four groups of mice: (A) mice given PBS gavage (control, CT); (B) mice given 3% DSS gavage (DSS); (C) mice given 200 µg/kg MC-LR gavage (MC-LR); and (D) mice given 3% DSS + 200 µg/kg MC-LR gavage (DSS + MC-LR). Compared with the CT group, the MC-LR group and the DSS group demonstrated more severe colitis results, which presented as higher weight loss, an increased Disease Activity Index (DAI) score, shorter colon length, a higher degree of tissue structural damage, more apoptotic cells, and greater pro-inflammatory cytokines. Similarly, the DSS + MC-LR group showed more severe colitis compared with the DSS group. Subsequent experiments confirmed that MC-LR or DSS increased the expression of pyroptosis-related proteins mediated by the nucleotide-binding domain-like receptor protein 3 (NLRP3). Likewise, compared with the DSS group, the DSS + MC-LR group expressed these proteins at a higher level. In conclusion, our research is the first to show that MC-LR may induce colitis, and even IBD, through NLRP3 inflammasome-mediated pyroptosis, and it could aggravate DSS-induced colitis in the same way.
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Affiliation(s)
- Yue Yang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 410078, China; (Y.Y.); (P.G.); (X.L.); (M.Y.); (S.T.)
| | - Pan Gong
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 410078, China; (Y.Y.); (P.G.); (X.L.); (M.Y.); (S.T.)
| | - Xiuyan Long
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 410078, China; (Y.Y.); (P.G.); (X.L.); (M.Y.); (S.T.)
| | - Yuanjuan Jiang
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, University of South China, Hengyang 421001, China;
| | - Mingmei Ye
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 410078, China; (Y.Y.); (P.G.); (X.L.); (M.Y.); (S.T.)
| | - Sifan Tao
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 410078, China; (Y.Y.); (P.G.); (X.L.); (M.Y.); (S.T.)
| | - Yahui Su
- Xiangya School of Medicine, Central South University, 172 Tongzipo Road, Changsha 410078, China;
| | - Fei Yang
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, University of South China, Hengyang 421001, China;
- Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang 421001, China
| | - Li Tian
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 410078, China; (Y.Y.); (P.G.); (X.L.); (M.Y.); (S.T.)
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10
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Niture S, Gadi S, Qi Q, Rios-Colon L, Khatiwada S, Vandana, Fernando RA, Levine KE, Kumar D. Cyanotoxins Increase Cytotoxicity and Promote Nonalcoholic Fatty Liver Disease Progression by Enhancing Cell Steatosis. Toxins (Basel) 2023; 15:411. [PMID: 37505679 PMCID: PMC10467139 DOI: 10.3390/toxins15070411] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/12/2023] [Accepted: 06/21/2023] [Indexed: 07/29/2023] Open
Abstract
Freshwater prokaryotic cyanobacteria within harmful algal blooms produce cyanotoxins which are considered major pollutants in the aquatic system. Direct exposure to cyanotoxins through inhalation, skin contact, or ingestion of contaminated drinking water can target the liver and may cause hepatotoxicity. In the current study, we investigated the effect of low concentrations of cyanotoxins on cytotoxicity, inflammation, modulation of unfolded protein response (UPR), steatosis, and fibrosis signaling in human hepatocytes and liver cell models. Exposure to low concentrations of microcystin-LR (MC-LR), microcystin-RR (MC-RR), nodularin (NOD), and cylindrospermopsin (CYN) in human bipotent progenitor cell line HepaRG and hepatocellular carcinoma (HCC) cell lines HepG2 and SK-Hep1 resulted in increased cell toxicity. MC-LR, NOD, and CYN differentially regulated inflammatory signaling, activated UPR signaling and lipogenic gene expression, and induced cellular steatosis and fibrotic signaling in HCC cells. MC-LR, NOD, and CYN also regulated AKT/mTOR signaling and inhibited autophagy. Chronic exposure to MC-LR, NOD, and CYN upregulated the expression of lipogenic and fibrosis biomarkers. Moreover, RNA sequencing (RNA seq) data suggested that exposure of human hepatocytes, HepaRG, and HCC HepG2 cells to MC-LR and CYN modulated expression levels of several genes that regulate non-alcoholic fatty liver disease (NAFLD). Our data suggest that low concentrations of cyanotoxins can cause hepatotoxicity and cell steatosis and promote NAFLD progression.
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Affiliation(s)
- Suryakant Niture
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Sashi Gadi
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Qi Qi
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Leslimar Rios-Colon
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Sabin Khatiwada
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Vandana
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Reshan A. Fernando
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, NC 27707, USA
| | - Keith E. Levine
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, NC 27707, USA
| | - Deepak Kumar
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
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11
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Feng S, Cao M, Tang P, Deng S, Chen L, Tang Y, Zhu L, Chen X, Huang Z, Shen M, Yang F. Microcystins Exposure Associated with Blood Lipid Profiles and Dyslipidemia: A Cross-Sectional Study in Hunan Province, China. Toxins (Basel) 2023; 15:toxins15040293. [PMID: 37104231 PMCID: PMC10143012 DOI: 10.3390/toxins15040293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/01/2023] [Accepted: 04/05/2023] [Indexed: 04/28/2023] Open
Abstract
Increasing evidence from experimental research suggests that exposure to microcystins (MCs) may induce lipid metabolism disorder. However, population-based epidemiological studies of the association between MCs exposure and the risk of dyslipidemia are lacking. Therefore, we conducted a population-based cross-sectional study involving 720 participants in Hunan Province, China, and evaluated the effects of MCs on blood lipids. After adjusting the lipid related metals, we used binary logistic regression and multiple linear regression models to examine the associations among serum MCs concentration, the risk of dyslipidemia and blood lipids (triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)). Moreover, the additive model was used to explore the interaction effects on dyslipidemia between MCs and metals. Compared to the lowest quartile of MCs exposure, the risk of dyslipidemia [odds ratios (OR) = 2.27, 95% confidence interval (CI): 1.46, 3.53] and hyperTG (OR = 3.01, 95% CI: 1.79, 5.05) in the highest quartile was significantly increased, and showed dose-response relationships. MCs were positively associated with TG level (percent change, 9.43%; 95% CI: 3.53%, 15.67%) and negatively associated with HDL-C level (percent change, -3.53%; 95% CI: -5.70%, -2.10%). In addition, an additive antagonistic effect of MCs and Zn on dyslipidemia was also reported [relative excess risk due to interaction (RERI) = -1.81 (95% CI: -3.56, -0.05)], and the attributable proportion of the reduced risk of dyslipidemia due to the antagonism of these two exposures was 83% (95% CI: -1.66, -0.005). Our study first indicated that MCs exposure is an independent risk factor for dyslipidemia in a dose-response manner.
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Affiliation(s)
- Shuidong Feng
- Department of Epidemiology and Health Statistics, The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, School of Basic Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Mengyue Cao
- Department of Epidemiology and Health Statistics, The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, School of Basic Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Peng Tang
- Department of Epidemiology and Health Statistics, The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, School of Basic Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Shuxiang Deng
- Department of Epidemiology and Health Statistics, The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, School of Basic Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Limou Chen
- Department of Epidemiology and Health Statistics, The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, School of Basic Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Yan Tang
- Department of Epidemiology and Health Statistics, The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, School of Basic Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Lemei Zhu
- School of Public Health, Changsha Medical University, Changsha 410219, China
| | - Xiang Chen
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Clinical Research Center for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha 410008, China
- Furong Laboratory, Changsha 410008, China
| | - Zhijun Huang
- Furong Laboratory, Changsha 410008, China
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Minxue Shen
- Furong Laboratory, Changsha 410008, China
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Department of Social Medicine and Health Management, Central South University, Changsha 410000, China
| | - Fei Yang
- Department of Epidemiology and Health Statistics, The Key Laboratory of Typical Environmental Pollution and Health Hazards of Hunan Province, School of Basic Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Department of Social Medicine and Health Management, Central South University, Changsha 410000, China
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12
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Liu Y, Qi CL, Li DW, Li HY, Li RM, Yang WD. Microcystin-LR exposure interfered maintenance of colonic microenvironmental homeostasis in rat. Food Chem Toxicol 2023; 173:113611. [PMID: 36657700 DOI: 10.1016/j.fct.2023.113611] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/17/2023]
Abstract
Microcystin-leucine arginine (MCLR) is a phycotoxin produced by cyanobacteria. As a hepatotoxin, increasing evidence suggests that it has some negative effects on the mammal gastrointestinal tract, but further studies are warranted. In this study, we investigated the effects of MCLR on the intestinal epithelial microenvironment by oral administration of MCLR. As expected, MCLR at doses of 200 and 400 μg kg-1 bw showed hepatorenal toxicity in rats but without significant gastrointestinal symptoms. MCLR exposure decreased the thickness of the colonic epithelial mucus layer, and down-regulated the expression of main mucin protein (MUC2), cytoskeletal assembly-related genes (Arpc1a, Enah) and cytoskeletal stability-related genes (Ptk2, Prkca, Actn1, Pxn, Tln1, Cttn, Vcl) in colonic tissue to varying degrees, but did not affect the expression of cell connection-related genes including Zo1, Ocln, Cldn2 and Cdh1. In addition, MCLR exposure had a limited effect on gut bacterial diversity but clearly enriched specific bacteria. Prevotella, which plays a crucial role in balancing health and disease, was inhibited, whereas Muribaculaceae concerning the epithelial barrier, was promoted. Together, our findings demonstrate that MCLR exposure can weaken the colonic epithelial barrier by interfering with the stability of the cytoskeleton, which in turn exacerbates the homeostasis maintenance in the intestinal microenvironment.
