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Jaeger-Honz S, Hackett R, Fotler R, Dietrich DR, Schreiber F. Conformation and binding of 12 Microcystin (MC) congeners to PPP1 using molecular dynamics simulations: A potential approach in support of an improved MC risk assessment. Chem Biol Interact 2025; 407:111372. [PMID: 39788475 DOI: 10.1016/j.cbi.2025.111372] [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: 07/10/2024] [Revised: 12/20/2024] [Accepted: 12/21/2024] [Indexed: 01/12/2025]
Abstract
Microcystins (MCs) occur frequently during cyanobacterial blooms worldwide, representing a group of currently about 300 known MC congeners, which are structurally highly similar. Human exposure to MCs via contaminated water, food or dietary supplements can lead to severe intoxications with ensuing high morbidity and in some cases mortality. Currently, one MC congener (MC-LR) is almost exclusively considered for risk assessment (RA) by the WHO. Many MC congeners co-occur during bloom events, of which MC-LR is not the most toxic. Indeed, MC congeners differ dramatically in their inherent toxicity, consequently raising question about the reliability of the WHO RA and the derived guidance values. Molecular dynamics (MD) simulation can aid in understanding differences in toxicity, as experimental validation for all known MC congeners is not feasible. Therefore, we present MD simulations of a total of twelve MC congeners, of which eight MC congeners were simulated for the first time. We show that depending on their structure and toxicity class, MCs adapt to different backbone conformations. These backbone conformations are specific to certain MC congeners and can change or shift to other conformations upon binding to PPP1, affecting the stability of the binding. Analysis of the interactions with PPP1 demonstrated that there are frequently occurring patterns for individual MC congeners, and that published PPP interactions could be reproduced. In addition, common but also unique patterns were found for individual MC congeners, suggesting differences in binding behaviour. The MD simulations presented here therefore enhance our understanding of MC congener-specific differences and demonstrated that congener-specific investigations are prerequisite for allowing characterisation of yet untested or even unknown MC congeners, thereby allowing for a novel potential approach in support of an improved RA of microcystins in humans.
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Affiliation(s)
- Sabrina Jaeger-Honz
- Department of Informatics and Information Science, University of Konstanz, Germany
| | - Raymund Hackett
- Department of Informatics and Information Science, University of Konstanz, Germany
| | - Regina Fotler
- Department of Biology, University of Konstanz, Germany
| | | | - Falk Schreiber
- Department of Informatics and Information Science, University of Konstanz, Germany; Faculty of Information Technology, Monash University, Australia.
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Ma Y, Xu D, Gan Y, Chen Z, Chen Y, Han X. Adverse outcome pathway of Alzheimer's disease-like changes resulting from autophagy flux blockade after MC-LR exposure. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 364:125322. [PMID: 39549990 DOI: 10.1016/j.envpol.2024.125322] [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: 10/08/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 11/18/2024]
Abstract
Microcystins (MCs) pollution is a worldwide environmental issue concerning about human health. Microcystin-leucine-arginine (MC-LR), the most common type of MCs produced by cyanobacteria, could enter the brain and bring about damage to the nervous system. Up to date, it is not clear about the mechanism of MC-LR-induced neurotoxicity. Amyloid-β (Aβ) deposits are hallmark of Alzheimer's disease (AD). In this study, we revealed that MC-LR exposure at environment-related doses (1, 7.5, 15 μg/L) could promote Aβ accumulation in mouse brain. Mechanically, we firstly found that Aβ accumulation is closely associated with abnormal Aβ degradation due to autophagy flux blockade and lysosome dysfunctions in neurons after MC-LR exposure. Moreover, an adverse outcome pathway (AOP) framework oriented to neurotoxicity of MC-LR was conducted in this study. MC-LR inhibited the activity of protein phosphatase 2A (PP2A) in neurons, which is regarded as a molecular initiating event (MIE). In addition, the abnormalities in autophagy were observed after MC-LR exposure. The hindered autophagosome-lysosome fusion and disrupted lysosomal function were key events (KEs) after MC-LR exposure, which contributed to proteostasis dysregulation, ultimately leading to Aβ abnormal degradation and learning deficits as adverse outcomes (AO) of neurotoxicity. This study provided novel information about MC-LR neurotoxicity and new insights into understanding the mechanisms underlying the environmental chemicals-induced neurodegeneration diseases, which has deep implications for public health.
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Affiliation(s)
- Yuhan Ma
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China
| | - Dihui Xu
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China
| | - Yibin Gan
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China
| | - Zining Chen
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China
| | - Yabing Chen
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
| | - Xiaodong Han
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
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Spencer PS, Valdes Angues R, Palmer VS. Nodding syndrome: A role for environmental biotoxins that dysregulate MECP2 expression? J Neurol Sci 2024; 462:123077. [PMID: 38850769 DOI: 10.1016/j.jns.2024.123077] [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: 10/01/2023] [Revised: 05/15/2024] [Accepted: 05/30/2024] [Indexed: 06/10/2024]
Abstract
Nodding syndrome is an epileptic encephalopathy associated with neuroinflammation and tauopathy. This initially pediatric brain disease, which has some clinical overlap with Methyl-CpG-binding protein 2 (MECP2) Duplication Syndrome, has impacted certain impoverished East African communities coincident with local civil conflict and internal displacement, conditions that forced dependence on contaminated food and water. A potential role in Nodding syndrome for certain biotoxins (freshwater cyanotoxins plus/minus mycotoxins) with neuroinflammatory, excitotoxic, tauopathic, and MECP2-dysregulating properties, is considered here for the first time.
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Affiliation(s)
- Peter S Spencer
- Department of Neurology, School of Medicine and Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USA; Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USA; Gulu University School of Medicine, Gulu, Uganda.
| | - Raquel Valdes Angues
- Department of Neurology, School of Medicine and Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USA
| | - Valerie S Palmer
- Department of Neurology, School of Medicine and Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USA; Gulu University School of Medicine, Gulu, Uganda
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4
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Ge K, Du X, Liu H, Meng R, Wu C, Zhang Z, Liang X, Yang J, Zhang H. The cytotoxicity of microcystin-LR: ultrastructural and functional damage of cells. Arch Toxicol 2024; 98:663-687. [PMID: 38252150 DOI: 10.1007/s00204-023-03676-0] [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: 10/23/2023] [Accepted: 12/20/2023] [Indexed: 01/23/2024]
Abstract
Microcystin-LR (MC-LR) is a toxin produced by cyanobacteria, which is widely distributed in eutrophic water bodies and has multi-organ toxicity. Previous cytotoxicity studies have mostly elucidated the effects of MC-LR on intracellular-related factors, proteins, and DNA at the molecular level. However, there have been few studies on the adverse effects of MC-LR on cell ultrastructure and function. Therefore, research on the cytotoxicity of MC-LR in recent years was collected and summarized. It was found that MC-LR can induce a series of cytotoxic effects, including decreased cell viability, induced autophagy, apoptosis and necrosis, altered cell cycle, altered cell morphology, abnormal cell migration and invasion as well as leading to genetic damage. The above cytotoxic effects were related to the damage of various ultrastructure and functions such as cell membranes and mitochondria. Furthermore, MC-LR can disrupt cell ultrastructure and function by inducing oxidative stress and inhibiting protein phosphatase activity. In addition, the combined toxic effects of MC-LR and other environmental pollutants were investigated. This review explored the toxic targets of MC-LR at the subcellular level, which will provide new ideas for the prevention and treatment of multi-organ toxicity caused by MC-LR.
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Affiliation(s)
- Kangfeng Ge
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Xingde Du
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Haohao Liu
- Department of Public Health, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China
| | - Ruiyang Meng
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Chunrui Wu
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Zongxin Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiao Liang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Jun Yang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
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Hu Z, Meng G, Zhang L, Zhang M, Cui H, Tang H. Protective effect of Huanglianjiedu Decoction on microcystin-LR induced nerve injury. Comp Biochem Physiol C Toxicol Pharmacol 2023; 272:109698. [PMID: 37442312 DOI: 10.1016/j.cbpc.2023.109698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 06/26/2023] [Accepted: 07/09/2023] [Indexed: 07/15/2023]
Abstract
Microcystin-LR (MC-LR) presented in eutrophic water has been identified as having the capacity to induce damage to the mammalian nervous system by crossing the blood-brain barrier through organic anion transporting polypeptides. However, the lack of effective preventive and protective strategies remains a concern. Huanglianjiedu Decoction (HLJD), a classical Chinese traditional formula originating from the Tang Dynasty and comprising Rhizoma Coptidis, Radix Scutellariae, Cortex Phellodendri, and Fructus Gardeniae, has exhibited neuroprotective effects attributed to its antioxidant properties. In this study, we investigated the potential of HLJD in counteracting the neurotoxic effects induced by MC-LR. Our findings revealed that MC-LR dose-dependently inhibited the activity of the PP2A enzyme in PC 12 cells and significantly elevated the phosphorylation levels of JNK, ERK1/2, and p38. Moreover, MC-LR administration resulted in synaptic damage in mouse neurons, hyperphosphorylation of the microtubule-related protein Tau, cognitive impairment, and deficits in learning and memory in C57BL/6J mice. Notably, HLJD effectively reversed the cytotoxicity caused by MC-LR in PC 12 cells, and attenuated MC-LR-induced neuronal damage while improving learning ability in mice. These results highlight the potential of HLJD as a promising protective strategy against MC-LR-induced neurological injury.
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Affiliation(s)
- Zhengqiang Hu
- Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Guanmin Meng
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada; Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310013, China
| | - Lejun Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Meng Zhang
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310013, China
| | - Huashun Cui
- Department of Acupuncture and Moxibustion, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China.
| | - Huifang Tang
- Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou 310058, China.
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Nugumanova G, Ponomarev ED, Askarova S, Fasler-Kan E, Barteneva NS. Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases. Toxins (Basel) 2023; 15:toxins15030233. [PMID: 36977124 PMCID: PMC10057253 DOI: 10.3390/toxins15030233] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 03/13/2023] [Accepted: 03/19/2023] [Indexed: 03/30/2023] Open
Abstract
Cyanobacteria produce a wide range of structurally diverse cyanotoxins and bioactive cyanopeptides in freshwater, marine, and terrestrial ecosystems. The health significance of these metabolites, which include genotoxic- and neurotoxic agents, is confirmed by continued associations between the occurrence of animal and human acute toxic events and, in the long term, by associations between cyanobacteria and neurodegenerative diseases. Major mechanisms related to the neurotoxicity of cyanobacteria compounds include (1) blocking of key proteins and channels; (2) inhibition of essential enzymes in mammalian cells such as protein phosphatases and phosphoprotein phosphatases as well as new molecular targets such as toll-like receptors 4 and 8. One of the widely discussed implicated mechanisms includes a misincorporation of cyanobacterial non-proteogenic amino acids. Recent research provides evidence that non-proteinogenic amino acid BMAA produced by cyanobacteria have multiple effects on translation process and bypasses the proof-reading ability of the aminoacyl-tRNA-synthetase. Aberrant proteins generated by non-canonical translation may be a factor in neuronal death and neurodegeneration. We hypothesize that the production of cyanopeptides and non-canonical amino acids is a more general mechanism, leading to mistranslation, affecting protein homeostasis, and targeting mitochondria in eukaryotic cells. It can be evolutionarily ancient and initially developed to control phytoplankton communities during algal blooms. Outcompeting gut symbiotic microorganisms may lead to dysbiosis, increased gut permeability, a shift in blood-brain-barrier functionality, and eventually, mitochondrial dysfunction in high-energy demanding neurons. A better understanding of the interaction between cyanopeptides metabolism and the nervous system will be crucial to target or to prevent neurodegenerative diseases.