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Affiliation(s)
- Yang Liu
- Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, China; Key Laboratory of Aquatic Eutrophication and Control of Harmful Algal Blooms of Guangdong Higher Education Institute, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Chun-Li Qi
- Institution of Laboratory Animal, Jinan University, Guangzhou, China
| | - Da-Wei Li
- Key Laboratory of Aquatic Eutrophication and Control of Harmful Algal Blooms of Guangdong Higher Education Institute, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Hong-Ye Li
- Key Laboratory of Aquatic Eutrophication and Control of Harmful Algal Blooms of Guangdong Higher Education Institute, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Rui-Man Li
- Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
| | - Wei-Dong Yang
- Key Laboratory of Aquatic Eutrophication and Control of Harmful Algal Blooms of Guangdong Higher Education Institute, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
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13
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Liu X, Ye JC, Li F, Gao RJ, Wang XX, Cheng JL, Liu BL, Xiang L, Li YW, Cai QY, Zhao HM, Mo CH, Li QX. Revealing microcystin-LR ecotoxicity to earthworm (Eisenia fetida) at the intestinal cell level. CHEMOSPHERE 2023; 311:137046. [PMID: 36419272 DOI: 10.1016/j.chemosphere.2022.137046] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 06/16/2023]
Abstract
Potential adverse effects of microcystin-LR (MC-LR) on soil invertebrates have not been studied. Here we investigated the mechanism of MC-LR toxicity to earthworm (Eisenia fetida) intestine at the individual level and at the cellular level. The results showed an inverse relationship between the bodyweight and survival rate of earthworms over exposure time- and MC-LR doses in soil. Dose-dependent intestinal lesions and disturbances of enzymatic activities (e.g., cellulase, Na+/K+-ATPase, and AChE) were observed, which resulted in intestinal dysfunction. Excessive reactive oxygen species generation led to DNA damage and lipid peroxidation of intestinal cells. The oxidative damage to DNA prolonged cell cycle arrest at the G2/M-phase transition in mitosis, thus stimulating and accelerating apoptosis in earthworm intestine. MC-LR target earthworm intestine tissue. MC-LR at low concentrations can damage earthworm intestine regardless of exposure routes (oral or contact). High toxicity of MC-LR to earthworms delineates its ecological risks to terrestrial ecosystems.
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Affiliation(s)
- Xiang Liu
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Jin-Cheng Ye
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Fen Li
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Rong-Jun Gao
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Xiao-Xiao Wang
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Ji-Liang Cheng
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Bai-Lin Liu
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Lei Xiang
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Yan-Wen Li
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Quan-Ying Cai
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Hai-Ming Zhao
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; Guangdong Provincial Key Laboratory of Agricultural & Rural Pollution Abatement and Environmental Safety, Guangzhou, 510642, China.
| | - Ce-Hui Mo
- Guangdong Provincial Research Center for Environment Pollution Control and Remediation Materials, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
| | - Qing X Li
- Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI, 96822, USA
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14
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Chu H, Du C, Yang Y, Feng X, Zhu L, Chen J, Yang F. MC-LR Aggravates Liver Lipid Metabolism Disorders in Obese Mice Fed a High-Fat Diet via PI3K/AKT/mTOR/SREBP1 Signaling Pathway. Toxins (Basel) 2022; 14:toxins14120833. [PMID: 36548730 PMCID: PMC9784346 DOI: 10.3390/toxins14120833] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/10/2022] [Accepted: 11/18/2022] [Indexed: 12/05/2022] Open
Abstract
Obesity, a metabolic disease caused by excessive fat accumulation in the body, has attracted worldwide attention. Microcystin-LR (MC-LR) is a hepatotoxic cyanotoxin which has been reportedly to cause lipid metabolism disorder. In this study, C57BL/6J mice were fed a high-fat diet (HFD) for eight weeks to build obese an animal model, and subsequently, the obese mice were fed MC-LR for another eight weeks, and we aimed to determine how MC-LR exposure affects the liver lipid metabolism in high-fat-diet-induced obese mice. The results show that MC-LR increased the obese mice serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), indicating damaged liver function. The lipid parameters include serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and liver TG, which were all increased, whilst the high-density lipoprotein cholesterol (HDL-c) was decreased. Furthermore, after MC-LR treatment, histopathological observation revealed that the number of red lipid droplets increased, and that steatosis was more severe in the obese mice. In addition, the lipid synthesis-related genes were increased and the fatty acid β-oxidation-related genes were decreased in the obese mice after MC-LR exposure. Meanwhile, the protein expression levels of phosphorylation phosphatidylinositol 3-kinase (p-PI3K), phosphorylation protein kinase B (p-AKT), phosphorylation mammalian target of rapamycin (p-mTOR), and sterol regulatory element binding protein 1c (SREBP1-c) were increased; similarly, the p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and SREBP1/β-actin were significantly up-regulated in obese mice after being exposed to MC-LR, and the activated PI3K/AKT/mTOR/SREBP1 signaling pathway. In addition, MC-LR exposure reduced the activity of superoxide dismutase (SOD) and increased the level of malondialdehyde (MDA) in the obese mice's serum. In summary, the MC-LR could aggravate the HFD-induced obese mice liver lipid metabolism disorder by activating the PI3K/AKT/mTOR/SREBP1 signaling pathway to hepatocytes, increasing the SREBP1-c-regulated key enzymes for lipid synthesis, and blocking fatty acid β-oxidation.
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Affiliation(s)
- Hanyu Chu
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, University of South China, Hengyang 421001, China
| | - Can Du
- Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Yue Yang
- Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Xiangling Feng
- Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Lemei Zhu
- School of Public Health, Changsha Medical University, Changsha 410219, China
| | - Jihua Chen
- Xiangya School of Public Health, Central South University, Changsha 410078, China
- Correspondence: (J.C.); (F.Y.)
| | - Fei Yang
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, University of South China, Hengyang 421001, China
- Xiangya School of Public Health, Central South University, Changsha 410078, China
- The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province, Department of Education, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
- Correspondence: (J.C.); (F.Y.)
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15
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Gu S, Jiang M, Zhang B. Microcystin-LR in Primary Liver Cancers: An Overview. Toxins (Basel) 2022; 14:toxins14100715. [PMID: 36287983 PMCID: PMC9611980 DOI: 10.3390/toxins14100715] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/29/2022] [Accepted: 10/17/2022] [Indexed: 12/01/2022] Open
Abstract
The cyanobacterial blooms produced by eutrophic water bodies have become a serious environmental issue around the world. After cellular lysing or algaecide treatment, microcystins (MCs), which are regarded as the most frequently encountered cyanobacterial toxins in fresh water, are released into water. Among all the variants of MCs, MC-LR has been widely studied due to its severe hepatotoxicity. Since 1992, various studies have identified the important roles of MC-LR in the origin and progression of primary liver cancers (PLCs), although few reviews have focused on it. Therefore, this review aims to summarize the major achievements and shortcomings observed in the past few years. Based on the available literature, the mechanisms of how MC-LR induces or promotes PLCs are elucidated in this review. This review aims to enhance our understanding of the role that MC-LR plays in PLCs and provides a rational approach for future applications.
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Affiliation(s)
- Shen Gu
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
- Translational Medicine Research Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
- Correspondence: ; Tel.: +86-0571-56007664
| | - Mingxuemei Jiang
- Institute of Scientific and Technical Information of Zhejiang Province, Hangzhou 310001, China
| | - Bo Zhang
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
- Translational Medicine Research Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
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16
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Lad A, Hunyadi J, Connolly J, Breidenbach JD, Khalaf FK, Dube P, Zhang S, Kleinhenz AL, Baliu-Rodriguez D, Isailovic D, Hinds TD, Gatto-Weis C, Stanoszek LM, Blomquist TM, Malhotra D, Haller ST, Kennedy DJ. Antioxidant Therapy Significantly Attenuates Hepatotoxicity following Low Dose Exposure to Microcystin-LR in a Murine Model of Diet-Induced Non-Alcoholic Fatty Liver Disease. Antioxidants (Basel) 2022; 11:1625. [PMID: 36009344 PMCID: PMC9404967 DOI: 10.3390/antiox11081625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/13/2022] [Accepted: 08/17/2022] [Indexed: 12/15/2022] Open
Abstract
We have previously shown in a murine model of Non-alcoholic Fatty Liver Disease (NAFLD) that chronic, low-dose exposure to the Harmful Algal Bloom cyanotoxin microcystin-LR (MC-LR), resulted in significant hepatotoxicity including micro-vesicular lipid accumulation, impaired toxin metabolism as well as dysregulation of the key signaling pathways involved in inflammation, immune response and oxidative stress. On this background we hypothesized that augmentation of hepatic drug metabolism pathways with targeted antioxidant therapies would improve MC-LR metabolism and reduce hepatic injury in NAFLD mice exposed to MC-LR. We chose N-acetylcysteine (NAC, 40 mM), a known antioxidant that augments the glutathione detoxification pathway and a novel peptide (pNaKtide, 25 mg/kg) which is targeted to interrupting a specific Src-kinase mediated pro-oxidant amplification mechanism. Histological analysis showed significant increase in hepatic inflammation in NAFLD mice exposed to MC-LR which was attenuated on treatment with both NAC and pNaKtide (both p ≤ 0.05). Oxidative stress, as measured by 8-OHDG levels in urine and protein carbonylation in liver sections, was also significantly downregulated upon treatment with both antioxidants after MC-LR exposure. Genetic analysis of key drug transporters including Abcb1a, Phase I enzyme-Cyp3a11 and Phase II metabolic enzymes-Pkm (Pyruvate kinase, muscle), Pklr (Pyruvate kinase, liver, and red blood cell) and Gad1 (Glutamic acid decarboxylase) was significantly altered by MC-LR exposure as compared to the non-exposed control group (all p ≤ 0.05). These changes were significantly attenuated with both pNaKtide and NAC treatment. These results suggest that MC-LR metabolism and detoxification is significantly impaired in the setting of NAFLD, and that these pathways can potentially be reversed with targeted antioxidant treatment.
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Affiliation(s)
- Apurva Lad
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Jonathan Hunyadi
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Jacob Connolly
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | | | - Fatimah K. Khalaf
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
- Department of Clinical Pharmacy, University of Alkafeel, Najaf 54001, Iraq
| | - Prabhatchandra Dube
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Shungang Zhang
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Andrew L. Kleinhenz
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - David Baliu-Rodriguez
- Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA
| | - Dragan Isailovic
- Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA
| | - Terry D. Hinds
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40506, USA
| | - Cara Gatto-Weis
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Lauren M. Stanoszek
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Thomas M. Blomquist
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Deepak Malhotra
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Steven T. Haller
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - David J. Kennedy
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
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Du C, Zheng S, Yang Y, Feng X, Chen J, Tang Y, Wang H, Yang F. Chronic exposure to low concentration of MC-LR caused hepatic lipid metabolism disorder. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 239:113649. [PMID: 35605325 DOI: 10.1016/j.ecoenv.2022.113649] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 05/01/2022] [Accepted: 05/11/2022] [Indexed: 06/15/2023]
Abstract
Microcystin-LR (MC-LR), a potent hepatotoxin can cause liver damages. However, research on hepatic lipid metabolism caused by long-term exposure to environmental concentrations MC-LR is limited. In the current study, mice were exposed to various low concentrations of MC-LR (0, 1, 30, 60, 90, 120 μg/L in the drinking water) for 9 months. The general parameters, serum and liver lipids, liver tissue pathology, lipid metabolism-related genes and proteins of liver were investigated. The results show that chronic MC-LR exposure had increased the levels of triglyceride (TG) and total cholesterol (TC) in serum and liver. In addition, histological observation revealed that hepatic lobules were disordered with obvious inflammatory cell infiltration and lipid droplets. More importantly, the mRNA and proteins expression levels of lipid synthesis-related nuclear sterol regulatory element binding protein-1c (nSREBP-1c), SREBP-1c, cluster of differentiation 36 (CD36), acetyl-CoA-carboxylase1 (ACC1), stearoyl-CoA desaturase1 (SCD1) and fatty acid synthase (FASN) were increased in MC-LR treated groups, the expression levels of fatty acids β-oxidation related genes peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) was decreased after exposure to 60-120 μg/L MC-LR. Furthermore, the inflammatory factors interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were higher than that in the control group. All the findings indicated that mice were exposed to chronic low concentrations MC-LR caused liver inflammation and hepatic lipid metabolism disorder .
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Affiliation(s)
- Can Du
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Shuilin Zheng
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Yue Yang
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Xiangling Feng
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Jihua Chen
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Yan Tang
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, University of South China, Hengyang 421001, China
| | - Hui Wang
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, University of South China, Hengyang 421001, China
| | - Fei Yang
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, China; Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, University of South China, Hengyang 421001, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China.
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Lad A, Breidenbach JD, Su RC, Murray J, Kuang R, Mascarenhas A, Najjar J, Patel S, Hegde P, Youssef M, Breuler J, Kleinhenz AL, Ault AP, Westrick JA, Modyanov NN, Kennedy DJ, Haller ST. As We Drink and Breathe: Adverse Health Effects of Microcystins and Other Harmful Algal Bloom Toxins in the Liver, Gut, Lungs and Beyond. Life (Basel) 2022; 12:life12030418. [PMID: 35330169 PMCID: PMC8950847 DOI: 10.3390/life12030418] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 03/03/2022] [Accepted: 03/08/2022] [Indexed: 12/19/2022] Open
Abstract
Freshwater harmful algal blooms (HABs) are increasing in number and severity worldwide. These HABs are chiefly composed of one or more species of cyanobacteria, also known as blue-green algae, such as Microcystis and Anabaena. Numerous HAB cyanobacterial species produce toxins (e.g., microcystin and anatoxin—collectively referred to as HAB toxins) that disrupt ecosystems, impact water and air quality, and deter recreation because they are harmful to both human and animal health. Exposure to these toxins can occur through ingestion, inhalation, or skin contact. Acute health effects of HAB toxins have been well documented and include symptoms such as nausea, vomiting, abdominal pain and diarrhea, headache, fever, and skin rashes. While these adverse effects typically increase with amount, duration, and frequency of exposure, susceptibility to HAB toxins may also be increased by the presence of comorbidities. The emerging science on potential long-term or chronic effects of HAB toxins with a particular emphasis on microcystins, especially in vulnerable populations such as those with pre-existing liver or gastrointestinal disease, is summarized herein. This review suggests additional research is needed to define at-risk populations who may be helped by preventative measures. Furthermore, studies are required to develop a mechanistic understanding of chronic, low-dose exposure to HAB toxins so that appropriate preventative, diagnostic, and therapeutic strategies can be created in a targeted fashion.
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Affiliation(s)
- Apurva Lad
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - Joshua D. Breidenbach
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - Robin C. Su
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - Jordan Murray
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - Rebecca Kuang
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - Alison Mascarenhas
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - John Najjar
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - Shivani Patel
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - Prajwal Hegde
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - Mirella Youssef
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - Jason Breuler
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - Andrew L. Kleinhenz
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - Andrew P. Ault
- Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Judy A. Westrick
- Lumigen Instrumentation Center, Department of Chemistry, Wayne State University, Detroit, MI 48202, USA;
| | - Nikolai N. Modyanov
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
| | - David J. Kennedy
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
- Correspondence: (D.J.K.); (S.T.H.); Tel.: +1-419-383-6822 (D.J.K.); +1-419-383-6859 (S.T.H.)
| | - Steven T. Haller
- College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA; (A.L.); (J.D.B.); (R.C.S.); (J.M.); (R.K.); (A.M.); (J.N.); (S.P.); (P.H.); (M.Y.); (J.B.); (A.L.K.); (N.N.M.)
- Correspondence: (D.J.K.); (S.T.H.); Tel.: +1-419-383-6822 (D.J.K.); +1-419-383-6859 (S.T.H.)
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Lin W, Guo H, Yang L, Kuang Y, Li D, Yang P, Li L. Alleviation of microcystin-LR-induced hepatic lipidosis and apoptosis in zebrafish by use of rice straw-derived biochar. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 229:113054. [PMID: 34894426 DOI: 10.1016/j.ecoenv.2021.113054] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 11/23/2021] [Accepted: 12/01/2021] [Indexed: 06/14/2023]
Abstract
Microcystin-LR (MC-LR), mainly released by Microcystis aeruginosa, is posing a tremendous risk to aquatic animals and human health. Meanwhile, biochar (BC) is gradually be used as a sustainable adsorbent to immobilize and remove water pollutants. In our study, we for the first time conducted a full-scale investigation on lipid metabolism and its regulation mechanism of female zebrafish (Danio rerio) exposed to 0, 10 μg/L MC-LR, 100 μg/L BC, and 10 μg/L MC-LR+ 100 μg/L BC. The results indicated that sub-chronic MC-LR exposure induced hepatic lipidosis and apoptosis, including the formation of lipid droplets, significantly elevation of hepatic triglyceride (TG) level as well as significant upregulated expression of lipogenesis-related genes (foxo1a, elovl5, pparγ) and pro-apoptotic genes (bax, casp3). Nevertheless, no significant alteration was observed in the single BC group and the combined exposure group, which indicated that BC may solely functioned as an absorbent agent to lower MC-LR bioaccumulation in zebrafish liver and alleviate MC-LR-induced hepatotoxicity. Our findings revealed that the utilization of rice straw-derived BC can adsorb and immobile MC-LR in the water, subsequently alleviated the MC-LR-induced hepatic lipidosis and apoptosis in female zebrafish. On the basis of fish health, it is urgent to explore the feasibility of using environmentally friendly materials like BC to adsorb pollutants in water.
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Affiliation(s)
- Wang Lin
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; College of Life and Environmental Sciences, Hunan University of Arts and Science, Changde 415000, China
| | - Honghui Guo
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Liping Yang
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Yu Kuang
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Dapeng Li
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; Engineering Research Center of Green development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan 430070, China; Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan 430070, China
| | - Pinhong Yang
- College of Life and Environmental Sciences, Hunan University of Arts and Science, Changde 415000, China
| | - Li Li
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; Engineering Research Center of Green development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan 430070, China; Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan 430070, China.
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20
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Ahari H, Nowruzi B, Anvar AA, Porzani SJ. The Toxicity Testing of Cyanobacterial Toxins In Vivo and In Vitro by Mouse Bioassay: A Review. Mini Rev Med Chem 2021; 22:1131-1151. [PMID: 34720080 DOI: 10.2174/1389557521666211101162030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 07/26/2021] [Accepted: 08/21/2021] [Indexed: 11/22/2022]
Abstract
Different biological methods based on bioactivity are available to detect cyanotoxins, including neurotoxicity, immunological interactions, hepatotoxicity, cytotoxicity, and enzymatic activity. The mouse bioassay is the first test employed in laboratory cultures, cell extracts, and water bloom materials to detect toxins. It is also used as a traditional method to estimate the LD50. Concerning the ease of access and low cost, it is the most common method for this purpose. In this method, a sample is injected intraperitoneally into adult mice, and accordingly, they are assayed and monitored for about 24 hours for toxic symptoms. The toxin can be detected using this method from minutes to a few hours; its type, e.g., hepatotoxin, neurotoxin, etc., can also be determined. However, this method is nonspecific, fails to detect low amounts, and cannot distinguish between homologues. Although the mouse bioassay is gradually replaced with new chemical and immunological methods, it is still the main technique to detect the bioactivity and efficacy of cyanotoxins using LD50 determined based on the survival time of animals exposed to the toxin. In addition, some countries oppose animal use in toxicity studies. However, high cost, ethical considerations, low-sensitivity, non-specificity, and prolonged processes persuade researchers to employ chemical and functional analysis techniques. The qualitative and quantitative analyses, as well as high specificity and sensitivity, are among the advantages of cytotoxicity tests to investigate cyanotoxins. The present study aimed at reviewing the results obtained from in-vitro and in-vivo investigations of the mouse bioassay to detect cyanotoxins, including microcystins, cylindrospermopsin, saxitoxins, etc.
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Affiliation(s)
- Hamed Ahari
- Department of Food Science and Technology, Science and Research Branch, Islamic Azad University, Tehran. Iran
| | - Bahareh Nowruzi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran. Iran
| | - Amir Ali Anvar
- Department of Food Hygiene, Science and Research Branch, Islamic Azad University, Tehran. Iran
| | - Samaneh Jafari Porzani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran. Iran
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21
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Su RC, Breidenbach JD, Alganem K, Khalaf FK, French BW, Dube P, Malhotra D, McCullumsmith R, Presloid JB, Wooten RM, Kennedy DJ, Haller ST. Microcystin-LR (MC-LR) Triggers Inflammatory Responses in Macrophages. Int J Mol Sci 2021; 22:9939. [PMID: 34576099 PMCID: PMC8472269 DOI: 10.3390/ijms22189939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/31/2021] [Accepted: 09/08/2021] [Indexed: 12/16/2022] Open
Abstract
We were the first to previously report that microcystin-LR (MC-LR) has limited effects within the colons of healthy mice but has toxic effects within colons of mice with pre-existing inflammatory bowel disease. In the current investigation, we aimed to elucidate the mechanism by which MC-LR exacerbates colitis and to identify effective therapeutic targets. Through our current investigation, we report that there is a significantly greater recruitment of macrophages into colonic tissue with pre-existing colitis in the presence of MC-LR than in the absence of MC-LR. This is seen quantitatively through IHC staining and the enumeration of F4/80-positive macrophages and through gene expression analysis for Cd68, Cd11b, and Cd163. Exposure of isolated macrophages to MC-LR was found to directly upregulate macrophage activation markers Tnf and Il1b. Through a high-throughput, unbiased kinase activity profiling strategy, MC-LR-induced phosphorylation events were compared with potential inhibitors, and doramapimod was found to effectively prevent MC-LR-induced inflammatory responses in macrophages.
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Affiliation(s)
- Robin C. Su
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Joshua D. Breidenbach
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Khaled Alganem
- Department of Neuroscience, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (K.A.); (R.M.)
| | - Fatimah K. Khalaf
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Benjamin W. French
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Prabhatchandra Dube
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Deepak Malhotra
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Robert McCullumsmith
- Department of Neuroscience, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (K.A.); (R.M.)