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Affiliation(s)
- Galina Nugumanova
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Astana 010000, Kazakhstan
| | - Eugene D Ponomarev
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Astana 010000, Kazakhstan
| | - Sholpan Askarova
- Center for Life Sciences, National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan
| | - Elizaveta Fasler-Kan
- Department of Pediatric Surgery, Children's Hospital, Inselspital Bern, University of Bern, 3010 Bern, Switzerland
| | - Natasha S Barteneva
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Astana 010000, Kazakhstan
- The Environment & Resource Efficiency Cluster (EREC), Nazarbayev University, Astana 010000, Kazakhstan
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Svirčev Z, Chen L, Sántha K, Drobac Backović D, Šušak S, Vulin A, Palanački Malešević T, Codd GA, Meriluoto J. A review and assessment of cyanobacterial toxins as cardiovascular health hazards. Arch Toxicol 2022; 96:2829-2863. [PMID: 35997789 PMCID: PMC9395816 DOI: 10.1007/s00204-022-03354-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 08/02/2022] [Indexed: 12/14/2022]
Abstract
Eutrophicated waters frequently support bloom-forming cyanobacteria, many of which produce potent cyanobacterial toxins (cyanotoxins). Cyanotoxins can cause adverse health effects in a wide range of organisms where the toxins may target the liver, other internal organs, mucous surfaces and the skin and nervous system. This review surveyed more than 100 studies concerning the cardiovascular toxicity of cyanotoxins and related topics. Over 60 studies have described various negative effects on the cardiovascular system by seven major types of cyanotoxins, i.e. the microcystin (MC), nodularin (NOD), cylindrospermopsin (CYN), anatoxin (ATX), guanitoxin (GNTX), saxitoxin (STX) and lyngbyatoxin (LTX) groups. Much of the research was done on rodents and fish using high, acutely toxin concentrations and unnatural exposure routes (such as intraperitoneal injection), and it is thus concluded that the emphasis in future studies should be on oral, chronic exposure of mammalian species at environmentally relevant concentrations. It is also suggested that future in vivo studies are conducted in parallel with studies on cells and tissues. In the light of the presented evidence, it is likely that cyanotoxins do not constitute a major risk to cardiovascular health under ordinary conditions met in everyday life. The risk of illnesses in other organs, in particular the liver, is higher under the same exposure conditions. However, adverse cardiovascular effects can be expected due to indirect effects arising from damage in other organs. In addition to risks related to extraordinary concentrations of the cyanotoxins and atypical exposure routes, chronic exposure together with co-existing diseases could make some of the cyanotoxins more dangerous to cardiovascular health.
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Affiliation(s)
- Zorica Svirčev
- University of Novi Sad, Faculty of Sciences, Department of Biology and Ecology, UNS, Trg Dositeja Obradovića 2, 21000, Novi Sad, Serbia.
- Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Tykistökatu 6A, 20520, Turku, Finland.
| | - Liang Chen
- Institute for Ecological Research and Pollution Control of Plateau Lakes, School of Ecology and Environmental Science, Yunnan University, Kunming, 650500, China
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology (IHB), Chinese Academy of Sciences (CAS), Wuhan, 430072, China
- State Key Laboratory of Eco-Hydraulics in Northwest Arid Region, Faculty of Water Resources and Hydroelectric Engineering, Xi'an University of Technology, Xi'an, 710048, China
| | - Kinga Sántha
- University of Novi Sad, Faculty of Sciences, Department of Biology and Ecology, UNS, Trg Dositeja Obradovića 2, 21000, Novi Sad, Serbia
| | - Damjana Drobac Backović
- University of Novi Sad, Faculty of Sciences, Department of Biology and Ecology, UNS, Trg Dositeja Obradovića 2, 21000, Novi Sad, Serbia
| | - Stamenko Šušak
- University of Novi Sad, Faculty of Medicine, UNS, Hajduk Veljkova 3, 21000, Novi Sad, Serbia
- Institute of Cardiovascular Diseases of Vojvodina, Sremska Kamenica, Serbia
| | - Aleksandra Vulin
- University of Novi Sad, Faculty of Medicine, UNS, Hajduk Veljkova 3, 21000, Novi Sad, Serbia
- Institute of Cardiovascular Diseases of Vojvodina, Sremska Kamenica, Serbia
| | - Tamara Palanački Malešević
- University of Novi Sad, Faculty of Sciences, Department of Biology and Ecology, UNS, Trg Dositeja Obradovića 2, 21000, Novi Sad, Serbia
| | - Geoffrey A Codd
- School of Natural Sciences, University of Stirling, Stirling, FK9 4LA, UK
- School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
| | - Jussi Meriluoto
- University of Novi Sad, Faculty of Sciences, Department of Biology and Ecology, UNS, Trg Dositeja Obradovića 2, 21000, Novi Sad, Serbia
- Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Tykistökatu 6A, 20520, Turku, Finland
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Ronaldson PT, Davis TP. Transport Mechanisms at the Blood-Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs. Pharmaceutics 2022; 14:1501. [PMID: 35890396 PMCID: PMC9324459 DOI: 10.3390/pharmaceutics14071501] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 02/06/2023] Open
Abstract
Ischemic stroke is a primary origin of morbidity and mortality in the United States and around the world. Indeed, several research projects have attempted to discover new drugs or repurpose existing therapeutics to advance stroke pharmacotherapy. Many of these preclinical stroke studies have reported positive results for neuroprotective agents; however, only one compound (3K3A-activated protein C (3K3A-APC)) has advanced to Phase III clinical trial evaluation. One reason for these many failures is the lack of consideration of transport mechanisms at the blood-brain barrier (BBB) and neurovascular unit (NVU). These endogenous transport processes function as a "gateway" that is a primary determinant of efficacious brain concentrations for centrally acting drugs. Despite the knowledge that some neuroprotective agents (i.e., statins and memantine) are substrates for these endogenous BBB transporters, preclinical stroke studies have largely ignored the role of transporters in CNS drug disposition. Here, we review the current knowledge on specific BBB transporters that either limit drug uptake into the brain (i.e., ATP-binding cassette (ABC) transporters) or can be targeted for optimized drug delivery (i.e., solute carrier (SLC) transporters). Additionally, we highlight the current knowledge on transporter expression in astrocytes, microglia, pericytes, and neurons with an emphasis on transport mechanisms in these cell types that can influence drug distribution within the brain.
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Affiliation(s)
- Patrick T. Ronaldson
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724-5050, USA;
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Hafey MJ, Aleksunes LM, Bridges CC, Brouwer KR, Chien HC, Leslie EM, Hu S, Li Y, Shen J, Sparreboom A, Sprowl J, Tweedie D, Lai Y. Transporters and Toxicity: Insights from the International Transporter Consortium Workshop 4. Clin Pharmacol Ther 2022; 112:527-539. [PMID: 35546260 DOI: 10.1002/cpt.2638] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/30/2022] [Indexed: 12/29/2022]
Abstract
Over the last decade, significant progress been made in elucidating the role of membrane transporters in altering drug disposition, with important toxicological consequences due to changes in localized concentrations of compounds. The topic of "Transporters and Toxicity" was recently highlighted as a scientific session at the International Transporter Consortium (ITC) Workshop 4 in 2021. The current white paper is not intended to be an extensive review on the topic of transporters and toxicity but an opportunity to highlight aspects of the role of transporters in various toxicities with clinically relevant implications as covered during the session. This includes a review of the role of solute carrier transporters in anticancer drug-induced organ injury, transporters as key players in organ barrier function, and the role of transporters in metal/metalloid toxicity.
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Affiliation(s)
- Michael J Hafey
- ADME and Discovery Toxicology, Merck & Co., Inc., Rahway, New Jersey, USA
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
| | - Christy C Bridges
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, Georgia, USA
| | | | - Huan-Chieh Chien
- Pharmacokinetics and Drug Metabolism, Amgen, Inc., South San Francisco, California, USA
| | - Elaine M Leslie
- Departments of Physiology and Lab Med and Path, Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada
| | - Shuiying Hu
- Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Yang Li
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Jinshan Shen
- Relay Therapeutics, Cambridge, Massachusetts, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Jason Sprowl
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
| | | | - Yurong Lai
- Drug Metabolism, Gilead Sciences Inc., Foster City, California, USA
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10
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Albuquerque MVDC, Ramos RDO, Leite VD, de Sousa JT, de Araújo MCU, de Ceballos BSO, Lopes WS. Studies of the liposolubility and the ecotoxicity of MC-LR degradation by-products using computational molecular modeling and in-vivo tests with Chlorella vulgaris and Daphnia magna. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2022; 245:106127. [PMID: 35248895 DOI: 10.1016/j.aquatox.2022.106127] [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: 12/09/2021] [Revised: 01/23/2022] [Accepted: 02/22/2022] [Indexed: 06/14/2023]
Abstract
Computational molecular modelling, mass spectrometry and in-vivo tests with Chlorella vulgaris (C. vulgaris) and Daphnia magna (D. magna) were used to investigate the liposolubility and ecotoxicity of MC-LR degradation by-products generated after oxidation by OH• radicals in Fenton process. Exposure of MC-LR (5 µg.L-1) to the most severe oxidation conditions (Fe2+ 20 mM and H2O2 60 mM) resulted in a reduction in the toxin concentration of 96% (0.16 µg.L-1), however, with the formation of many by-products. The by-product of m/z 445 was the most resistant to degradation and retained a toxic structure of diene bonds present in the Adda amino acid. Computational modeling revealed that m/z 445 (tPSA = 132.88 Ų; KOW = 2.02) is more fat-soluble than MC-LR (tPSA = 340.64 Ų; KOW = 0.68), evidencing an easier transport process of this by-product. Given this, toxicity tests using C. vulgaris and D. magna indicated greater toxicity of the by-product m/z 445 compared to MC-LR. When the conversion of MC-LR to by-products was 77%, the growth inhibition of C. vulgaris and the D. magna immobility were, respectively, 6.14 and 0%, with 96% conversion; growth inhibition and the immobility were both 100% for both species.
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Affiliation(s)
| | - Railson de Oliveira Ramos
- Departamento de Engenharia Sanitária e Ambiental, Universidade Estadual da Paraíba, Campina Grande, Paraíba 58429-500, Brazil.
| | - Valderi Duarte Leite
- Departamento de Engenharia Sanitária e Ambiental, Universidade Estadual da Paraíba, Campina Grande, Paraíba 58429-500, Brazil
| | - José Tavares de Sousa
- Departamento de Engenharia Sanitária e Ambiental, Universidade Estadual da Paraíba, Campina Grande, Paraíba 58429-500, Brazil
| | - Mário César Ugulino de Araújo
- Departamento de Química, Universidade Federal da Paraíba, CCEN, Caixa Postal 5093, João Pessoa, Paraíba CEP 58051-970, Brazil
| | | | - Wilton Silva Lopes
- Departamento de Engenharia Sanitária e Ambiental, Universidade Estadual da Paraíba, Campina Grande, Paraíba 58429-500, Brazil
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Bieczynski F, Painefilú JC, Venturino A, Luquet CM. Expression and Function of ABC Proteins in Fish Intestine. Front Physiol 2021; 12:791834. [PMID: 34955897 PMCID: PMC8696203 DOI: 10.3389/fphys.2021.791834] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 11/17/2021] [Indexed: 12/15/2022] Open
Abstract
In fish, the intestine is fundamental for digestion, nutrient absorption, and other functions like osmoregulation, acid-base balance, and excretion of some metabolic products. These functions require a large exchange surface area, which, in turn, favors the absorption of natural and anthropogenic foreign substances (xenobiotics) either dissolved in water or contained in the food. According to their chemical nature, nutrients, ions, and water may cross the intestine epithelium cells' apical and basolateral membranes by passive diffusion or through a wide array of transport proteins and also through endocytosis and exocytosis. In the same way, xenobiotics can cross this barrier by passive diffusion or taking advantage of proteins that transport physiological substrates. The entry of toxic substances is counterbalanced by an active efflux transport mediated by diverse membrane proteins, including the ATP binding cassette (ABC) proteins. Recent advances in structure, molecular properties, and functional studies have shed light on the importance of these proteins in cellular and organismal homeostasis. There is abundant literature on mammalian ABC proteins, while the studies on ABC functions in fish have mainly focused on the liver and, to a minor degree, on the kidney and other organs. Despite their critical importance in normal physiology and as a barrier to prevent xenobiotics incorporation, fish intestine's ABC transporters have received much less attention. All the ABC subfamilies are present in the fish intestine, although their functionality is still scarcely studied. For example, there are few studies of ABC-mediated transport made with polarized intestinal preparations. Thus, only a few works discriminate apical from basolateral transport activity. We briefly describe the main functions of each ABC subfamily reported for mammals and other fish organs to help understand their roles in the fish intestine. Our study considers immunohistochemical, histological, biochemical, molecular, physiological, and toxicological aspects of fish intestinal ABC proteins. We focus on the most extensively studied fish ABC proteins (subfamilies ABCB, ABCC, and ABCG), considering their apical or basolateral location and distribution along the intestine. We also discuss the implication of fish intestinal ABC proteins in the transport of physiological substrates and aquatic pollutants, such as pesticides, cyanotoxins, metals, hydrocarbons, and pharmaceutical products.