- Neurosciences Center, Promedica, Toledo, OH 43614, USA
| | - John B. Presloid
- Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (J.B.P.); (R.M.W.)
| | - R. Mark Wooten
- Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (J.B.P.); (R.M.W.)
| | - David J. Kennedy
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
| | - Steven T. Haller
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; (R.C.S.); (J.D.B.); (F.K.K.); (B.W.F.); (P.D.); (D.M.)
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22
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Xiao W, Zhong Q, Sun F, Wang W, Zhao Z, Gu K. Differences in Abnormal Water Metabolism between SD Rats and KM Mice Intoxicated by Microcystin-RR. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:1900. [PMID: 33669356 PMCID: PMC7920292 DOI: 10.3390/ijerph18041900] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 01/17/2023]
Abstract
The effects of microcystin-RR (MC-RR) on water metabolism were studied on Sprague-Dawley (SD) rats and KunMing (KM) mice. In the single dose toxicity test, polydipsia, polyuria, hematuria and proteinuria were found in group of rats receiving a MC-RR dose of 574.7 μg/kg, and could be relieved by dexamethasone (DXM). Gradient damage was observed in kidney and liver in rats with gradient MC-RR doses of 574.7, 287.3, and 143.7 μg/kg. No significant water metabolic changes or kidney injuries were observed in mice treated with MC-RR doses of 210.0, 105.0, and 52.5 μg/kg. In the continuous exposure test, in which mice were administrated with 140.0, 70.0, and 35.0 μg/kg MC-RR for 28 days, mice in the 140.0 μg/kg group presented increasing polydipsia, polyuria, and liver damage. However, no anatomic or histological changes, including related serological and urinary indices, were found in the kidney. In summary, abnormal water metabolism can be induced by MC-RR in rats through kidney injury in single dose exposure; the kidney of SD rats is more sensitive to MC-RR than that of KM mouse; and polydipsia and polyuria in mice exposed to MC-RR for 28 days occurred but could not be attributed to kidney damage.
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Affiliation(s)
| | | | | | | | | | - Kangding Gu
- MOE Key Lab of Environment and Health, Institute of Environmental Medicine, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (W.X.); (Q.Z.); (F.S.); (W.W.); (Z.Z.)
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Chernoff N, Hill D, Lang J, Schmid J, Farthing A, Huang H. Dose-Response Study of Microcystin Congeners MCLA, MCLR, MCLY, MCRR, and MCYR Administered Orally to Mice. Toxins (Basel) 2021; 13:86. [PMID: 33498948 PMCID: PMC7911753 DOI: 10.3390/toxins13020086] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 01/25/2023] Open
Abstract
Microcystins are common freshwater cyanobacterial toxins that affect liver function. The toxicities of five microcystin congeners (microcystin-LA (MCLA), MCLR, MCLY, MCRR, and MCYR) commonly observed in harmful algal blooms (HABs) were evaluated in BALB/c mice after a single oral administration of doses ranging from those that were no observed adverse effect levels (NOAELs) to lowest observed adverse effect levels (LOAELs). Animals were monitored for changes in behavior and appearance, and euthanized 24 h after dosing. Test endpoints included clinical changes, necropsy observations, and serum indicators of hepatic toxicity and general homeostasis. Doses were 0.5-7 mg/kg MCLA, 0.5-11 mg/kg MCLR, 1-7 mg/kg MCLY, 7-22 mg/kg MCRR, and 3-11 mg/kg MCYR. MCLA at 3 mg/kg elevated liver/body weight ratio and liver score, ALT, AST, and GLDH, indicating hepatic toxicity, reduced serum glucose and highly elevated total serum bilirubin. MCLR and MCLY induced similar effects with LOAELs of 5 mg/kg, although a greater extent and severity of effects were observed in MCLR animals. MCRR exposure at 22 mg/kg was associated with reduced serum glucose. MCYR induced scattered liver effects at 7 mg/kg and reduced serum glucose levels at 5 mg/kg. The results indicate significant differences in congener-induced toxicity after microcystin exposure.
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Affiliation(s)
- Neil Chernoff
- Center for Public Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA; (D.H.); (J.S.)
| | - Donna Hill
- Center for Public Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA; (D.H.); (J.S.)
| | - Johnsie Lang
- Oak Ridge Institute for Science and Education, Oak Ridge, TN 37831, USA; (J.L.); (A.F.); (H.H.)
| | - Judith Schmid
- Center for Public Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA; (D.H.); (J.S.)
| | - Amy Farthing
- Oak Ridge Institute for Science and Education, Oak Ridge, TN 37831, USA; (J.L.); (A.F.); (H.H.)
| | - Hwa Huang
- Oak Ridge Institute for Science and Education, Oak Ridge, TN 37831, USA; (J.L.); (A.F.); (H.H.)
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24
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Sarkar S, Saha P, Seth RK, Mondal A, Bose D, Kimono D, Albadrani M, Mukherjee A, Porter DE, Scott GI, Xiao S, Brooks B, Ferry J, Nagarkatti M, Nagarkatti P, Chatterjee S. Higher intestinal and circulatory lactate associated NOX2 activation leads to an ectopic fibrotic pathology following microcystin co-exposure in murine fatty liver disease. Comp Biochem Physiol C Toxicol Pharmacol 2020; 238:108854. [PMID: 32781293 PMCID: PMC7541568 DOI: 10.1016/j.cbpc.2020.108854] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 06/14/2020] [Accepted: 07/03/2020] [Indexed: 12/11/2022]
Abstract
Clinical studies implicated an increased risk of intestinal fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Our previous studies have shown that microcystin-LR (MC-LR) exposure led to altered gut microbiome and increased abundance of lactate producing bacteria and intestinal inflammation in underlying NAFLD. This led us to further investigate the effects of the MC-LR, a PP2A inhibitor in activating the TGF-β fibrotic pathway in the intestines that might be mediated by increased lactate induced redox enzyme NOX2. Exposure to MC-LR led to higher lactate levels in circulation and in the intestinal content. The higher lactate levels were associated with NOX2 activation in vivo that led to increased Smad2/3-Smad4 co-localization and high alpha-smooth muscle actin (α-SMA) immunoreactivity in the intestines. Mechanistically, primary mouse intestinal epithelial cells treated with lactate and MC-LR separately led to higher NOX2 activation, phosphorylation of TGFβR1 receptor and subsequent Smad 2/3-Smad4 co-localization inhibitable by apocynin (NOX2 inhibitor), FBA (a peroxynitrite scavenger) and DMPO (a nitrone spin trap), catalase and superoxide dismutase. Inhibition of NOX2-induced redox signaling also showed a significant decrease in collagen protein thus suggesting a strong redox signaling induced activation of an ectopic fibrotic manifestation in the intestines. In conclusion, the present study provides mechanistic insight into the role of microcystin in dysbiosis-linked lactate production and subsequently advances our knowledge in lactate-induced NOX2 exacerbation of the cell differentiation and fibrosis in the NAFLD intestines.
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Affiliation(s)
- Sutapa Sarkar
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, USA
| | - Punnag Saha
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, USA
| | - Ratanesh K Seth
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, USA
| | - Ayan Mondal
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, USA
| | - Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, USA
| | - Diana Kimono
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, USA
| | - Muayad Albadrani
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, USA
| | | | - Dwayne E Porter
- NIEHS Center for Oceans and Human Health on Climate Change Interactions, Department of Environmental Health Sciences, University of South Carolina, USA
| | - Geoff I Scott
- NIEHS Center for Oceans and Human Health on Climate Change Interactions, Department of Environmental Health Sciences, University of South Carolina, USA
| | - Shuo Xiao
- NIEHS Center for Oceans and Human Health on Climate Change Interactions, Department of Environmental Health Sciences, University of South Carolina, USA
| | - Bryan Brooks
- Department of Environmental Science, Baylor University, USA
| | - John Ferry
- Department of Chemistry and Biochemistry, University of South Carolina, USA
| | - Mitzi Nagarkatti
- Pathology, Microbiology and Immunology(,) University of South Carolina School of Medicine, USA
| | - Prakash Nagarkatti
- Pathology, Microbiology and Immunology(,) University of South Carolina School of Medicine, USA
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, USA.
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25
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Sedan D, Malaissi L, Vaccarini CA, Ventosi E, Laguens M, Rosso L, Giannuzzi L, Andrinolo D. [D-Leu 1]MC-LR Has Lower PP1 Inhibitory Capability and Greater Toxic Potency than MC-LR in Animal and Plant Tissues. Toxins (Basel) 2020; 12:toxins12100632. [PMID: 33019556 PMCID: PMC7600089 DOI: 10.3390/toxins12100632] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/15/2020] [Accepted: 09/21/2020] [Indexed: 01/04/2023] Open
Abstract
Two microcystins, MC-LR and [D-Leu1]MC-LR, present in La Plata Basin blooms, are differentiated by substitution of D-Alanine for D-Leucine at position 1. Our objective was to evaluate acute toxicity of [D-Leu1]MC-LR and MC-LR in mice (N:NIH Swiss) and beans (Phaseolus vulgaris). We observed variations in [D-Leu1]MC-LR lethal doses with respect to those reported for MC-LR (100 μg/kg), with an increased liver/body weight ratio and intrahepatic hemorrhages in mice exposed to 50–200 μg [D-Leu1]MC-LR/kg and slight steatosis after a single 25 μg [D-Leu1]MC-LR/kg i.p. dose. Our study in the plant model showed alterations in germination, development, morphology and TBARs levels after a single contact with the toxins during imbibition (3.5 and 15 µg/mL), those treated with [D-Leu1]MC-LR being more affected than those treated with the same concentration of MC-LR. Protein phosphatase 1 (PP1) IC50 values were 40.6 nM and 5.3 nM for [D-Leu1]MC-LR and MC-LR, respectively. However, the total phosphatase activity test in root homogenate showed 60% inhibition for [D-Leu1]MC-LR and 12% for MC-LR. In mouse liver homogenate, 50% inhibition was observed for [D-Leu1]MC-LR and 40% for MC-LR. Our findings indicate the need for further research into [D-Leu1]MC-LR toxicity since together with oxidative stress, the possible inhibition of other phosphatases could explain the differences detected in the potency of the two toxins.
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Affiliation(s)
- Daniela Sedan
- Center for Environmental Research (CIM), National Council for Scientific and Technical Research (CONICET), National University of La Plata (UNLP), La Plata 1900, Argentina
- Area of Toxicology, School of Exact Sciences, National University of La Plata (UNLP), La Plata 1900, Argentina
| | - Luciano Malaissi
- Center for Environmental Research (CIM), National Council for Scientific and Technical Research (CONICET), National University of La Plata (UNLP), La Plata 1900, Argentina
- Area of Toxicology, School of Exact Sciences, National University of La Plata (UNLP), La Plata 1900, Argentina
| | - Cristian Adrián Vaccarini
- Center for Environmental Research (CIM), National Council for Scientific and Technical Research (CONICET), National University of La Plata (UNLP), La Plata 1900, Argentina
- Area of Toxicology, School of Exact Sciences, National University of La Plata (UNLP), La Plata 1900, Argentina
| | - Ezequiel Ventosi
- Area of Toxicology, School of Exact Sciences, National University of La Plata (UNLP), La Plata 1900, Argentina
| | - Martín Laguens
- Pathology B Cathedra, School of Medical Sciences, National University of La Plata (UNLP), La Plata 1900, Argentina
| | - Lorena Rosso
- Area of Toxicology, School of Exact Sciences, National University of La Plata (UNLP), La Plata 1900, Argentina
| | - Leda Giannuzzi
- Research Center in Food Cryotechnology (CIDCA), National Council for Scientific and Technical Research (CONICET), La Plata 1900, Argentina
| | - Darío Andrinolo
- Center for Environmental Research (CIM), National Council for Scientific and Technical Research (CONICET), National University of La Plata (UNLP), La Plata 1900, Argentina
- Area of Toxicology, School of Exact Sciences, National University of La Plata (UNLP), La Plata 1900, Argentina
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26
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Su RC, Lad A, Breidenbach JD, Kleinhenz AL, Modyanov N, Malhotra D, Haller ST, Kennedy DJ. Assessment of diagnostic biomarkers of liver injury in the setting of microcystin-LR (MC-LR) hepatotoxicity. CHEMOSPHERE 2020; 257:127111. [PMID: 32485513 DOI: 10.1016/j.chemosphere.2020.127111] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/11/2020] [Accepted: 05/16/2020] [Indexed: 06/11/2023]
Abstract
Microcystin-leucine arginine (MC-LR) is a potent liver toxin produced by freshwater cyanobacteria, also known as blue-green algae. While harmful algal blooms are increasing in frequency and severity worldwide, there is still no established method for the diagnosis and assessment of MC-LR induced liver damage. The guidelines for MC-LR safe exposure limits have been previously established based on healthy animal studies, however we have previously demonstrated that pre-existing non-alcoholic fatty liver disease (NAFLD) increases susceptiblity to the hepatotoxic effects of MC-LR. In this study, we sought to investigate the suitability of clinically used biomarkers of liver injury, specifically alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as potential diagnostic tools for liver damage induced by chronic low dose administration of MC-LR in the setting of pre-existing NAFLD. In our Leprdb/J mouse model of NAFLD, we found that while MC-LR induced significant histopathologic damage in the setting of NAFLD, gene expression of ALT and ALP failed to increase with MC-LR exposure. Serum ALT and ALP also failed to increase with MC-LR exposure, except for a moderate increase in ALP with the highest dose of MC-LR used (100 μg/kg). In HepG2 human liver epithelial cells, we observed that increasing MC-LR exposure levels do not lead to an increase in ALT or ALP gene expression, intracellular enzyme activity, or extracellular activity, despite a significant increase in MC-LR induced cytotoxicity. These findings demonstrate that ALT and ALP may be unsuitable as diagnostic biomarkers for MC-LR induced liver damage.
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Affiliation(s)
- Robin C Su
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - Apurva Lad
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - Joshua D Breidenbach
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - Andrew L Kleinhenz
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - Nikolai Modyanov
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - Deepak Malhotra
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - Steven T Haller
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - David J Kennedy
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
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27
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[D-Leu 1]MC-LR and MC-LR: A Small-Large Difference: Significantly Different Effects on Phaseolus vulgaris L. (Fabaceae) Growth and Phototropic Response after Single Contact during Imbibition with Each of These Microcystin Variants. Toxins (Basel) 2020; 12:toxins12090585. [PMID: 32932764 PMCID: PMC7551030 DOI: 10.3390/toxins12090585] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 11/16/2022] Open
Abstract
[D-Leu1]MC-LR and MC-LR, two microcystins differing in one amino acid, constitute a sanitary and environmental problem owing to their frequent and concomitant presence in water bodies of the Americas and their association with human intoxication during recreational exposure to cyanobacterial bloom. Present in reservoirs used for irrigation as well, they can generate problems in the development of crops such as Phaseolus vulgaris, of nutritional and economic interest to the region. Although numerous works address the toxic effects of MC-LR, information on the toxicity of [D-Leu1]MC-LR is limited. Our objective was to study the toxic effects of [D-Leu1]MC-LR and MC-LR (3.5 µg/ml) on P. vulgaris after a single contact at the imbibition stage. Our findings indicate that 10 days post treatment, [D-Leu1]MC-LR generates morphological and physiological alterations more pronounced than those caused by MC-LR. In addition to the alterations produced by [D-Leu1]MC-LR in the development of seedlings and the structure of the leaves, roots and stems, we also found alterations in leaf stomatal density and conductivity, a longer delay in the phototropic response and a decrease in the maximum curvature angles achieved with respect to that observed for MC-LR. Our findings indicate that these alterations are linked to the greater inhibition of phosphatase activity generated by [D-Leu1]MC-LR, rather than to oxidative damage. We observed that 30 days after treatment with MC-LR, plants presented better development and recovery than those treated with [D-Leu1]MC-LR. Further studies are required on [D-Leu1]MC-LR and MC-LR toxicity and their underlying mechanisms of action.
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28
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Wang R, Liu X, Wu J, Liu H, Wang W, Chen X, Yuan L, Wang Y, Du X, Ma Y, Losiewicz MD, Zhang X, Zhang H. Role of microRNA-122 in microcystin-leucine arginine-induced dysregulation of hepatic iron homeostasis in mice. ENVIRONMENTAL TOXICOLOGY 2020; 35:822-830. [PMID: 32170997 DOI: 10.1002/tox.22918] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 02/27/2020] [Accepted: 03/01/2020] [Indexed: 06/10/2023]
Abstract
Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide hepatotoxin produced by cyanobacteria. MicroRNA-122 (miR-122) is specifically expressed in the liver. This study focuses on the role of miR-122 in MC-LR-induced dysregulation of hepatic iron homeostasis in C57BL/6 mice. The thirty mice were randomly divided into five groups (Control, 12.5 μg/kg·BW MC-LR, 25 μg/kg·BW MC-LR, Negative control agomir and 25 μg/kg·BW MC-LR + miR-122 agomir). The results show that MC-LR decreases the expressions of miR-122, Hamp, and its related regulators, while increasing the content of hepatic iron and the expressions of FPN1 and Tmprss6. Furthermore, miR-122 agomir pretreatment improves MC-LR induced dysregulation of hepatic iron homeostasis by arousing the related regulators and reducing the expression of Tmprss6. These results suggest that miR-122 agomir can prevent the accumulation of hepatic iron induced by MC-LR, which may be related to the regulation of hepcidin by BMP/SMAD and IL-6/STAT signaling pathways.
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Affiliation(s)
- Rui Wang
- College of Public Health, Zhengzhou University, Zhengzhou, People's Republic of China
| | - Xiaohui Liu
- School of Basic Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, People's Republic of China
| | - Jinxia Wu
- College of Public Health, Zhengzhou University, Zhengzhou, People's Republic of China
| | - Haohao Liu
- College of Public Health, Zhengzhou University, Zhengzhou, People's Republic of China
| | - Wenjun Wang
- School of Public Health, Jining Medical University, Jining, People's Republic of China
| | - Xinghai Chen
- Department of Chemistry and Biochemistry, St Mary's University, San Antonio, Texas, USA
| | - Le Yuan
- College of Public Health, Zhengzhou University, Zhengzhou, People's Republic of China
| | - Yueqin Wang
- College of Public Health, Zhengzhou University, Zhengzhou, People's Republic of China
| | - Xingde Du
- College of Public Health, Zhengzhou University, Zhengzhou, People's Republic of China
| | - Ya Ma
- College of Public Health, Zhengzhou University, Zhengzhou, People's Republic of China
| | - Michael D Losiewicz
- Department of Chemistry and Biochemistry, St Mary's University, San Antonio, Texas, USA
| | - Xiaofeng Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, People's Republic of China
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, People's Republic of China
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29
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The Comparative Toxicity of 10 Microcystin Congeners Administered Orally to Mice: Clinical Effects and Organ Toxicity. Toxins (Basel) 2020; 12:toxins12060403. [PMID: 32570788 PMCID: PMC7354475 DOI: 10.3390/toxins12060403] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 06/16/2020] [Accepted: 06/16/2020] [Indexed: 12/16/2022] Open
Abstract
Microcystins (MCs) are common cyanobacterial toxins that occur in freshwaters worldwide. Only two of the >200 MC variants have been tested for potential toxicity after oral exposure. This paper reports on the toxicity of 10 different MC congeners identified in algal blooms, microcystin-LR (MCLR), MCLA, MCLF, MCLW, MCLY, MCRR, [Asp3]MCRR, [Asp3,Dhb7]MCRR, MCWR, and MCYR after single administrations to BALB/c mice. In a preliminary MCLR dose–response study of 3 to 9 mg/kg doses, ≥5 mg/kg induced clinical changes, increased serum levels of ALT, AST, and GLDH, liver congestion, increased liver/body weight ratios, and reduced serum glucose and total protein. Based on the extent of these effects, the 10 congeners were administered as single 7 mg/kg oral doses and toxicity evaluated. The greatest toxicity was observed with MCLA and MCLR including a high percentage of moribundity. In addition to eliciting effects similar to those listed above for MCLR, MCLA also induced serum alterations indicative of jaundice. MCLY, and MCYR induced changes like those noted with MCLR, but to lesser extents. MCLW and MCLF exhibited some serum and morphological changes associated with hepatic toxicity, while there were few indications of toxicity after exposures to MCRR, [Asp3]MCRR, [Asp3,Dhb7]MCRR, or MCWR. These data illustrate a wide spectrum of hepatic effects and different potencies of these MC congeners.