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Affiliation(s)
- Flavia Bieczynski
- Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue – Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional del Comahue, Neuquén, Argentina
| | - Julio C. Painefilú
- Instituto Patagónico de Tecnologías Biológicas y Geoambientales, Consejo Nacional de Investigaciones Científicas y Técnicas – Universidad Nacional del Comahue, Bariloche, Argentina
| | - Andrés Venturino
- Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue – Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional del Comahue, Neuquén, Argentina
| | - Carlos M. Luquet
- Laboratorio de Ecotoxicología Acuática, Subsede INIBIOMA-CEAN (CONICET – UNCo), Junín de los Andes, Argentina
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12
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Zhang Y, Fan X, Su Z, Yuan T, Yin H, Gu H, Zuo Y, Chen S, Zhou H, Su G. Pretreatment with metformin prevents microcystin-LR-induced tau hyperphosphorylation via mTOR-dependent PP2A and GSK-3β activation. ENVIRONMENTAL TOXICOLOGY 2021; 36:2414-2425. [PMID: 34432352 DOI: 10.1002/tox.23354] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 07/23/2021] [Accepted: 08/12/2021] [Indexed: 06/13/2023]
Abstract
Microcystin-leucine-arginine (MC-LR) is a toxin secreted by freshwater cyanobacteria that is considered a potential environmental risk factor for Alzheimer's disease (AD). A previous study indicated that tau protein hyperphosphorylation via protein phosphatase 2A (PP2A) and GSK-3β inhibition was the mechanism by which MC-LR induces neurotoxicity; however, how MC-LR-induced neurotoxicity can be effectively prevented remains unclear. In this study, the reversal effect of metformin on MC-LR-induced neurotoxicity was investigated. The results showed that metformin effectively prevented tau hyperphosphorylation at Ser202 caused by MC-LR through PP2A and GSK-3b activity. The effect of metformin on PP2A activity was dependent on the inhibition of mTOR in MC-LR-treated SH-SY5Y cells. Metformin prevented spatial memory deficits in rats caused by intrahippocampal MC-LR administration. In sum, the results suggested that metformin can ameliorate the MC-LR-induced AD-like phenotype by preventing tau phosphorylation at Ser202, which was mainly mediated by mTOR-dependent PP2A and GSK-3β activation.
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Affiliation(s)
- Yali Zhang
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China
| | - Xing Fan
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China
| | - Zhangyao Su
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China
| | - Tianli Yuan
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China
| | - Haimeng Yin
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China
| | - Haohao Gu
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China
| | - Yue Zuo
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China
| | - Shiyin Chen
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China
| | - Hongyu Zhou
- Institute of Environmental Research at Greater Bay Area, Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou, China
| | - Gaoxing Su
- School of Pharmacy, Nantong University, Nantong, China
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13
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Ma Y, Wang J, Xu D, Chen Y, Han X. Chronic MC-LR exposure promoted Aβ and p-tau accumulation via regulating Akt/GSK-3β signal pathway. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 794:148732. [PMID: 34323745 DOI: 10.1016/j.scitotenv.2021.148732] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/10/2021] [Accepted: 06/25/2021] [Indexed: 06/13/2023]
Abstract
It has been reported that microcystin-leucine-arginine (MC-LR) can enter into the brain and demonstrate neurotoxicity resulting in learning and memory deficits. While, there is still a lack of clear understanding of the related molecular mechanisms. In this study, we observed β-amyloid (Aβ) accumulation and tau hyperphosphorylation (p-tau) at sites of Ser396 and Thr205 in mouse hippocampus and cortex, Alzheimer's disease (AD) like changes, after chronic exposure to MC-LR at different concentrations (1, 7.5, 15 and 30 μg/L) for 180 days. The hallmarks of AD are characterized by senile plaques and neurofibrillary tangles (NFT), with associated loss of neurons, resulting in cognitive impairment and dementia. Similarly, the production of Aβ and tau hyperphosphorylation was also detected in HT-22 cells treated with MC-LR. In addition, MC-LR promoted increased expressions of BACE1 and PS1, but reduced mRNA expressions of ADAM family members both in vivo and in vitro, promoting the Aβ production. Moreover, we identified Akt/GSK-3β signal pathway mediated the Aβ and p-tau accumulation, bringing about Alzheimer's disease-like changes. Furthermore, microglial cells were activated in those mice exposed to MC-LR. Inflammatory cytokines were also found being activated to release in vitro. In conclusion, this study could provide a clue for MC-LR-induced neurotoxicity, which gave insights into the environmental risks of Alzheimer's disease.
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Affiliation(s)
- Yuhan Ma
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China
| | - Jing Wang
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China
| | - Dihui Xu
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China
| | - Yabing Chen
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.
| | - Xiaodong Han
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.
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14
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Zhao S, Xu J, Zhang W, Yan W, Li G. Paternal exposure to microcystin-LR triggers developmental neurotoxicity in zebrafish offspring via an epigenetic mechanism involving MAPK pathway. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 792:148437. [PMID: 34153754 DOI: 10.1016/j.scitotenv.2021.148437] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/27/2021] [Accepted: 06/09/2021] [Indexed: 06/13/2023]
Abstract
Microcystin-LR (MCLR) induced impairment to male reproductive system and revealed the effects of transgenerational toxicity on offspring. But very little is known about the inheritance of these effects to offspring and the mechanisms involved. Here, we used methylated DNA immunoprecipitation sequencing (MeDIP-Seq) and microarray to characterize whole-genome DNA methylation and mRNA expression patterns in zebrafish testis after 6-week exposure to 5 and 20 μg/L MCLR. Accompanied with these analyses it revealed that MAPK pathway and ER pathway significantly enriched in zebrafish testes. Apoptosis and testicular damage were also observed in testis. Next, we test the transmission of effects to compare control-father and MCLR exposure-father progenies. DNA methylation analyses (via reduced representation bisulfite sequencing) reveal that the enrichment of differentially methylated regions on neurodevelopment after paternal MCLR exposure. Meanwhile, several genes associated with neurodevelopment were markedly downregulated in zebrafish larvae, and swimming speed was also reduced in the larvae. Interestingly, paternal MCLR exposure also triggered activation the phosphorylation of mitogen-activated protein kinase (MAPK) pathway which is also associated with neurodevelopmental disorders. These results demonstrated the significant effect that paternal MCLR exposure may have on gene-specific DNA methylation patterns in testis. Inherited epigenetic alterations through the germline may be the mechanism leading to developmental neurotoxicity in the offspring.
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Affiliation(s)
- Sujuan Zhao
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Jiayi Xu
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Weiyun Zhang
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Wei Yan
- Institute of Agricultural Quality Standards & Testing Technology, Hubei Academy of Agricultural Sciences, Wuhan 430064, China
| | - Guangyu Li
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
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15
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Cyanotoxins and the Nervous System. Toxins (Basel) 2021; 13:toxins13090660. [PMID: 34564664 PMCID: PMC8472772 DOI: 10.3390/toxins13090660] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/31/2021] [Accepted: 09/09/2021] [Indexed: 11/16/2022] Open
Abstract
Cyanobacteria are capable of producing a wide range of bioactive compounds with many considered to be toxins. Although there are a number of toxicological outcomes with respect to cyanobacterial exposure, this review aims to examine those which affect the central nervous system (CNS) or have neurotoxicological properties. Such exposures can be acute or chronic, and we detail issues concerning CNS entry, detection and remediation. Exposure can occur through a variety of media but, increasingly, exposure through air via inhalation may have greater significance and requires further investigation. Even though cyanobacterial toxins have traditionally been classified based on their primary mode of toxicity, increasing evidence suggests that some also possess neurotoxic properties and include known cyanotoxins and unknown compounds. Furthermore, chronic long-term exposure to these compounds is increasingly being identified as adversely affecting human health.
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16
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Mondal A, Saha P, Bose D, Chatterjee S, Seth RK, Xiao S, Porter DE, Brooks BW, Scott GI, Nagarkatti M, Nagarkatti P, Chatterjee S. Environmental Microcystin exposure in underlying NAFLD-induced exacerbation of neuroinflammation, blood-brain barrier dysfunction, and neurodegeneration are NLRP3 and S100B dependent. Toxicology 2021; 461:152901. [PMID: 34416350 PMCID: PMC8503918 DOI: 10.1016/j.tox.2021.152901] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/28/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has been shown to be associated with extrahepatic comorbidities including neuronal inflammation and Alzheimer's-like pathology. Environmental and genetic factors also act as a second hit to modulate severity and are expected to enhance the NAFLD-linked neuropathology. We hypothezied that environmental microcystin-LR (MC-LR), a toxin produced by harmful algal blooms of cyanobacteria, exacerbates the neuroinflammation and degeneration of neurons associated with NAFLD. Using a mouse model of NAFLD, exposed to MC-LR subsequent to the onset of fatty liver, we show that the cyanotoxin could significantly increase proinflammatory cytokine expression in the frontal cortex and cause increased expression of Lcn2 and HMGB1. The above effects were NLRP3 inflammasome activation-dependent since the use of NLRP3 knockout mice abrogated the increase in inflammation. NLRP3 was also responsible for decreased expression of the blood-brain barrier (BBB) tight junction proteins Occludin and Claudin 5 suggesting BBB dysfunction was parallel to neuroinflammation following microcystin exposure. An increased circulatory S100B release, a hallmark of astrocyte activation in MC-LR exposed NAFLD mice also confirmed BBB integrity loss, but the astrocyte activation observed in vivo was NLRP3 independent suggesting an important role of a secondary S100B mediated crosstalk. Mechanistically, conditioned medium from reactive astrocytes and parallel S100B incubation in neuronal cells caused increased inducible NOS, COX-2, and higher BAX/ Bcl2 protein expression suggesting oxidative stress-mediated neuronal cell apoptosis crucial for neurodegeneration. Taken together, MC-LR exacerbated neuronal NAFLD-linked comorbidities leading to cortical inflammation, BBB dysfunction, and neuronal apoptosis.
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Affiliation(s)
- Ayan Mondal
- Environmental Health and Disease Laboratory, Arnold School of Public Health, University of South Carolina, Columbia, SC, 29208, USA
| | - Punnag Saha
- Environmental Health and Disease Laboratory, Arnold School of Public Health, University of South Carolina, Columbia, SC, 29208, USA
| | - Dipro Bose
- Environmental Health and Disease Laboratory, Arnold School of Public Health, University of South Carolina, Columbia, SC, 29208, USA; Columbia VA Medical Center, Columbia, SC, 29209, USA
| | - Somdatta Chatterjee
- Environmental Health and Disease Laboratory, Arnold School of Public Health, University of South Carolina, Columbia, SC, 29208, USA
| | - Ratanesh K Seth
- Environmental Health and Disease Laboratory, Arnold School of Public Health, University of South Carolina, Columbia, SC, 29208, USA; Columbia VA Medical Center, Columbia, SC, 29209, USA
| | - Shuo Xiao
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy at Rutgers University, Piscataway, NJ, 08854, USA
| | - Dwayne E Porter
- NIEHS Center for Oceans and Human Health on Climate Change Interactions, Department of Environmental Health Sciences, University of South Carolina, 29208, USA
| | - Bryan W Brooks
- Department of Environmental Science, Baylor University, Waco, TX, 76798-7266, USA
| | - Geoff I Scott
- NIEHS Center for Oceans and Human Health on Climate Change Interactions, Department of Environmental Health Sciences, University of South Carolina, 29208, USA
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Arnold School of Public Health, University of South Carolina, Columbia, SC, 29208, USA; Columbia VA Medical Center, Columbia, SC, 29209, USA.
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17
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Gao L, Chen J, Li J, Cui AQ, Zhang WW, Li XL, Wang J, Zhang XY, Zhao Y, Chen YH, Zhang C, Wang H, Xu DX. Microcystin-LR inhibits testosterone synthesis via reactive oxygen species-mediated GCN2/eIF2α pathway in mouse testes. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 781:146730. [PMID: 33798882 DOI: 10.1016/j.scitotenv.2021.146730] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/21/2021] [Accepted: 03/21/2021] [Indexed: 06/12/2023]
Abstract
Previous studies demonstrated that microcystin-leucine-arginine (MC-LR) disrupted testosterone (T) synthesis, but the underlying mechanisms are not entirely elucidated. This study aims to explore the role of reactive oxygen species (ROS)-mediated GCN2/eIF2α activation on MC-LR-induced disruption of testicular T synthesis. Male mice were intraperitoneally injected with MC-LR (0 or 20 μg/kg) daily for 5 weeks. Serum T was decreased in MC-LR-exposed mice (0.626 ± 0.122 vs 24.565 ± 8.486 ng/ml, P < 0.01), so did testicular T (0.667 ± 0.15 vs 8.317 ± 1.387 ng/mg protein, P < 0.01). Steroidogenic proteins including StAR, CYP11A1 and CYP17A1 were downregulated in MC-LR-exposed mouse testes and TM3 cells. Mechanistically, p-GCN2 and p-eIF2α were elevated in MC-LR-exposed TM3 cells. GCN2iB attenuated MC-LR-induced GCN2 and eIF2α phosphorylation in TM3 cells. Moreover, GCN2iB attenuated MC-LR-induced downregulation of steroidogenic proteins in TM3 cells. Further analysis found that cellular ROS were elevated and HO-1 was upregulated in MC-LR-exposed TM3 cells. PBN rescued MC-LR-induced activation of GCN2/eIF2α signaling in TM3 cells. Additionally, pretreatment with PBN attenuated MC-LR induced downregulation of steroidogenic proteins and synthases in TM3 cells. These results suggest that ROS-mediated GCN2/eIF2α activation contributes partially to MC-LR-caused downregulation of steroidogenic proteins and synthases. The present study provides a new clue for understanding the mechanism of MC-LR-induced endocrine disruption.