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30
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Su RC, Meyers CM, Warner EA, Garcia JA, Refsnider JM, Lad A, Breidenbach JD, Modyanov N, Malhotra D, Haller ST, Kennedy DJ. Harmful Algal Bloom Toxicity in Lithobates catesbeiana Tadpoles. Toxins (Basel) 2020; 12:toxins12060378. [PMID: 32521650 PMCID: PMC7354472 DOI: 10.3390/toxins12060378] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/23/2020] [Accepted: 06/03/2020] [Indexed: 11/16/2022] Open
Abstract
Harmful algal blooms (HAB) have become a major health concern worldwide, not just to humans that consume and recreate on contaminated waters, but also to the fauna that inhabit the environments surrounding affected areas. HABs contain heterotrophic bacteria, cyanobacterial lipopolysaccharide, and cyanobacterial toxins such as microcystins, that can cause severe toxicity in many aquatic species as well as bioaccumulation within various organs. Thus, the possibility of trophic transference of this toxin through the food chain has potentially important health implications for other organisms in the related food web. While some species have developed adaptions to attenuate the toxic effects of HAB toxins, there are still numerous species that remain vulnerable, including Lithobates catesbeiana (American bullfrog) tadpoles. In the current study we demonstrate that acute, short-term exposure of tadpoles to HAB toxins containing 1 µg/L (1 nmol/L) of total microcystins for only 7 days results in significant liver and intestinal toxicity within tadpoles. Exposed tadpoles had increased intestinal diameter, decreased intestinal fold heights, and a constant number of intestinal folds, indicating pathological intestinal distension, similar to what is seen in various disease processes, such as toxic megacolon. HAB-toxin-exposed tadpoles also demonstrated hepatocyte hypertrophy with increased hepatocyte binucleation consistent with carcinogenic and oxidative processes within the liver. Both livers and intestines of HAB-toxin-exposed tadpoles demonstrated significant increases in protein carbonylation consistent with oxidative stress and damage. These findings demonstrate that short-term exposure to HAB toxins, including microcystins, can have significant adverse effects in amphibian populations. This acute, short-term toxicity highlights the need to evaluate the influence HAB toxins may have on other vulnerable species within the food web and how those may ultimately also impact human health.
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Affiliation(s)
- Robin C. Su
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
| | - Casey M. Meyers
- Department of Biology, Wittenberg University, Springfield, OH 45504, USA;
| | - Emily A. Warner
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
| | - Jessica A. Garcia
- Department of Environmental Sciences, The University of Toledo, Toledo, OH 43606, USA; (J.A.G.); (J.M.R.)
| | - Jeanine M. Refsnider
- Department of Environmental Sciences, The University of Toledo, Toledo, OH 43606, USA; (J.A.G.); (J.M.R.)
| | - Apurva Lad
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
| | - Joshua D. Breidenbach
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
| | - Nikolai Modyanov
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA;
| | - Deepak Malhotra
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
| | - Steven T. Haller
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
- Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
- Correspondence: (S.T.H.); (D.J.K.); Tel.: +1-419-383-6822 (D.J.K. & S.T.H.)
| | - David J. Kennedy
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
- Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
- Correspondence: (S.T.H.); (D.J.K.); Tel.: +1-419-383-6822 (D.J.K. & S.T.H.)
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31
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CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis. Biomedicines 2020; 8:biomedicines8060149. [PMID: 32498446 PMCID: PMC7345682 DOI: 10.3390/biomedicines8060149] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/30/2020] [Accepted: 05/31/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory Bowel Disease (IBD) is one of the most common gastrointestinal (GI) disorders around the world, and includes diagnoses such as Crohn’s disease and ulcerative colitis. The etiology of IBD is influenced by genetic and environmental factors. One environmental perturbagen that is not well studied within the intestines is microcystin-leucine arginine (MC-LR), which is a toxin produced by cyanobacteria in freshwater environments around the world. We recently reported that MC-LR has limited effects within the intestines of healthy mice, yet interestingly has significant toxicity within the intestines of mice with pre-existing colitis induced by dextran sulfate sodium (DSS). MC-LR was found to prolong DSS-induced weight loss, prolong DSS-induced bloody stools, exacerbate DSS-induced colonic shortening, exacerbate DSS-induced colonic ulceration, and exacerbate DSS-induced inflammatory cytokine upregulation. In addition, we previously reported a significant increase in expression of the pro-inflammatory receptor CD40 in the colons of these mice, along with downstream products of CD40 activation, including plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1). In the current study, we demonstrate that knocking out CD40 attenuates the effects of MC-LR in mice with pre-existing colitis by decreasing the severity of weight loss, allowing a full recovery in bloody stools, preventing the exacerbation of colonic shortening, preventing the exacerbation of colonic ulceration, and preventing the upregulation of the pro-inflammatory and pro-fibrotic cytokines IL-1β, MCP-1, and PAI-1. We also demonstrate the promising efficacy of a CD40 receptor blocking peptide to ameliorate the effects of MC-LR exposure in a proof-of-concept study. Our findings suggest for the first time that MC-LR acts through a CD40-dependent mechanism to exacerbate colitis.
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Zhao Y, Yan Y, Xie L, Wang L, He Y, Wan X, Xue Q. Long-term environmental exposure to microcystins increases the risk of nonalcoholic fatty liver disease in humans: A combined fisher-based investigation and murine model study. ENVIRONMENT INTERNATIONAL 2020; 138:105648. [PMID: 32187572 DOI: 10.1016/j.envint.2020.105648] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 02/21/2020] [Accepted: 03/08/2020] [Indexed: 06/10/2023]
Abstract
Microcystins (MCs) produced by cyanobacteria pose serious threats to human health. However, the contribution of long-term exposure to MCs to the development of nonalcoholic fatty liver disease (NAFLD) remains poorly documented. In this study, we estimated the environmental uptake of MCs by a small population of fishers who have lived for many years on Meiliang Bay of Lake Taihu, where cyanobacterial blooms occur frequently. Serum biochemical indices of liver function and their relationships with MC contamination in these people were also investigated. Moreover, to mimic the long-term effects of MC on the livers of fishers, an animal model was established in which mice were exposed to MC-LR at an environmentally relevant level, a reference level (the no-observed adverse effect level, NOAEL), and three times the NOAEL through drinking water for 12 months. We estimated the total daily intake of MCs by fishers through contaminated lake water and food to be 5.95 μg MC-LReq, far exceeding the tolerable daily intake (2.40 μg MC-LReq) proposed by the World Health Organization (WHO). More than 80% of participants had at least one abnormal serum marker. The indices of aspartate aminotransferase (AST)/alanine aminotransferase (ALT), triglyceride (TG), globulin (GLB), and lactate dehydrogenase (LDH) had close positive associations with MC contamination, indicating that both liver damage and lipid metabolism dysfunction were induced by chronic MC exposure. Furthermore, the animal experimental results showed that long-term exposure to MC-LR at the environmentally relevant level led to hepatic steatosis with molecular alterations in circadian rhythm regulation, lipid metabolic processes, and the cell cycle pathway. Exposure to MC-LR at or above the NOAEL worsened the pathological phenotype towards nonalcoholic steatohepatitis disease (NASH) or fibrosis. These results suggest that prolonged exposure to the reference level (NOAEL) of MC-LR could cause severe liver injury to mammals. People with long-term environmental exposure to MCs might be at high risk for developing NAFLD.
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Affiliation(s)
- Yanyan Zhao
- State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China.
| | - Yunjun Yan
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China
| | - Liqiang Xie
- State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China
| | - Lixiao Wang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China
| | - Yaojia He
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China
| | - Xiang Wan
- State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China
| | - Qingju Xue
- State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China
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Protected Freshwater Ecosystem with Incessant Cyanobacterial Blooming Awaiting a Resolution. WATER 2019. [DOI: 10.3390/w12010129] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
For 50 years persistent cyanobacterial blooms have been observed in Lake Ludoš (Serbia), a wetland area of international significance listed as a Ramsar site. Cyanobacteria and cyanotoxins can affect many organisms, including valuable flora and fauna, such as rare and endangered bird species living or visiting the lake. The aim was to carry out monitoring, estimate the current status of the lake, and discuss potential resolutions. Results obtained showed: (a) the poor chemical state of the lake; (b) the presence of potentially toxic (genera Dolichospermum, Microcystis, Planktothrix, Chroococcus, Oscillatoria, Woronichinia and dominant species Limnothrix redekei and Pseudanabaena limnetica) and invasive cyanobacterial species Raphidiopsis raciborskii; (c) the detection of microcystin (MC) and saxitoxin (STX) coding genes in biomass samples; (d) the detection of several microcystin variants (MC-LR, MC-dmLR, MC-RR, MC-dmRR, MC-LF) in water samples; (e) histopathological alterations in fish liver, kidney and gills. The potential health risk to all organisms in the ecosystem and the ecosystem itself is thus still real and present. Although there is still no resolution in sight, urgent remediation measures are needed to alleviate the incessant cyanobacterial problem in Lake Ludoš to break this ecosystem out of the perpetual state of limbo in which it has been trapped for quite some time.
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Design, synthesis and evaluation of 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-Based fibrates as potential hypolipidemic and hepatoprotective agents. Bioorg Med Chem Lett 2019; 29:126723. [PMID: 31624042 DOI: 10.1016/j.bmcl.2019.126723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/25/2019] [Accepted: 09/27/2019] [Indexed: 11/21/2022]
Abstract
Six novel target compounds 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT) based fibrates were synthesized and evaluated. All the synthesized compounds were preliminarily screened by using the Triton WR-1339-induecd hyperlipidemia model, in which T1 exhibited more potent hypolipidemic property than positive drug fenofibrate (FF). T1 also significantly decreased serum triglycerides (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in methionine solution (Mets) induced hyperlipidemic mice. Moreover, hepatic transaminases (AST and ALT) were obviously ameliorated after treatment with T1 and the histological observation indicated that T1 ameliorated the injury in liver tissue and inhibited the hepatic lipid accumulation. In the livers of T1-administrated rat, the levels of PPARα related to lipids metabolism were up-regulated. Additional effects such as antioxidant, anti-inflammatory and H2S releasing action confirmed and reinforced the activity of T1 as a potential multifunctional hypolipidemic and hepatoprotective agent.
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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. Toxins (Basel) 2019; 11:toxins11090486. [PMID: 31450746 PMCID: PMC6783870 DOI: 10.3390/toxins11090486] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/15/2019] [Accepted: 08/19/2019] [Indexed: 12/17/2022] Open
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.
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Effects of Microcystin-LR on the Microstructure and Inflammation-Related Factors of Jejunum in Mice. Toxins (Basel) 2019; 11:toxins11090482. [PMID: 31438657 PMCID: PMC6783826 DOI: 10.3390/toxins11090482] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 08/12/2019] [Accepted: 08/17/2019] [Indexed: 12/16/2022] Open
Abstract
The increasing cyanobacterial blooms have recently been considered a severe environmental problem. Microcystin-leucine arginine (MC-LR) is one of the secondary products of cyanobacteria metabolism and most harmful cyanotoxins found in water bodies. Studies show MC-LR negatively affects various human organs when exposed to it. The phenotype of the jejunal chronic toxicity induced by MC-LR has not been well described. The aim of this paper was to investigate the effects of MC-LR on the jejunal microstructure and expression level of inflammatory-related factors in jejunum. Mice were treated with different doses (1, 30, 60, 90 and 120 μg/L) of MC-LR for six months. The microstructure and mRNA expression levels of inflammation-related factors in jejunum were analyzed. Results showed that the microstructure of the jejunum was destroyed and expression levels of inflammation-related factors interleukin (IL)-1β, interleukin (IL)-8, tumor necrosis factor alpha, transforming growth factor-β1 and interleukin (IL)-10 were altered at different MC-LR concentrations. To the best of our knowledge, this is the first study that mice were exposed to a high dose of MC-LR for six months. Our data demonstrated MC-LR had the potential to cause intestinal toxicity by destroying the microstructure of the jejunum and inducing an inflammatory response in mice, which provided new insight into understanding the prevention and diagnosis of the intestinal diseases caused by MC-LR.
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Garcia Y, Canfarotta F, Smolinska-Kempisty K, Piletsky SA, Pereira E. Competitive pseudo-ELISA based on molecularly imprinted nanoparticles for microcystin-LR detection in water. PURE APPL CHEM 2019. [DOI: 10.1515/pac-2018-1207] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Abstract
Microcystins (MCs) are dangerous cyanotoxins for the public health, and microcystin-LR (MC-LR) is one of most toxic, dangerous, and frequently found in water bodies. Typically, the detection of MCs is carried out by means of competitive ELISAs which, however, need special precautions for handling and storage, due to the stability of the antibodies used in this test. Molecularly imprinted nanoparticles (nanoMIPs) represents more robust and cost-effective alternative to antibodies. In this work, we developed a competitive pseudo-ELISA based on nanoMIPs (which are used in place of natural antibodies), for the detection of microcystin-LR (MC-LR). This pseudo-ELISA showed a linear response towards MC-LR, showing high affinity and low cross-reactivity against another analogue toxin (microcystin-YR). The analytical recovery of MC-LR in the analysis of water samples by the proposed pseudo-ELISA was 96 %–130 % and the limit of detection was 2.64 × 10−4 nM. The obtained results suggest that this competitive pseudo-ELISA could have high potential in the detection of toxins, due to its rapid, sensitive and accurate detection of toxin in water samples.
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Affiliation(s)
- Yadiris Garcia
- Department of Analytical and Inorganic Chemistry, Faculty of Chemical Science , University of Concepción , Concepción , Chile
| | - Francesco Canfarotta
- MIP Diagnostics Ltd, University of Leicester , Fielding Johnson Building , Leicester LE1 7RH , UK
| | - Katarzyna Smolinska-Kempisty
- Department of Chemistry , University of Leicester , University Road , Leicester, LE1 7RH , UK
- Wroclaw University of Science and Technology , Faculty of Chemistry, Department of Polymer and Carbon Materials , Wyb. St. Wyspianskiego 27 , 50-370 Wroclaw , Poland
| | - Sergey A. Piletsky
- Department of Chemistry , University of Leicester , University Road , Leicester, LE1 7RH , UK
| | - Eduardo Pereira
- Department of Analytical and Inorganic Chemistry, Faculty of Chemical Science , University of Concepción , Concepción , Chile
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Ruibal-Conti AL, Ruiz MA, Rodriguez MI, Lerda D, Romero MD. Assessment of specific antibodies as biological indicators of human chronic exposure to microcystins. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 175:236-242. [PMID: 30903879 DOI: 10.1016/j.ecoenv.2019.03.071] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 03/14/2019] [Accepted: 03/16/2019] [Indexed: 06/09/2023]
Abstract
Cyanobacteria can produce potent natural toxins known as cyanotoxins. Blooms of cyanobacteria, produced mainly as result of the pollution of water bodies with excessive amounts of phosphorus, represent a severe environmental problem; not only do they affect the normal equilibrium of the aquatic ecosystem but may also affect animal and human health. The occurrence of algal blooms have been increasing globally (it has been recently reported in at least 100 countries) and it has been considered by WHO as an emerging public health issue. The toxic effects of cyanotoxins have been thoroughly demonstrated in laboratory experiments, however, the effects on humans and the extent of these effects have been more difficult to assess. Epidemiological research is difficult as there are no specific symptoms or routine biomarkers to diagnose intoxication with cyanotoxins, in particular those cases associated with chronic exposure. The objectives of this study were to assess the exposure of a population settled near a lake with recurrent cyanobacteria blooms and to investigate the presence of biological markers of chronic exposure to cyanotoxins, in particular the microcystins (MCs). We first investigated the exposure of the population to cyanobacteria by using a questionnaire on how the population used the water and by analyzing water samples for the presence of cyanobacteria and total microcystins (TMCs). Secondly, we investigated the presence of biological indicators by analyzing the biochemical and immunological parameters in sera of the exposed population. The questionnaires and the water analyses revealed that the population under study (n = 47) is exposed to several exposure routes. The biochemical analyses of the sera showed the alteration of at least one hepatic enzyme in 25% of the exposed people, but this cannot be associated solely to MCs exposure. On the contrary, the immunological analyses, which included microcystin-LR specific antibodies IgE and IgG, showed significant differences between the exposed and non-exposed groups. The presence of MCs specific antibodies confirms the exposure to MCs. We propose the study of specific antibodies as a non-complex biomarker to detect chronic exposure to the toxin and to assist epidemiological studies.
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Affiliation(s)
- Ana L Ruibal-Conti
- Area de Limnología Aplicada y Calidad de Agua. Centro de La Región Semiárida. Instituto Nacional Del Agua. Córdoba, Argentina; Facultad de Ciencias Químicas. Universidad Católica de Córdoba, Argentina.
| | - Marcia A Ruiz
- Area de Limnología Aplicada y Calidad de Agua. Centro de La Región Semiárida. Instituto Nacional Del Agua. Córdoba, Argentina; Facultad de Ciencias Químicas. Universidad Católica de Córdoba, Argentina
| | - María I Rodriguez
- Area de Limnología Aplicada y Calidad de Agua. Centro de La Región Semiárida. Instituto Nacional Del Agua. Córdoba, Argentina
| | - Daniel Lerda
- Facultad de Ciencias de La Salud. Universidad Católica de Córdoba, Argentina
| | - Marta D Romero
- L I I D O. Laboratorio de Inmunopatología. Córdoba, Argentina
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Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis. Toxins (Basel) 2019; 11:toxins11060371. [PMID: 31242640 PMCID: PMC6628444 DOI: 10.3390/toxins11060371] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 06/20/2019] [Accepted: 06/22/2019] [Indexed: 01/07/2023] Open
Abstract
Inflammatory Bowel Disease (IBD) represents a collection of gastrointestinal disorders resulting from genetic and environmental factors. Microcystin-leucine arginine (MC-LR) is a toxin produced by cyanobacteria during algal blooms and demonstrates bioaccumulation in the intestinal tract following ingestion. Little is known about the impact of MC-LR ingestion in individuals with IBD. In this study, we sought to investigate MC-LR’s effects in a dextran sulfate sodium (DSS)-induced colitis model. Mice were separated into four groups: (a) water only (control), (b) DSS followed by water (DSS), (c) water followed by MC-LR (MC-LR), and (d) DSS followed by MC-LR (DSS + MC-LR). DSS resulted in weight loss, splenomegaly, and severe colitis marked by transmural acute inflammation, ulceration, shortened colon length, and bloody stools. DSS + MC-LR mice experienced prolonged weight loss and bloody stools, increased ulceration of colonic mucosa, and shorter colon length as compared with DSS mice. DSS + MC-LR also resulted in greater increases in pro-inflammatory transcripts within colonic tissue (TNF-α, IL-1β, CD40, MCP-1) and the pro-fibrotic marker, PAI-1, as compared to DSS-only ingestion. These findings demonstrate that MC-LR exposure not only prolongs, but also worsens the severity of pre-existing colitis, strengthening evidence of MC-LR as an under-recognized environmental toxin in vulnerable populations, such as those with IBD.
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Clarke JD, Dzierlenga A, Arman T, Toth E, Li H, Lynch KD, Tian DD, Goedken M, Paine MF, Cherrington N. Nonalcoholic fatty liver disease alters microcystin-LR toxicokinetics and acute toxicity. Toxicon 2019; 162:1-8. [PMID: 30849452 PMCID: PMC6447445 DOI: 10.1016/j.toxicon.2019.03.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 02/27/2019] [Accepted: 03/03/2019] [Indexed: 02/08/2023]
Abstract
Microcystin-LR (MCLR) is a cyanotoxin produced by blue-green algae that causes liver and kidney toxicities. MCLR toxicity is dependent on cellular uptake through the organic anion transporting polypeptide (OATP) transporters. Nonalcoholic fatty liver disease (NAFLD) progresses through multiple stages, alters expression of hepatic OATPs, and is associated with chronic kidney disease. The purpose of this study was to determine whether NAFLD increases systemic exposure to MCLR and influences acute liver and kidney toxicities. Rats were fed a control diet or two dietary models of NAFLD; methionine and choline deficient (MCD) or high fat/high cholesterol (HFHC). Two studies were performed in these groups: 1) a single dose intravenous toxicokinetic study (20 μg/kg), and 2) a single dose intraperitoneal toxicity study (60 μg/kg). Compared to control rats, plasma MCLR area under the concentration-time curve (AUC) in MCD rats doubled, whereas biliary clearance (Clbil) was unchanged; in contrast, plasma AUC in HFHC rats was unchanged, whereas Clbil approximately doubled. Less MCLR bound to PP2A was observed in the liver of MCD rats. This shift in exposure decreased the severity of liver pathology only in the MCD rats after a single toxic dose of MCLR (60 μg/kg). In contrast, the single toxic dose of MCLR increased hepatic inflammation, plasma cholesterol, proteinuria, and urinary KIM1 in HFHC rats more than MCLR exposed control rats. In conclusion, rodent models of NAFLD alter MCLR toxicokinetics and acute toxicity and may have implications for liver and kidney pathologies in NAFLD patients.