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Affiliation(s)
- Lan Gao
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China.
| | - Jing Chen
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China
| | - Jian Li
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China
| | - An-Qi Cui
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China
| | - Wei-Wei Zhang
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China
| | - Xiu-Liang Li
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China
| | - Jing Wang
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China
| | - Xiao-Yi Zhang
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China
| | - Ye Zhao
- Department of Nuclear Medicine, Anhui Medical University, Hefei 230032, China
| | - Yuan-Hua Chen
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China
| | - Cheng Zhang
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China
| | - Hua Wang
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China.
| | - De-Xiang Xu
- Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China.
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18
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Hwang Y, Kim HC, Shin EJ. Repeated exposure to microcystin-leucine-arginine potentiates excitotoxicity induced by a low dose of kainate. Toxicology 2021; 460:152887. [PMID: 34352349 DOI: 10.1016/j.tox.2021.152887] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/15/2021] [Accepted: 07/30/2021] [Indexed: 02/08/2023]
Abstract
Microcystin-leucine-arginine (MLCR) is a cyanobacterial toxin, and has been demonstrated to cause neurotoxicity. In addition, MCLR has been identified as an inhibitor of protein phosphatase (PP)1 and PP2A, which are known to regulate the phosphorylation of various molecules related to synaptic excitability. Thus, in the present study, we examined whether MCLR exposure affects seizures induced by a low dose of kainic acid (KA; 0.05 μg, i.c.v.) administration. KA-induced seizure occurrence and seizure score significantly increased after repeated exposure to MCLR (2.5 or 5.0 μg/kg, i.p., once a day for 10 days), but not after acute MCLR exposure (2.5 or 5.0 μg/kg, i.p., 2 h and 30 min prior to KA administration), and hippocampal neuronal loss was consistently facilitated by repeated exposure to MCLR. In addition, repeated MCLR significantly elevated the membrane expression of kainate receptor GluK2 subunits, p-pan-protein kinase C (PKC), and p-extracellular signal-related kinase (ERK) at 1 h after KA. However, KA-induced membrane expression of Ca2+/calmodulin-dependent kinase II (CaMKII) was significantly reduced by repeated MCLR exposure. Consistent with the enhanced seizures and neurodegeneration, MCLR exposure significantly potentiated KA-induced oxidative stress and microglial activation, which was accompanied by increased expression of p-ERK and p-PKCδ in the hippocampus. The combined results suggest that repeated MCLR exposure potentiates KA-induced excitotoxicity in the hippocampus by increasing membrane GluK2 expression and enhancing oxidative stress and neuroinflammation through the modulation of p-CaMKII, p-PKC, and p-ERK.
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Affiliation(s)
- Yeonggwang Hwang
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Hyoung-Chun Kim
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chuncheon, 24341, Republic of Korea.
| | - Eun-Joo Shin
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chuncheon, 24341, Republic of Korea.
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Pawlik-Skowrońska B, Bownik A. Cyanobacterial anabaenopeptin-B, microcystins and their mixture cause toxic effects on the behavior of the freshwater crustacean Daphnia magna (Cladocera). Toxicon 2021; 198:1-11. [PMID: 33915136 DOI: 10.1016/j.toxicon.2021.04.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/30/2021] [Accepted: 04/23/2021] [Indexed: 10/21/2022]
Abstract
Comparison of the toxic effects caused by the pure cyanobacterial cyclic hexapeptide anabaenopeptin-B (AN-B), the heptapeptides: microcystin-LR (MC-LR) and MC-LF as well as a binary mixture of AN-B with MC-LR on the swimming speed and hopping frequency - essential activities of Daphnia, was experimentally determined. Till now, no information on behavioral effects of AN-B and its mixture with microcystins, commonly produced by cyanobacteria, was available. Also MC-LF effect on aquatic crustaceans was determined for the first time. The results showed that AN-B exerted considerable inhibition of D. magna swimming speed and hopping frequency similar to MC-LR and MC-LF. The mixture of AN-B and MC-LR caused stronger toxic effects, than the individual oligopeptides used at the same concentration. The much lower 48 h- EC50 value of the AN-B and MC-LR mixture (0.95 ± 0.12 μg/mL) than those of individual oligopeptides AN-B (6.3 ± 0.63 μg/mL), MC-LR (4.0 ± 0.27 μg/mL), MC-LF (3.9 ± 0.20 μg/mL) that caused swimming speed inhibition explains the commonly observed stronger toxicity of complex crude cyanobacterial extracts to daphnids than individual microcystins. The obtained results indicated that AN-B, microcystins and their mixture exerted time- and concentration-dependent motility disturbances of crustaceans and they can be good candidates for evaluation of toxicity in early warning systems. Other cyanobacterial oligopeptides beyond microcystins should be considered as a real threat for aquatic organisms.
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Affiliation(s)
- Barbara Pawlik-Skowrońska
- Department of Hydrobiology and Protection of Ecosystems, Faculty of Environmental Biology, University of Life Sciences in Lublin, Dobrzańskiego 37, 20-262, Lublin, Poland.
| | - Adam Bownik
- Department of Hydrobiology and Protection of Ecosystems, Faculty of Environmental Biology, University of Life Sciences in Lublin, Dobrzańskiego 37, 20-262, Lublin, Poland
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20
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Shi L, Du X, Liu H, Chen X, Ma Y, Wang R, Tian Z, Zhang S, Guo H, Zhang H. Update on the adverse effects of microcystins on the liver. ENVIRONMENTAL RESEARCH 2021; 195:110890. [PMID: 33617868 DOI: 10.1016/j.envres.2021.110890] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 06/12/2023]
Abstract
Microcystins (MCs) are the most common cyanobacteria toxins in eutrophic water, which have strong hepatotoxicity. In the past decade, epidemiological and toxicological studies on liver damage caused by MCs have proliferated, and new mechanisms of hepatotoxicity induced by MCs have also been discovered and confirmed. However, there has not been a comprehensive and systematic review of these new findings. Therefore, this paper summarizes the latest advances in studies on the hepatotoxicity of MCs to reveal the effects and mechanisms of hepatotoxicity induced by MCs. Current epidemiological studies have confirmed that symptoms or signs of liver damage appear after human exposure to MCs, and a long time of exposure can even lead to liver cancer. Toxicological studies have shown that MCs can affect the expression of oncogenes by activating cell proliferation pathways such as MAPK and Akt, thereby promoting the occurrence and development of cancer. The latest evidence shows that epigenetic modifications may play an important role in MCs-induced liver cancer. MCs can cause damage to the liver by inducing hepatocyte death, mainly manifested as apoptosis and necrosis. The imbalance of liver metabolic homeostasis may be involved in hepatotoxicity induced by MCs. In addition, the combined toxicity of MCs and other toxins are also discussed in this article. This detailed information will be a valuable reference for further exploring of MCs-induced hepatotoxicity.
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Affiliation(s)
- Linjia Shi
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Xingde Du
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Haohao Liu
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Xinghai Chen
- Department of Chemistry and Biochemistry, St Mary's University, San Antonio, TX, USA
| | - Ya Ma
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Rui Wang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhihui Tian
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Shiyu Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Hongxiang Guo
- College of Life Sciences, Henan Agricultural University, Zhengzhou, Henan, China
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.
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21
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Zeng H, Tan Y, Wang L, Xiang M, Zhou Z, Chen JA, Wang J, Zhang R, Tian Y, Luo J, Huang Y, Lv C, Shu W, Qiu Z. Association of serum microcystin levels with neurobehavior of school-age children in rural area of Southwest China: A cross-sectional study. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 212:111990. [PMID: 33524912 DOI: 10.1016/j.ecoenv.2021.111990] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 06/12/2023]
Abstract
To investigate whether microcystin-LR (MC-LR) influences children's cognitive function and memory ability, we measured serum MC-LR and whole blood lead levels in 697 primary students, and collected their academic and neurobehavioral test scores. The median of serum MC-LR levels was 0.80 µg/L (the value below the limit of detection to 1.67 µg/L). The shapes of the associations of serum MC-LR levels (cut-point: 0.95 µg/L) with scores on academic achievements, digit symbol substitution test and long-term memory test were parabolic curves. Logistic regression analysis showed that MC-LR at concentrations of 0.80-0.95 µg/L was associated with the increased probability of higher achievements on academic achievements [odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.28-3.79], and also with scores on digit symbol substitution test (OR = 1.73, 95% CI: 1.05-2.86), overall memory quotient (OR = 2.27, 95% CI: 1.21-4.26), long-term memory (OR = 1.85, 95% CI: 1.01-3.38) and short-term memory (OR = 2.13, 95% CI: 1.14-3.98) after adjustment for confounding factors. Antagonism of MC-LR and lead on long-term memory was observed (synergism index = 0.15, 95% CI: 0.03-0.74). In conclusion, serum MC-LR at concentrations of 0.80-0.95 µg/L was positively associated with higher scores on cognitive and neurobehavioral tests, and antagonism between MC-LR at concentrations of 0.80-1.67 µg/L and lead exposure was obviously observed on long-term memory in children. Concerning that MC-LR is a neurotoxin at high doses, our observation is interesting and need further investigation.
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Affiliation(s)
- Hui Zeng
- Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yao Tan
- Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Lingqiao Wang
- Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Menglong Xiang
- Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ziyuan Zhou
- Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ji-An Chen
- Department of Health Education, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jia Wang
- Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Renping Zhang
- The Center for Disease Control and Prevention in Fuling District, Chongqing, China
| | - Yingqiao Tian
- The Center for Disease Control and Prevention in Fuling District, Chongqing, China
| | - Jiaohua Luo
- Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yujing Huang
- Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Chen Lv
- Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Weiqun Shu
- Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China.
| | - Zhiqun Qiu
- Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China.
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22
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Zhang Y, Zhu P, Wu X, Yuan T, Su Z, Chen S, Zhou Y, Tao WA. Microcystin-LR Induces NLRP3 Inflammasome Activation via FOXO1 Phosphorylation, Resulting in Interleukin-1β Secretion and Pyroptosis in Hepatocytes. Toxicol Sci 2021; 179:53-69. [PMID: 33078829 DOI: 10.1093/toxsci/kfaa159] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Microcystin-LR (MC-LR), the most common and toxic microcystin (MC) present in freshwater, poses a substantial threat to human health, especially hepatotoxicity. Recent evidence reveals that the NLRP3 inflammasome plays an important role in liver injury by activating caspase-1 to promote interleukin-1β (IL-1β) secretion. In this study, we investigated the possible role of NLRP3 inflammasome activation in MC-LR-induced mouse liver inflammatory injury. We found that MC-LR administered to mice by oral gavage mainly accumulated in liver and induced the activation of the NLRP3 inflammasome and production of mature IL-1β. Additionally, we observed an increase in the levels of NLRP3 inflammasome-related proteins and the proportion of pyroptosis in MC-LR-treated AML-12 cells. We also found that inhibition of NLRP3 in mice attenuated MC-LR-induced IL-1β production, indicating an essential role for NLRP3 in MC-LR-induced liver inflammatory injury. In addition, we found that inhibition of FOXO1 by AKT-mediated hyperphosphorylation, due to protein phosphatase 2A (PP2A) inhibition, is required for MC-LR-induced expression of NLRP3. Taken together, our in vivo and in vitro findings suggest a model in which the NLRP3 inflammasome activation, a result of AKT-mediated hyperphosphorylation of FOXO1 through inhibition of PP2A, plays a key role in MC-LR-induced liver inflammatory injury via IL-1β secretion and pyroptotic cell death.