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Affiliation(s)
- John D Clarke
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA.
| | - Anika Dzierlenga
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA
| | - Tarana Arman
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA
| | - Erica Toth
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA
| | - Hui Li
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA
| | - Katherine D Lynch
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA
| | - Dan-Dan Tian
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA
| | - Michael Goedken
- Rutgers Translational Sciences, Rutgers University, Piscataway, NJ, 08901, USA
| | - Mary F Paine
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA
| | - Nathan Cherrington
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA
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Wu J, Yang L, Zhang X, Li Y, Wang J, Zhang S, Liu H, Huang H, Wang Y, Yuan L, Cheng X, Zhuang D, Zhang H, Chen X. MC-LR induces dysregulation of iron homeostasis by inhibiting hepcidin expression: A preliminary study. CHEMOSPHERE 2018; 212:572-584. [PMID: 30172039 DOI: 10.1016/j.chemosphere.2018.08.077] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 08/11/2018] [Accepted: 08/14/2018] [Indexed: 06/08/2023]
Abstract
The liver is an important iron storage site and a primary MC-LR target. C57BL/6 and Hfe-/- mice were used to investigate effects and mechanisms of MC-LR on systematic iron homeostasis. Body weight, tissue iron content, hematological and serological indexes, and histopathological were evaluated. Ultrastructure and iron metabolism-related genes and proteins were analyzed. MC-LR induced dose-dependent increases in red blood cells, hemoglobin, and hematocrit. In contrast MC-LR-induced dose-dependent decreases in mean corpuscular volume, hemoglobin, and hemoglobin concentration were observed both C57BL/6 and Hfe-/- mice. In both mouse species, serological indexes increased. Aggravated liver and spleen iron were observed in C57BL/6 mice, consistent with Perls' Prussian blue staining. However, an opposite trend was observed in Hfe-/- mice. C57BL/6 mice had lower Hamp1 (Hepcidn), Bmp6, Il-6, and Tmprss6. Significant increased Hjv, Hif-1α and Hif-2α were observed in both C57BL/6 and Hfe-/- mice. MC-LR-induced pathological lesions were dose-dependent increase in C57BL/6 mice. More severe pathological injuries in MC-LR groups (25 μg/kg) were observed in Hfe-/- mice than in C57BL/6 mice. In Hfe-/- mice, upon exposure to 25 μg/kg MC-LR, mitochondrial membranes were damaged and mitochondrial counts increased with significant swelling. These results indicated that MC-LR can induce the accumulation of iron in C57BL/6 mice with the occurrence of anemia, similar to thalassemia. Moreover, dysregulation of iron homeostasis may be due to MC-LR-induced Hamp1 downregulation, possibly mediated by hypoxia or the IL6-STAT3 and BMP-SMAD signaling pathways.
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Affiliation(s)
- Jinxia Wu
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Lei Yang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China; School of Nursing, Xinxiang Medical University, Xinxiang, Henan, 453003, PR China
| | - Xiaofeng Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Yang Li
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Jianyao Wang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Shenshen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Haohao Liu
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Hui Huang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Yueqin Wang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Le Yuan
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Xuemin Cheng
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Donggang Zhuang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
| | - Xinghai Chen
- Department of Chemistry and Biochemistry, St Mary's University, San Antonio, TX, USA
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Wu JX, Huang H, Yang L, Zhang XF, Zhang SS, Liu HH, Wang YQ, Yuan L, Cheng XM, Zhuang DG, Zhang HZ. Gastrointestinal toxicity induced by microcystins. World J Clin Cases 2018; 6:344-354. [PMID: 30283797 PMCID: PMC6163130 DOI: 10.12998/wjcc.v6.i10.344] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 06/08/2018] [Accepted: 06/28/2018] [Indexed: 02/05/2023] Open
Abstract
Microcystins (MCs) are produced by certain bloom-forming cyanobacteria that can induce toxicity in various organs, including renal toxicity, reproductive toxicity, cardiotoxicity, and immunosuppressive effects. It has been a significant global environmental issue due to its harm to the aquatic environment and human health. Numerous investigators have demonstrated that MC exposure can induce a widespread epidemic of enterogastritis with symptoms similar to food poisoning in areas close to lakes. Both in vivo and in vitro studies have provided evidence of positive associations between MC exposure and gastrointestinal toxicity. The toxicity of MCs on the gastrointestinal tract is multidimensional. MCs can affect gastrointestinal barrier function and shift the structure of gut microbiota in different gut regions. Furthermore, MCs can inhibit the secretion of gastrointestinal digestive enzymes and the release of inflammatory cytokines, which affects the expression of immune-related genes in the intestine. The damage of the intestine is closely correlated to MC exposure because the intestine is the main site for the digestion and absorption of nutrients. The damage to the gastrointestinal tract due to MCs was summarized from different aspects, which can be used as a foundation for further exploration of molecular damage mechanisms.
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Affiliation(s)
- Jin-Xia Wu
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Hui Huang
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Lei Yang
- Department of Nutriology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Xiao-Feng Zhang
- Department of Nutriology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Shen-Shen Zhang
- Department of Nutriology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Hao-Hao Liu
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Yue-Qin Wang
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Le Yuan
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Xue-Min Cheng
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Dong-Gang Zhuang
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Hui-Zhen Zhang
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
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Affiliation(s)
- Judy A. Westrick
- Lumigen Instrument Center, Department of Chemistry; Wayne State University; Detroit Mich
| | - David Szlag
- Department of Chemistry; Oakland University; Rochester Mich
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Water metabolism dysfunction via renin-angiotensin system activation caused by liver damage in mice treated with microcystin-RR. Toxicol Lett 2017; 273:86-96. [PMID: 28330766 DOI: 10.1016/j.toxlet.2017.03.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 03/10/2017] [Accepted: 03/17/2017] [Indexed: 01/12/2023]
Abstract
Microcystins (MCs) are a group of monocyclic heptapeptide toxins that have been shown to act as potent hepatotoxins. However, the observed symptoms of water metabolism disruption induced by microcystin-RR (MC-RR) or MCs have rarely been reported, and a relatively clear mechanism has not been identified. In the present study, male mice were divided into 4 groups (A: 140μg/kg, B: 70μg/kg,C: 35μg/kg, and D: 0μg/kg) and administered MC-RR daily for a month. On day 8 of treatment, an increase in water intake and urine output was observed in the high-dose group compared with the control, and the symptoms worsened with the repeated administration of the toxin until day 30. In addition, the urine specific gravity decreased and serum enzymes that can reflect hepatic damage increased in the high-dose group compared with the control (P<0.05). The mRNA level of angiotensinogen (AGT) in hepatocytes was upregulated to approximately 150% of the control (P<0.05), and the serum renin-angiotensin system (RAS) was activated in the high-dose group; however, signs of renal injury were not observed throughout the experiment. After the toxin treatment was completed, the high levels of the RAS and vasopressin in group A returned to normal levels within 1 week. As expected, the symptoms of polyuria and polydipsia also disappeared. Therefore, we propose that water metabolism dysfunction occurs via RAS activation caused by liver damage because the increased serum RAS levels in the experiment were consistent with the increased urine output and water intake in the mice during the observation period. In addition, we found for the first time that a RAS blocker could alleviate the observed polyuria and polydipsia and inactivate the high level of the RAS induced by MC-RR in a dose-dependent manner, which further supported our hypothesis.
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Lundqvist J, Pekar H, Oskarsson A. Microcystins activate nuclear factor erythroid 2-related factor 2 (Nrf2) in human liver cells in vitro – Implications for an oxidative stress induction by microcystins. Toxicon 2017; 126:47-50. [DOI: 10.1016/j.toxicon.2016.12.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 12/16/2016] [Accepted: 12/21/2016] [Indexed: 01/27/2023]
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Buratti FM, Manganelli M, Vichi S, Stefanelli M, Scardala S, Testai E, Funari E. Cyanotoxins: producing organisms, occurrence, toxicity, mechanism of action and human health toxicological risk evaluation. Arch Toxicol 2017; 91:1049-1130. [DOI: 10.1007/s00204-016-1913-6] [Citation(s) in RCA: 384] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 12/13/2016] [Indexed: 12/11/2022]
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Drobac D, Tokodi N, Lujić J, Marinović Z, Subakov-Simić G, Dulić T, Važić T, Nybom S, Meriluoto J, Codd GA, Svirčev Z. Cyanobacteria and cyanotoxins in fishponds and their effects on fish tissue. HARMFUL ALGAE 2016; 55:66-76. [PMID: 28073548 DOI: 10.1016/j.hal.2016.02.007] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 02/03/2016] [Accepted: 02/03/2016] [Indexed: 06/06/2023]
Abstract
Cyanobacteria can produce toxic metabolites known as cyanotoxins. Common and frequently investigated cyanotoxins include microcystins (MCs), nodularin (NOD) and saxitoxins (STXs). During the summer of 2011 extensive cyanobacterial growth was found in several fishponds in Serbia. Sampling of the water and fish (common carp, Cyprinus carpio) was performed. Water samples from 13 fishponds were found to contain saxitoxin, microcystin, and/or nodularin. LC-MS/MS showed that MC-RR was present in samples of fish muscle tissue. Histopathological analyses of fish grown in fishponds with cyanotoxin production showed histopathological damage to liver, kidney, gills, intestines and muscle tissues. This study is among the first so far to report severe hyperplasia of intestinal epithelium and severe degeneration of muscle tissue of fish after cyanobacterial exposure. These findings emphasize the importance of cyanobacterial and cyanotoxin monitoring in fishponds in order to recognize cyanotoxins and their potential effects on fish used for human consumption and, further, on human health.
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Affiliation(s)
- Damjana Drobac
- Department of Biology and Ecology, Faculty of Science, University of Novi Sad, Trg Dositeja Obradovića 2, Novi Sad 21000, Serbia.
| | - Nada Tokodi
- Department of Biology and Ecology, Faculty of Science, University of Novi Sad, Trg Dositeja Obradovića 2, Novi Sad 21000, Serbia
| | - Jelena Lujić
- Department of Aquaculture, Szent István University, Páter Károly u. 1, Gödöllő 2100, Hungary
| | - Zoran Marinović
- Department of Biology and Ecology, Faculty of Science, University of Novi Sad, Trg Dositeja Obradovića 2, Novi Sad 21000, Serbia; Department of Aquaculture, Szent István University, Páter Károly u. 1, Gödöllő 2100, Hungary
| | - Gordana Subakov-Simić
- Faculty of Biology, University of Belgrade, Studentski trg 16, Belgrade 11000, Serbia
| | - Tamara Dulić
- Department of Biology and Ecology, Faculty of Science, University of Novi Sad, Trg Dositeja Obradovića 2, Novi Sad 21000, Serbia
| | - Tamara Važić
- Department of Biology and Ecology, Faculty of Science, University of Novi Sad, Trg Dositeja Obradovića 2, Novi Sad 21000, Serbia
| | - Sonja Nybom
- Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Tykistökatu 6 A, Turku 20520, Finland
| | - Jussi Meriluoto
- Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Tykistökatu 6 A, Turku 20520, Finland; Department of Biology and Ecology, Faculty of Science, University of Novi Sad, Trg Dositeja Obradovića 2, Novi Sad 21000, Serbia
| | - Geoffrey A Codd
- School of the Environment, Flinders University, Adelaide 5042, SA, Australia
| | - Zorica Svirčev
- Department of Biology and Ecology, Faculty of Science, University of Novi Sad, Trg Dositeja Obradovića 2, Novi Sad 21000, Serbia; Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Tykistökatu 6 A, Turku 20520, Finland
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