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Affiliation(s)
- Yali Zhang
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
| | - Peipei Zhu
- Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907
| | - Xiaofeng Wu
- Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907
| | - Tianli Yuan
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
| | - Zhangyao Su
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
| | - Shiyin Chen
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
| | - Yajun Zhou
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
| | - Weiguo Andy Tao
- Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907
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23
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Stage TB, Hu S, Sparreboom A, Kroetz DL. Role for Drug Transporters in Chemotherapy-Induced Peripheral Neuropathy. Clin Transl Sci 2020; 14:460-467. [PMID: 33142018 PMCID: PMC7993259 DOI: 10.1111/cts.12915] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 10/05/2020] [Indexed: 01/03/2023] Open
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity to widely used chemotherapeutics. Although the exact molecular mechanism of chemotherapy-induced peripheral neuropathy remains elusive, there is consensus that it is caused by damage to the peripheral nervous system leading to sensory symptoms. Recently developed methodologies have provided evidence of expression of drug transporters in the peripheral nervous system. In this literature review, we explore the role for drug transporters in CIPN. First, we assessed the transport of chemotherapeutics that cause CIPN (taxanes, platins, vincristine, bortezomib, epothilones, and thalidomide). Second, we cross-referenced the transporters implicated in genetic or functional studies with CIPN with their expression in the peripheral nervous system. Several drug transporters are involved in the transport of chemotherapeutics that cause peripheral neuropathy and particularly efflux transporters, such as ABCB1 and ABCC1, are expressed in the peripheral nervous system. Previous literature has linked genetic variants in efflux transporters to higher risk of peripheral neuropathy with the taxanes paclitaxel and docetaxel and the vinca alkaloid vincristine. We propose that this might be due to accumulation of the chemotherapeutics in the peripheral nervous system due to reduced neuronal efflux capacity. Thus, concomitant administration of efflux transporter inhibitors may lead to higher risk of adverse events of drugs that cause CIPN. This might prove valuable in drug development where screening new drugs for neurotoxicity might also require drug transporter consideration. There are ongoing efforts targeting drug transporters in the peripheral nervous system to reduce intraneuronal concentrations of chemotherapeutics that cause CIPN, which might ultimately protect against this dose-limiting adverse event.
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Affiliation(s)
- Tore B Stage
- Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmaceutical Sciences, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmaceutical Sciences, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Deanna L Kroetz
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
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24
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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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25
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Zhang C, Wang J, Zhu J, Chen Y, Han X. Microcystin-leucine-arginine induced neurotoxicity by initiating mitochondrial fission in hippocampal neurons. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 703:134702. [PMID: 31753492 DOI: 10.1016/j.scitotenv.2019.134702] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 09/24/2019] [Accepted: 09/27/2019] [Indexed: 06/10/2023]
Abstract
Microcystin-leucine-arginine (MC-LR) can cross the blood-brain barrier (BBB) and demonstrate potent acute hippocampal neurotoxicity. Chronic exposure to MC-LR has been confirmed to cause learning and memory deficits in mice, but the potential molecular mechanism of MC-LR-caused neurotoxicity is still unclear. In this research, we observed that MC-LR induced oxidative stress, mitochondrial fission and apoptosis in HT-22 hippocampal neurons. Moreover, further studies identified that MC-LR induced mitochondrial fragmentation via activating Dynamin-related protein 1 (Drp1) and Mitochondrial fission factor (Mff), contributing to apoptosis of hippocampal neuronal cells. The observed effects were associated with increased intracellular Ca2+ and reduced activity of protein phosphatases 2A (PP2A) as results of MC-LR exposure in hippocampal neuron cells. Ca2+ activates CaMK II and Akt to enhance phosphorylation of Drp1 at Ser616 residue. Inhibition of PP2A activity increased AMPK activity to mediate phosphorylation of Mff. Our data proved that MC-LR can cause mitochondrial fragmentation in hippocampal neurons, which provides novel perception to explore the underlying molecular mechanism associated with MC-LR-induced neurotoxicity and Alzheimer's disease-like changes.
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Affiliation(s)
- Changliang Zhang
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China
| | - Jing Wang
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China
| | - Jinling Zhu
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China
| | - Yabing Chen
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.
| | - Xiaodong Han
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.
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26
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Anderson JT, Huang KM, Lustberg MB, Sparreboom A, Hu S. Solute Carrier Transportome in Chemotherapy-Induced Adverse Drug Reactions. Rev Physiol Biochem Pharmacol 2020; 183:177-215. [PMID: 32761456 DOI: 10.1007/112_2020_30] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics. These proteins are highly expressed in the gastrointestinal tract and eliminating organs such as the liver and kidney, and are considered to be of particular importance in governing drug absorption and elimination. Many of the same transporters are also expressed in a wide variety of organs targeted by clinically important anticancer drugs, directly affect cellular sensitivity to these agents, and indirectly influence treatment-related side effects. Furthermore, targeted intervention strategies involving the use of transport inhibitors have been recently developed, and have provided promising lead candidates for combinatorial therapies associated with decreased toxicity. Gaining a better understanding of the complex interplay between transporter-mediated on-target and off-target drug disposition will help guide the further development of these novel treatment strategies to prevent drug accumulation in toxicity-associated organs, and improve the safety of currently available treatment modalities. In this report, we provide an update on this rapidly emerging field with particular emphasis on anticancer drugs belonging to the classes of taxanes, platinum derivatives, nucleoside analogs, and anthracyclines.
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Affiliation(s)
- Jason T Anderson
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Kevin M Huang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Maryam B Lustberg
- Department of Medical Oncology, The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
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27
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Cao L, Massey IY, Feng H, Yang F. A Review of Cardiovascular Toxicity of Microcystins. Toxins (Basel) 2019; 11:toxins11090507. [PMID: 31480273 PMCID: PMC6783932 DOI: 10.3390/toxins11090507] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 08/27/2019] [Accepted: 08/28/2019] [Indexed: 12/30/2022] Open
Abstract
The mortality rate of cardiovascular diseases (CVD) in China is on the rise. The increasing burden of CVD in China has become a major public health problem. Cyanobacterial blooms have been recently considered a global environmental concern. Microcystins (MCs) are the secondary products of cyanobacteria metabolism and the most harmful cyanotoxin found in water bodies. Recent studies provide strong evidence of positive associations between MC exposure and cardiotoxicity, representing a threat to human cardiovascular health. This review focuses on the effects of MCs on the cardiovascular system and provides some evidence that CVD could be induced by MCs. We summarized the current knowledge of the cardiovascular toxicity of MCs, with regard to direct cardiovascular toxicity and indirect cardiovascular toxicity. Toxicity of MCs is mainly governed by the increasing level of reactive oxygen species (ROS), oxidative stress in mitochondria and endoplasmic reticulum, the inhibition activities of serine/threonine protein phosphatase 1 (PP1) and 2A (PP2A) and the destruction of cytoskeletons, which finally induce the occurrence of CVD. To protect human health from the threat of MCs, this paper also puts forward some directions for further research.
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Affiliation(s)
- Linghui Cao
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan, China
| | - Isaac Yaw Massey
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan, China
| | - Hai Feng
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan, China
| | - Fei Yang
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan, China.
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28
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Kaur G, Fahrner R, Wittmann V, Stieger B, Dietrich DR. Human MRP2 exports MC-LR but not the glutathione conjugate. Chem Biol Interact 2019; 311:108761. [PMID: 31348918 DOI: 10.1016/j.cbi.2019.108761] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 07/18/2019] [Accepted: 07/22/2019] [Indexed: 01/20/2023]
Abstract
Water contamination by cyanobacterial blooms is a worldwide health hazard to humans as well as livestock. Exposure to Microcystins (MCs), toxins produced by various cyanobacterial or blue green algae found in poorly treated drinking water or contaminated seafood such as fish or prawns are associated with hepatotoxicity, nephropathy and neurotoxicity and in extreme cases, death in humans. MC congeners, currently >240 known, differ dramatically in their uptake kinetics, i.e. their uptake via OATP1B1 and OATP1B3, in OATP overexpressing human HEK293 cells and primary human hepatocytes. It is thus likely that MC congeners will also differ with respect to the cellular efflux of the parent and conjugated congeners, e.g. via MRPs, MDRs, BCRP or BSEP. Consequently, the role and kinetics of different human efflux transporters - MRP, MDR, BCRP and BSEP in MC efflux was studied using insect membrane vesicles overexpressing the human transporters of interest. Of the efflux transporters investigated, MRP2 displayed MC transport. Michaelis-Menten kinetics displayed mild co-operativity and thus allosteric behavior of MRP2. MC transport by MRP2 was MC congener-specific, whereby MC-LF was transported more rapidly than MC-LR and -RR. Other human transporters (BCRP, BSEP, MRP1,3,5, MDR1) tested in this study did not exhibit interaction with MC. Although MRP2 showed specific MC transport, the MC-LR-GSH conjugate, was not transported suggesting the involvement of other transporters than MRP2 for the conjugate efflux.
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Affiliation(s)
- Gurjot Kaur
- Human and Environmental Toxicology, University of Konstanz, 78457, Konstanz, Germany; School of Pharmaceutical Sciences, Shoolini University, Solan, 173212, India.
| | - Raphael Fahrner
- Department of Chemistry, University of Konstanz, 78457, Konstanz, Germany.
| | - Valentin Wittmann
- Department of Chemistry, University of Konstanz, 78457, Konstanz, Germany.
| | - Bruno Stieger
- Department of Clinical Pharmacology and Toxicology, University Hospital, 8091, Zurich, Switzerland.
| | - Daniel Reto Dietrich
- Human and Environmental Toxicology, University of Konstanz, 78457, Konstanz, Germany.
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29
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Hinojosa MG, Gutiérrez-Praena D, Prieto AI, Guzmán-Guillén R, Jos A, Cameán AM. Neurotoxicity induced by microcystins and cylindrospermopsin: A review. THE SCIENCE OF THE TOTAL ENVIRONMENT 2019; 668:547-565. [PMID: 30856566 DOI: 10.1016/j.scitotenv.2019.02.426] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 02/25/2019] [Accepted: 02/27/2019] [Indexed: 05/26/2023]
Abstract
Microcystins (MCs) and cylindrospermopsin (CYN) are among the most frequent toxins produced by cyanobacteria. These toxic secondary metabolites are classified as hepatotoxins and cytotoxin, respectively. Furthermore, both may present the ability to induce damage to the nervous system. In this sense, there are many studies manifesting the potential of MCs to cause neurotoxicity both in vitro and in vivo, due to their probable capacity to cross the blood-brain-barrier through organic anion transporting polypeptides. Moreover, the presence of MCs has been detected in brain of several experimental models. Among the neurological effects, histopathological brain changes, deregulation of biochemical parameters in brain (production of oxidative stress and inhibition of protein phosphatases) and behavioral alterations have been described. It is noteworthy that minority variants such as MC-LF and -LW have demonstrated to exert higher neurotoxic effects compared to the most studied congener, MC-LR. By contrast, the available studies concerning CYN-neurotoxic effects are very scarce, mostly showing inflammation and apoptosis in neural murine cell lines, oxidative stress, and alteration of the acetylcholinesterase activity in vivo. However, more studies are required in order to clarify the neurotoxic potential of both toxins, as well as their possible contribution to neurodegenerative diseases.
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Affiliation(s)
- M G Hinojosa
- Area of Toxicology, Faculty of Pharmacy, Universidad de Sevilla, C/Profesor García González 2, 41012 Seville, Spain
| | - D Gutiérrez-Praena
- Area of Toxicology, Faculty of Pharmacy, Universidad de Sevilla, C/Profesor García González 2, 41012 Seville, Spain
| | - A I Prieto
- Area of Toxicology, Faculty of Pharmacy, Universidad de Sevilla, C/Profesor García González 2, 41012 Seville, Spain.
| | - R Guzmán-Guillén
- Area of Toxicology, Faculty of Pharmacy, Universidad de Sevilla, C/Profesor García González 2, 41012 Seville, Spain
| | - A Jos
- Area of Toxicology, Faculty of Pharmacy, Universidad de Sevilla, C/Profesor García González 2, 41012 Seville, Spain
| | - A M Cameán
- Area of Toxicology, Faculty of Pharmacy, Universidad de Sevilla, C/Profesor García González 2, 41012 Seville, Spain
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30
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Díez-Quijada L, Prieto AI, Guzmán-Guillén R, Jos A, Cameán AM. Occurrence and toxicity of microcystin congeners other than MC-LR and MC-RR: A review. Food Chem Toxicol 2018; 125:106-132. [PMID: 30597222 DOI: 10.1016/j.fct.2018.12.042] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 11/29/2018] [Accepted: 12/25/2018] [Indexed: 12/11/2022]
Abstract
The occurrence of cyanobacterial toxins is being increasingly reported. This is a reason for concern as they can induce toxic effects both in humans and in the environment. Among them, microcystins (MCs) are the best described and most diverse group of cyanobacterial toxins, and MC-LR and MC-RR are the congeners most widely investigated. However, the number of MC variants has also increased in recent years. Some of these minority variants have been shown to have a different toxicokinetic and toxicodynamic profile, but research focused on them is still limited. Moreover, in some water bodies these minority variants can be the predominant toxins. Nonetheless, MC-LR is the only one used for risk evaluation purposes at present. In order to contribute to more realistic risk assessments in the future, the aim of this review was to compile the available information in the scientific literature regarding the occurrence and concentration of minority MCs in water and food samples, and their toxic effects. The data retrieved demonstrate the congener-specific toxicity of MCs, as well as many data gaps in relation to analytical or mechanistic aspects, among others. Therefore, further research is needed to improve the toxicological characterization of these toxins and the exposure scenarios.
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Affiliation(s)
- Leticia Díez-Quijada
- Area of Toxicology, Faculty of Pharmacy, Universidad de Sevilla, C/Profesor García González 2, 41012, Seville, Spain
| | - Ana I Prieto
- Area of Toxicology, Faculty of Pharmacy, Universidad de Sevilla, C/Profesor García González 2, 41012, Seville, Spain
| | - Remedios Guzmán-Guillén
- Area of Toxicology, Faculty of Pharmacy, Universidad de Sevilla, C/Profesor García González 2, 41012, Seville, Spain
| | - Angeles Jos
- Area of Toxicology, Faculty of Pharmacy, Universidad de Sevilla, C/Profesor García González 2, 41012, Seville, Spain.
| | - Ana M Cameán
- Area of Toxicology, Faculty of Pharmacy, Universidad de Sevilla, C/Profesor García González 2, 41012, Seville, Spain
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31
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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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Shin EJ, Hwang YG, Pham DT, Lee JW, Lee YJ, Pyo D, Jeong JH, Lei XG, Kim HC. Glutathione peroxidase-1 overexpressing transgenic mice are protected from neurotoxicity induced by microcystin-leucine-arginine. ENVIRONMENTAL TOXICOLOGY 2018; 33:1019-1028. [PMID: 30076769 DOI: 10.1002/tox.22580] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 05/15/2018] [Accepted: 05/20/2018] [Indexed: 06/08/2023]
Abstract
Although it has been well-recognized that microcystin-leucine-arginine (MCLR), the most common form of microcystins, induces neurotoxicity, little is currently known about the underlying mechanism for this neurotoxicity. Here, we found that MCLR (10 ng/μL/mouse, i.c.v.) induces significant neuronal loss in the hippocampus of mice. MCLR-induced neurotoxicity was accompanied by oxidative stress, as shown by a significant increase in the level of 4-hydroxynonenal, protein carbonyl, and reactive oxygen species (ROS). Superoxide dismutase-1 (SOD-1) activity was significantly increased, but glutathione peroxidase (GPx) level was significantly decreased following MCLR insult. In addition, MCLR significantly inhibited GSH/GSSG ratio, and significantly induced NFκB DNA binding activity. Because reduced activity of GPx appeared to be critical for the imbalance between activities of SODs and GPx, we utilized GPx-1 overexpressing transgenic mice to ascertain the role of GPx-1 in this neurotoxicity. Genetic overexpression of GPx-1 or NFκB inhibitor pyrrolidine dithiocarbamate (PDTC) significantly attenuated MCLR-induced hippocampal neuronal loss in mice. However, PDTC did not exert any additive effect on neuroprotection mediated by GPx-1 overexpression, indicating that NFκB is a neurotoxic target of MCLR. Combined, these results suggest that MCLR-induced neurotoxicity requires oxidative stress associated with failure in compensatory induction of GPx, possibly through activation of the transcription factor NFκB.
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Affiliation(s)
- Eun-Joo Shin
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Republic of Korea
| | - Yeong Gwang Hwang
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Republic of Korea
| | - Duc Toan Pham
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Republic of Korea
| | - Ji Won Lee
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Republic of Korea
| | - Yu Jeung Lee
- Clinical Pharmacy, College of Pharmacy, Kangwon National University, Republic of Korea
| | - Dongjin Pyo
- Department of Chemistry, College of Natural Sciences, Kangwon National University, Republic of Korea
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Xin Gen Lei
- Department of Animal Science, Cornell University, New York
| | - Hyoung-Chun Kim
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Republic of Korea
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33
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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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34
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Wang X, Xu L, Li X, Chen J, Zhou W, Sun J, Wang Y. The differential effects of microcystin-LR on mitochondrial DNA in the hippocampus and cerebral cortex. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2018; 240:68-76. [PMID: 29729571 DOI: 10.1016/j.envpol.2018.04.103] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 04/23/2018] [Accepted: 04/23/2018] [Indexed: 06/08/2023]
Abstract
Microcystin-LR (MC-LR) is the most abundant toxicant among microcystin variants produced by cyanobacteria. MC-induced toxicity is broadly reported to pose a threat to aquatic animals and humans and has been associated with the dysfunction of some organs such as liver and kidney. However, MC-induced neurotoxicity has not been well characterized after long-term exposure. This study was designed to investigate the neurotoxic effects after chronic oral administration of MC-LR. In our trial, C57/BL6 mice received MC-LR at 0, 1, 5, 10, 20 and 40 μg/L in drinking water for twelve months. Our data demonstrated that mitochondrial DNA (mtDNA) damage was evident in the damaged neurons as a result of chronic exposure. Histopathological abnormalities and mtDNA damage were observed in the hippocampus and cerebral cortex. Furthermore, MC-LR exerted distinct effects on these two brain regions. The hippocampus was more susceptible to the treatment of MC-LR compared with the cerebral cortex. However, no strong relationships were observed between the genotoxic effects and exposure doses. In conclusion, this study has provided a mtDNA-related mechanism for underlying chronic neurotoxicity of MC-LR and suggested the presence of differential toxicant effects on the hippocampus and cerebral cortex.
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Affiliation(s)
- Xiaofen Wang
- Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, China
| | - Lizhi Xu
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, China; Experimental Center of Basic Medicine, Nanjing University School of Medicine, Nanjing, China
| | - Xinxiu Li
- Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, China
| | - Jingwen Chen
- Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, China
| | - Wei Zhou
- Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, China
| | - Jiapeng Sun
- Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, China
| | - Yaping Wang
- Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, China.
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Toxic Cyanobacteria in Svalbard: Chemical Diversity of Microcystins Detected Using a Liquid Chromatography Mass Spectrometry Precursor Ion Screening Method. Toxins (Basel) 2018; 10:toxins10040147. [PMID: 29614044 PMCID: PMC5923313 DOI: 10.3390/toxins10040147] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/27/2018] [Accepted: 03/29/2018] [Indexed: 11/16/2022] Open
Abstract
Cyanobacteria synthesize a large variety of secondary metabolites including toxins. Microcystins (MCs) with hepato- and neurotoxic potential are well studied in bloom-forming planktonic species of temperate and tropical regions. Cyanobacterial biofilms thriving in the polar regions have recently emerged as a rich source for cyanobacterial secondary metabolites including previously undescribed congeners of microcystin. However, detection and detailed identification of these compounds is difficult due to unusual sample matrices and structural congeners produced. We here report a time-efficient liquid chromatography-mass spectrometry (LC-MS) precursor ion screening method that facilitates microcystin detection and identification. We applied this method to detect six different MC congeners in 8 out of 26 microbial mat samples of the Svalbard Archipelago in the Arctic. The congeners, of which [Asp3, ADMAdda5, Dhb7] MC-LR was most abundant, were similar to those reported in other polar habitats. Microcystins were also determined using an Adda-specific enzyme-linked immunosorbent assay (Adda-ELISA). Nostoc sp. was identified as a putative toxin producer using molecular methods that targeted 16S rRNA genes and genes involved in microcystin production. The mcy genes detected showed highest similarities to other Arctic or Antarctic sequences. The LC-MS precursor ion screening method could be useful for microcystin detection in unusual matrices such as benthic biofilms or lichen.
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Leblanc AF, Sprowl JA, Alberti P, Chiorazzi A, Arnold WD, Gibson AA, Hong KW, Pioso MS, Chen M, Huang KM, Chodisetty V, Costa O, Florea T, de Bruijn P, Mathijssen RH, Reinbolt RE, Lustberg MB, Sucheston-Campbell LE, Cavaletti G, Sparreboom A, Hu S. OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity. J Clin Invest 2018; 128:816-825. [PMID: 29337310 DOI: 10.1172/jci96160] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 11/28/2017] [Indexed: 01/11/2023] Open
Abstract
Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion-transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management.
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Affiliation(s)
- Alix F Leblanc
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Jason A Sprowl
- Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D'Youville College, Buffalo, New York, USA
| | - Paola Alberti
- Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Alessia Chiorazzi
- Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - W David Arnold
- Division of Neuromuscular Disorders, Department of Neurology, College of Medicine, The Ohio State University, Columbus, Ohio, USA
| | - Alice A Gibson
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Kristen W Hong
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Marissa S Pioso
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Mingqing Chen
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Kevin M Huang
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Vamsi Chodisetty
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Olivia Costa
- Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D'Youville College, Buffalo, New York, USA
| | - Tatiana Florea
- Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D'Youville College, Buffalo, New York, USA
| | - Peter de Bruijn
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Ron H Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | | | | | - Lara E Sucheston-Campbell
- Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Guido Cavaletti
- Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
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37
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Yang X, Liu W, Lin H, Zeng H, Zhang R, Pu C, Wang L, Zheng C, Tan Y, Luo Y, Feng X, Tian Y, Xiao G, Wang J, Huang Y, Luo J, Qiu Z, Chen JA, Wu L, He L, Shu W. Interaction Effects of AFB1 and MC-LR Co-exposure with Polymorphism of Metabolic Genes on Liver Damage: focusing on SLCO1B1 and GSTP1. Sci Rep 2017; 7:16164. [PMID: 29170472 PMCID: PMC5700940 DOI: 10.1038/s41598-017-16432-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 11/13/2017] [Indexed: 02/08/2023] Open
Abstract
AFB1 and MC-LR are two major environmental risk factors for liver damage worldwide, especially in warm and humid areas, but there are individual differences in health response of the toxin-exposed populations. Therefore, we intended to identify the susceptible genes in transport and metabolic process of AFB1 and MC-LR and find their effects on liver damage. We selected eight related SNPs that may affect liver damage outcomes in AFB1 and MC-LR exposed persons, and enrolled 475 cases with liver damage and 475 controls of healthy people in rural areas of China. The eight SNPs were genotyped by PCR and restriction fragment length polymorphism. We found that SLCO1B1 (T521C) is a risk factor for liver damage among people exposed to high AFB1 levels alone or combined with MC-LR, and that GSTP1 (A1578G) could indicate the risk of liver damage among those exposed to high MC-LR levels alone or combined with high AFB1 levels. However, GSTP1 (A1578G) could reduce the risk of liver damage in populations exposed to low MC-LR levels alone or combined with high AFB1 levels. In conclusion, SLCO1B1 (T521C) and GSTP1 (A1578G) are susceptible genes for liver damage in humans exposed to AFB1 and/or MC-LR in rural areas of China.
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Affiliation(s)
- Xiaohong Yang
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Wenyi Liu
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Hui Lin
- Department of Tropical Epidemiology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Hui Zeng
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Renping Zhang
- The Center for Disease Control and Prevention in Fuling District, Chongqing, 408000, China
| | - Chaowen Pu
- The Center for Disease Control and Prevention in Fuling District, Chongqing, 408000, China
| | - Lingqiao Wang
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Chuanfen Zheng
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Yao Tan
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Yang Luo
- Center for Nanomedicine, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Xiaobin Feng
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Yingqiao Tian
- The Center for Disease Control and Prevention in Fuling District, Chongqing, 408000, China
| | - Guosheng Xiao
- College of Life Science and Engineering, Chongqing Three Gorges University, Wanzhou, Chongqing, 404100, China
| | - Jia Wang
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Yujing Huang
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Jiaohua Luo
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Zhiqun Qiu
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Ji-An Chen
- Department of Health Education, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Liping Wu
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Lixiong He
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Weiqun Shu
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
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Altaner S, Puddick J, Wood SA, Dietrich DR. Adsorption of Ten Microcystin Congeners to Common Laboratory-Ware Is Solvent and Surface Dependent. Toxins (Basel) 2017; 9:toxins9040129. [PMID: 28383495 PMCID: PMC5408203 DOI: 10.3390/toxins9040129] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 03/23/2017] [Accepted: 03/31/2017] [Indexed: 11/21/2022] Open
Abstract
Cyanobacteria can produce heptapetides called microcystins (MC) which are harmful to humans due to their ability to inhibit cellular protein phosphatases. Quantitation of these toxins can be hampered by their adsorption to common laboratory-ware during sample processing and analysis. Because of their structural diversity (>100 congeners) and different physico-chemical properties, they vary in their adsorption to surfaces. In this study, the adsorption of ten different MC congeners (encompassing non-arginated to doubly-arginated congeners) to common laboratory-ware was assessed using different solvent combinations. Sample handling steps were mimicked with glass and polypropylene pipettes and vials with increasing methanol concentrations at two pH levels, before analysis by liquid chromatography-tandem mass spectrometry. We demonstrated that MC adsorb to polypropylene surfaces irrespective of pH. After eight successive pipet actions using polypropylene tips ca. 20% of the MC were lost to the surface material, which increased to 25%–40% when solutions were acidified. The observed loss was alleviated by changing the methanol (MeOH) concentration in the final solvent. The required MeOH concentration varied depending on which congener was present. Microcystins only adsorbed to glass pipettes (loss up to 30% after eight pipet actions) when in acidified aqueous solutions. The latter appeared largely dependent on the presence of ionizable groups, such as arginine residues.
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Affiliation(s)
- Stefan Altaner
- Human and Environmental Toxicology, University of Konstanz, P.O. Box 662, 78457 Konstanz, Germany.
| | | | - Susanna A Wood
- Environmental Research Institute, University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand.
| | - Daniel R Dietrich
- Human and Environmental Toxicology, University of Konstanz, P.O. Box 662, 78457 Konstanz, Germany.
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Ding J, Wang J, Xiang Z, Diao W, Su M, Shi W, Wan T, Han X. The organic anion transporting polypeptide 1a5 is a pivotal transporter for the uptake of microcystin-LR by gonadotropin-releasing hormone neurons. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2017; 182:1-10. [PMID: 27842270 DOI: 10.1016/j.aquatox.2016.11.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 11/03/2016] [Accepted: 11/04/2016] [Indexed: 06/06/2023]
Abstract
Microcystins (MCs) are widely distributed hepatotoxic polypeptides produced by cyanobacteria. Microcystin-LR (MC-LR) has the broadest distribution and strongest toxicity among more than 80 isoforms of hepatotoxic MCs. MC-LR suppresses the expression of gonadotropin-releasing hormone (GnRH) that is critically required for the release of testosterone, resulting in the induction of male reproductive toxicity. However, the specific mechanisms of the uptake of MC-LR by GnRH-secreting neurons still remain unclear. In this study, GT1-7 cells were exposed to MC-LR in order to determine whether the GnRH-secreting neurons were the target of MC-LR that could induce male reproductive toxicity. Our data demonstrated that at least four organic anion transporting polypeptides (Oatp1a4, Oatp1a5, Oatp5a1, Oatp2b1) were expressed in GnRH neurons at the mRNA level, but only Oatp1a5 was expressed at the protein level. Furthermore, we demonstrated that MC-LR could not be transported into Oatp1a5-deficient GT1-7 cells which were protected from cell viability loss induced by MC-LR. These data suggest that Oatp1a5 may play an important role in the toxic effect of MC-LR on GnRH neurons.
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Affiliation(s)
- Jie Ding
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China.
| | - Jing Wang
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China.
| | - Zou Xiang
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China Mailing address: Immunology and Reproductive Biology Laboratory, Medical School of Nanjing University, Hankou Road 22, Nanjing 210093, China.
| | - Weiyi Diao
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China.
| | - Moxi Su
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China.
| | - Weiwei Shi
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China.
| | - Ting Wan
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China.
| | - Xiaodong Han
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China.
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40
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Bulc Rozman K, Jurič DM, Šuput D. Selective cytotoxicity of microcystins LR, LW and LF in rat astrocytes. Toxicol Lett 2016; 265:1-8. [PMID: 27864109 DOI: 10.1016/j.toxlet.2016.11.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 11/08/2016] [Accepted: 11/14/2016] [Indexed: 12/24/2022]
Abstract
Microcystins (MCs) comprise a group of cyanobacterial toxins with hepatotoxic, nephrotoxic and, possibly, neurotoxic activity in mammals. In order to understand the development of their neurotoxicity we investigated the toxic effects of MC variants, MC-LR, MC-LW and MC-LF, in astrocytes that play a central role in maintaining brain homeostasis. 24h exposure of cultured rat cortical astrocytes to MCs revealed dose-dependent toxicity of MC-LF and MC-LW, but not of MC-LR, observed by significant reduction in cell number, declined viability monitored by MTT test and an increased percentage of apoptotic cells, confirmed by Annexin-V labelling. The cultured astrocytes expressed organic anion-transporting polypeptides (Oatp) Oatp1a4, Oatp1c1 and Oatp1a5, but not Oatp1b2. Intracellular localisation of MC-LF and MC-LW, proven by anti-Adda primary antibody, demonstrated transport of tested MCs into cultured astrocytes. Acute MC-LW and MC-LF intoxication induced cytoskeletal disruption as seen by the degradation of glial fibrillary acid protein (GFAP), actin and the tubulin network. In this in vitro study, MC-LF and MC-LW, but not MC-LR, are shown to cause the dysfunction of astrocytic homeostatic capabilities, already at low concentrations, suggesting that astrocyte atrophy, with loss of function, could be expected in the brain response to the toxic insult.
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Affiliation(s)
- Klara Bulc Rozman
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, Ljubljana, Slovenia.
| | - Damijana Mojca Jurič
- Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, Ljubljana, Slovenia.
| | - Dušan Šuput
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, Ljubljana, Slovenia.
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Zemskov I, Kropp HM, Wittmann V. Regioselective Cleavage of Thioether Linkages in Microcystin Conjugates. Chemistry 2016; 22:10990-7. [DOI: 10.1002/chem.201601660] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 05/06/2016] [Indexed: 11/07/2022]
Affiliation(s)
- Ivan Zemskov
- University of Konstanz; Department of Chemistry and Konstanz Research School Chemical Biology (KoRS-CB); 78457 Konstanz Germany
| | - Heike M. Kropp
- University of Konstanz; Department of Chemistry and Konstanz Research School Chemical Biology (KoRS-CB); 78457 Konstanz Germany
| | - Valentin Wittmann
- University of Konstanz; Department of Chemistry and Konstanz Research School Chemical Biology (KoRS-CB); 78457 Konstanz Germany
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42
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Hu Y, Chen J, Fan H, Xie P, He J. A review of neurotoxicity of microcystins. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2016; 23:7211-7219. [PMID: 26857003 DOI: 10.1007/s11356-016-6073-y] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 01/06/2016] [Indexed: 06/05/2023]
Abstract
Cyanobacterial blooms-produced microcystins are secondary metabolites which can accumulate in the food chain and contaminate water, thus posing a potential threat to the health of aquatic animals and even humans. Microcystin toxicity affects not only the liver but also the other organs, i.e., the brain. The serious neurotoxicity effects caused by microcystins then lead to various symptoms. This review focuses on the neurotoxicity of microcystins. Microcystins can cross blood-brain barrier with the transport of Oatps/OATPs, causing neurostructural, functional, and behavioral changes. In this review, potential uptake mechanisms and neurotoxicity mechanisms are summarized, including neurotransmissions, neurochannels, signal transduction, oxidative stress, and cytoskeleton disruption. However, further researches are needed for detailed studies on signaling pathways and the downstream pathways of neurotoxicity of microcystins.
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Affiliation(s)
- Yufei Hu
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, No.7 Donghu South Road, Wuhan, 430072, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jun Chen
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, No.7 Donghu South Road, Wuhan, 430072, China
| | - Huihui Fan
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ping Xie
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, No.7 Donghu South Road, Wuhan, 430072, China.
| | - Jun He
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, No.7 Donghu South Road, Wuhan, 430072, China
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43
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Harke MJ, Steffen MM, Gobler CJ, Otten TG, Wilhelm SW, Wood SA, Paerl HW. A review of the global ecology, genomics, and biogeography of the toxic cyanobacterium, Microcystis spp. HARMFUL ALGAE 2016; 54:4-20. [PMID: 28073480 DOI: 10.1016/j.hal.2015.12.007] [Citation(s) in RCA: 544] [Impact Index Per Article: 60.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 12/22/2015] [Indexed: 05/03/2023]
Abstract
This review summarizes the present state of knowledge regarding the toxic, bloom-forming cyanobacterium, Microcystis, with a specific focus on its geographic distribution, toxins, genomics, phylogeny, and ecology. A global analysis found documentation suggesting geographic expansion of Microcystis, with recorded blooms in at least 108 countries, 79 of which have also reported the hepatatoxin microcystin. The production of microcystins (originally "Fast-Death Factor") by Microcystis and factors that control synthesis of this toxin are reviewed, as well as the putative ecophysiological roles of this metabolite. Molecular biological analyses have provided significant insight into the ecology and physiology of Microcystis, as well as revealed the highly dynamic, and potentially unstable, nature of its genome. A genetic sequence analysis of 27 Microcystis species, including 15 complete/draft genomes are presented. Using the strictest biological definition of what constitutes a bacterial species, these analyses indicate that all Microcystis species warrant placement into the same species complex since the average nucleotide identity values were above 95%, 16S rRNA nucleotide identity scores exceeded 99%, and DNA-DNA hybridization was consistently greater than 70%. The review further provides evidence from around the globe for the key role that both nitrogen and phosphorus play in controlling Microcystis bloom dynamics, and the effect of elevated temperature on bloom intensification. Finally, highlighted is the ability of Microcystis assemblages to minimize their mortality losses by resisting grazing by zooplankton and bivalves, as well as viral lysis, and discuss factors facilitating assemblage resilience.
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Affiliation(s)
- Matthew J Harke
- Department of Earth and Environmental Sciences, Lamont-Doherty Earth Observatory, Columbia University, Palisades, NY 10964, United States
| | - Morgan M Steffen
- James Madison University, Department of Biology, 951 Carrier Dr., Harrisonburg, VA 22807, United States.
| | - Christopher J Gobler
- Stony Brook University, School of Marine and Atmospheric Sciences, 239 Montauk Hwy, Southampton, NY 11968, United States
| | - Timothy G Otten
- Oregon State University, Department of Microbiology, Nash Hall 226, Corvallis, OR 97331, United States
| | - Steven W Wilhelm
- University of Tennessee, Department of Microbiology, 1414 West Cumberland Ave., Knoxville, TN 37996, United States
| | - Susanna A Wood
- Cawthron Institute, Private Bag 2, Nelson, New Zealand and Environmental Research Institute, University of Waikato, Hamilton, New Zealand
| | - Hans W Paerl
- University of North Carolina at Chapel Hill, Institute of Marine Sciences, 3431 Arendell Street, Morehead City, NC 28557, United States
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44
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Zhao Y, Xue Q, Su X, Xie L, Yan Y, Wang L, Steinman AD. First Identification of the Toxicity of Microcystins on Pancreatic Islet Function in Humans and the Involved Potential Biomarkers. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2016; 50:3137-3144. [PMID: 26859764 DOI: 10.1021/acs.est.5b03369] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Microcystins (MCs) produced by cyanobacteria have been recognized as a major public health threat. However, the toxicity of MCs to humans is still largely unknown. In this study, we examined the changes in pancreatic islet function in fishers exposed to ambient levels of MCs at Lake Taihu and, using a mouse model, explored the molecular mechanisms involved in toxicity. MCs content in the serum of fishers tested positive, with a range from 0.10 to 0.64 μg/L. Both lower blood insulin levels (2.26 ± 0.96 μIU/mL) and impaired fasting glucose were found in participants from the Meiliang Bay area in Lake Taihu, where MC-LR levels were substantially greater than the MC threshold established by WHO for drinking water. Animal experiments showed that glucose level increased by 27.9% in mice exposed to 5 μg/kg bw and decreased by 41.5% in mice exposed to 20 μg/kg bw. Blood insulin levels declined by 21.9% and 56.2% in mice exposed to 5 and 20 μg/kg bw MC-LR, respectively, which was consistent with the results observed in fishers. Furthermore, the diabetes gene pdx1 and several other proteins (such as Ppp3ca, Ide, Marcks, Pgk1, Suclg1, Ndufs4) involved in insulin secretion were identified for the first time in mice following MC-LR exposure; these biomarkers were considered responsible for MC-LR induced islet dysfunction. This study suggests that subchronic exposure to environmental levels of MCs may increase the risk of the occurrence of diabetes in humans.
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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, P. R. 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, P. R. China
| | - Xiaomei Su
- State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences , 73 East Beijing Road, Nanjing 210008, P. R. 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, P. R. 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, P. R. 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, P. R. China
| | - Alan D Steinman
- Annis Water Resources Institute, Grand Valley State University , 740 West Shoreline Drive, Muskegon, Michigan 49441, United States
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45
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Moore CE, Juan J, Lin Y, Gaskill CL, Puschner B. Comparison of Protein Phosphatase Inhibition Assay with LC-MS/MS for Diagnosis of Microcystin Toxicosis in Veterinary Cases. Mar Drugs 2016; 14:E54. [PMID: 27005635 PMCID: PMC4820308 DOI: 10.3390/md14030054] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 02/29/2016] [Accepted: 03/03/2016] [Indexed: 11/16/2022] Open
Abstract
Microcystins are acute hepatotoxins of increasing global concern in drinking and recreational waters and are a major health risk to humans and animals. Produced by cyanobacteria, microcystins inhibit serine/threonine protein phosphatase 1 (PP1). A cost-effective PP1 assay using p-nitrophenyl phosphate was developed to quickly assess water and rumen content samples. Significant inhibition was determined via a linear model, which compared increasing volumes of sample to the log-transformed ratio of the exposed rate over the control rate of PP1 activity. To test the usefulness of this model in diagnostic case investigations, samples from two veterinary cases were tested. In August 2013 fifteen cattle died around two ponds in Kentucky. While one pond and three tested rumen contents had significant PP1 inhibition and detectable levels of microcystin-LR, the other pond did not. In August 2013, a dog became fatally ill after swimming in Clear Lake, California. Lake water samples collected one and four weeks after the dog presented with clinical signs inhibited PP1 activity. Subsequent analysis using liquid chromatography-mass spectrometry (LC-MS/MS) detected microcystin congeners -LR, -LA, -RR and -LF but not -YR. These diagnostic investigations illustrate the advantages of using functional assays in combination with LC-MS/MS.
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Affiliation(s)
- Caroline E Moore
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis, 1089 Veterinary Medicine Drive, 2225 VM3B, Davis, CA 95616, USA.
| | - Jeanette Juan
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis, 1089 Veterinary Medicine Drive, 2225 VM3B, Davis, CA 95616, USA.
| | - Yanping Lin
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis, 1089 Veterinary Medicine Drive, 2225 VM3B, Davis, CA 95616, USA.
| | - Cynthia L Gaskill
- Veterinary Diagnostic Laboratory, University of Kentucky, Lexington, KY 40511, USA.
| | - Birgit Puschner
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis, 1089 Veterinary Medicine Drive, 2225 VM3B, Davis, CA 95616, USA.
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46
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Chen L, Chen J, Zhang X, Xie P. A review of reproductive toxicity of microcystins. JOURNAL OF HAZARDOUS MATERIALS 2016; 301:381-99. [PMID: 26521084 DOI: 10.1016/j.jhazmat.2015.08.041] [Citation(s) in RCA: 256] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Revised: 08/20/2015] [Accepted: 08/23/2015] [Indexed: 05/25/2023]
Abstract
Animal studies provide strong evidence of positive associations between microcystins (MCs) exposure and reproductive toxicity, representing a threat to human reproductive health and the biodiversity of wild life. This paper reviews current knowledge of the reproductive toxicity of MCs, with regard to mammals, fishes, amphibians, and birds, mostly in males. Toxicity of MCs is primarily governed by the inhibition of protein phosphatases 1 and 2A (PP1 and PP2A) and disturbance of cellular phosphorylation balance. MCs exposure is related to excessive production of reactive oxygen species (ROS) and oxidative stress, leading to cytoskeleton disruption, mitochondria dysfunction, endoplasmic reticulum (ER) stress, and DNA damage. MCs induce cell apoptosis mediated by the mitochondrial and ROS and ER pathways. Through PP1/2A inhibition and oxidative stress, MCs lead to differential expression/activity of transcriptional factors and proteins involved in the pathways of cellular differentiation, proliferation, and tumor promotion. MC-induced DNA damage is also involved in carcinogenicity. Apart from a direct effect on testes and ovaries, MCs indirectly affect sex hormones by damaging the hypothalamic-pituitary-gonad (HPG) axis and liver. Parental exposure to MCs may result in hepatotoxicity and neurotoxicity of offspring. We also summarize the current research gaps which should be addressed by further studies.
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Affiliation(s)
- Liang Chen
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Jun Chen
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
| | - Xuezhen Zhang
- College of Fisheries, Huazhong Agricultural University, Freshwater Aquaculture Collaborative Innovation Center of Hubei Province, Wuhan 430070, China.
| | - Ping Xie
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
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47
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Cai F, Liu J, Li C, Wang J. Critical Role of Endoplasmic Reticulum Stress in Cognitive Impairment Induced by Microcystin-LR. Int J Mol Sci 2015; 16:28077-86. [PMID: 26602924 PMCID: PMC4691030 DOI: 10.3390/ijms161226083] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 11/16/2015] [Accepted: 11/17/2015] [Indexed: 01/11/2023] Open
Abstract
Recent studies showed that cyanobacteria-derived microcystin-leucine-arginine (MCLR) can cause hippocampal pathological damage and trigger cognitive impairment; but the underlying mechanisms have not been well understood. The objective of the present study was to investigate the mechanism of MCLR-induced cognitive deficit; with a focus on endoplasmic reticulum (ER) stress. The Morris water maze test and electrophysiological study demonstrated that MCLR caused spatial memory injury in male Wistar rats; which could be inhibited by ER stress blocker; tauroursodeoxycholic acid (TUDCA). Meanwhile; real-time polymerase chain reaction (real-time PCR) and immunohistochemistry demonstrated that the expression level of the 78-kDa glucose-regulated protein (GRP78); C/EBP homologous protein (CHOP) and caspase 12 were significantly up-regulated. These effects were rescued by co-administration of TUDCA. In agreement with this; we also observed that treatment of rats with TUDCA blocked the alterations in ER ultrastructure and apoptotic cell death in CA1 neurons from rats exposed to MCLR. Taken together; the present results suggested that ER stress plays an important role in potential memory impairments in rats treated with MCLR; and amelioration of ER stress may serve as a novel strategy to alleviate damaged cognitive function triggered by MCLR.
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Affiliation(s)
- Fei Cai
- Department of Pharmacology, Hubei University of Science and Technology, Xianning 437100, China.
| | - Jue Liu
- Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China.
| | - Cairong Li
- Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning 437100, China.
| | - Jianghua Wang
- Fisheries College, Huazhong Agricultural University, Wuhan 430070, China.
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48
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Cai F, Liu J, Li C, Wang J. Intracellular Calcium Plays a Critical Role in the Microcystin-LR-Elicited Neurotoxicity Through PLC/IP3 Pathway. Int J Toxicol 2015; 34:551-8. [PMID: 26395499 DOI: 10.1177/1091581815606352] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Neurotoxicity of microcystin-leucine-arginine (MCLR) has been widely reported. However, the mechanism is not fully understood. Using primary hippocampal neurons, we tested the hypothesis that MCLR-triggered activation in intracellular free calcium concentration ([Ca(2+)](i)) induces the death of neurons. Microcystin-leucine-arginine inhibited cell viability at a range of 0.1 to 30 μmol/L and caused a dose-dependent increase in [Ca(2+)](i). This increase in [Ca(2+)](i) was observed in Ca(2+)-free media and blocked by an endoplasmic reticulum Ca(2+) pump inhibitor, suggesting intracellular Ca(2+) release. Moreover, pretreatment of hippocampal neurons with intracellular Ca(2+) chelator (O,O'-bis (2-aminophenyl) ethyleneglycol-N,N,N',N'-tetraacetic acid, tetraacetoxy-methyl ester) and inositol 1,4,5-trisphosphate receptor antagonist (2-aminoethoxydiphenyl borate) could block both the Ca(2+) mobilization and the neuronal death following MCLR exposure. In contrast, the ryanodine receptor inhibitor (dantrolene) did not ameliorate the effect of MCLR. In conclusion, MCLR disrupts [Ca(2+)](i) homeostasis in neurons by releasing Ca(2+) from intracellular stores, and this increase in [Ca(2+)](i) may be a key determinant in the mechanism underlying MCLR-induced neurotoxicity.
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Affiliation(s)
- Fei Cai
- Department of Pharmacology, Hubei University of Science and Technology, Xianning, China
| | - Jue Liu
- Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cairong Li
- Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Jianghua Wang
- Fisheries College, Huazhong Agricultural University, Wuhan, China
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49
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Li G, Yan W, Dang Y, Li J, Liu C, Wang J. The role of calcineurin signaling in microcystin-LR triggered neuronal toxicity. Sci Rep 2015; 5:11271. [PMID: 26059982 PMCID: PMC4462030 DOI: 10.1038/srep11271] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 05/20/2015] [Indexed: 12/31/2022] Open
Abstract
Microcystin-LR (MCLR) is a commonly acting potent hepatotoxin and has been pointed out of potentially causing neurotoxicity, but the exact mechanisms of action still remain unclear. Using proteomic analysis, forty-five proteins were identified to be significantly altered in hippocampal neurons of rats treated with MCLR. Among them, Ca(2+)-activated phosphatase calcineurin (CaN) and the nuclear factor of activated T-cells isoform c3 (NFATc3) were up-regulated remarkably. Validation of the changes in CaN and NFATc3 expression by Western blotting demonstrated CaN cleavage and subsequent NFATc3 nuclear translocation were generated, suggesting that exposure to MCLR leads to activation of CaN, which in turn activates NFATc3. Activation of CaN signaling has been reported to result in apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member Bad. In agreement with this, our results revealed that treatment of neurons with the CaN inhibitor FK506 blocked the reduction in Bad dephosphorylation and cytochrome c (cyt c) release triggered by MCLR. Consistent with these biochemical results, we observed a marked decrease in apoptotic and necrotic cell death after MCLR exposure in the presence of FK506, supporting the hypothesis that MCLR appeared to cause neuronal toxicity by activation of CaN and the CaN-mediated mitochondrial apoptotic pathway.
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Affiliation(s)
- Guangyu Li
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Wei Yan
- Institute of Agricultural Quality Standards & Testing Technology, Hubei Academy of Agricultural Sciences, Wuhan 430064, China
| | - Yao Dang
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Jing Li
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Chunsheng Liu
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Jianghua Wang
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
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50
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Steiner K, Zimmermann L, Hagenbuch B, Dietrich D. Zebrafish Oatp-mediated transport of microcystin congeners. Arch Toxicol 2015; 90:1129-39. [PMID: 26055554 DOI: 10.1007/s00204-015-1544-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 05/28/2015] [Indexed: 01/07/2023]
Abstract
Microcystins (MC), representing >100 congeners being produced by cyanobacteria, are a hazard for aquatic species. As MC congeners vary in their toxicity, the congener composition of a bloom primarily dictates the severity of adverse effects and appears primarily to be governed by toxicokinetics, i.e., whether transport of MCs occurs via organic anion-transporting polypeptides (Oatps). Differences in observed MC toxicity in various fish species suggest differential expression of Oatp subtypes leading to varying tissue distribution of the very same MC congener within different species. The objectives of this study were the functional characterization and analysis of the tissue distribution of Oatp subtypes in zebrafish (Danio rerio) as a surrogate model for cyprinid fish. Zebrafish Oatps (zfOatps) were cloned, and the organ distribution was determined at the mRNA level. zfOatps were transiently expressed in HEK293 cells for functional characterization using the Oatp substrates estrone-3-sulfate, taurocholate and methotrexate and specific MC congeners (MC-LR, MC-RR, MC-LF and MC-LW). Novel zfOatp isoforms were isolated. Among these isoforms, the organ-specific expression of zfOatp1d1 and of members of the zfOatp1f subfamily was identified. At the functional level, zfOatp1d1, zfOatp1f2, zfOatp1f3 and zfOatp1f4 transported at least one of the Oatp substrates, and zfOatp1d1, zfOatp1f2 and zfOatp1f4 were shown to transport MC congeners. MC-LF and MC-LW were generally transported faster than MC-LR and MC-RR. The subtype-specific expression of zfOatp1d1 and of members of the zfOatp1f subfamily as well as differences in the transport of MC congeners could explain the MC congener-dependent differences in toxicity in cyprinids.
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Affiliation(s)
- Konstanze Steiner
- Human and Environmental Toxicology, Department of Biology, University of Konstanz, PO BOX 662, 78457, Constance, Germany
| | - Lisa Zimmermann
- Human and Environmental Toxicology, Department of Biology, University of Konstanz, PO BOX 662, 78457, Constance, Germany
| | - Bruno Hagenbuch
- Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Daniel Dietrich
- Human and Environmental Toxicology, Department of Biology, University of Konstanz, PO BOX 662, 78457, Constance, Germany.
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