Microcystin-LR Does Not Alter Cell Survival and Intracellular Signaling in Human Bronchial Epithelial Cells
Jazyk angličtina Země Švýcarsko Médium electronic
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
GJ17-25279Y
Grantová Agentura České Republiky - International
722493
EU Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant NaToxAq to B.K. - International
LM2018121
Czech Ministry of Education, Youth and Sports - International
857560 and 02.1.01/0.0/0.0/18_046/0015975
CETOCOEN EXCELLENCE Teaming 2 project supported by Horizon 2020 and the Czech ministry of Education, Youth and Sports - International
PubMed
32156079
PubMed Central
PMC7150819
DOI
10.3390/toxins12030165
PII: toxins12030165
Knihovny.cz E-zdroje
- Klíčová slova
- 16HBE14o-, mitogen-activated protein kinase, HBE1, OATP, cytotoxicity, human bronchial epithelial cells, in vitro, microcystin-LR,
- MeSH
- bronchy cytologie MeSH
- buněčné linie MeSH
- epitelové buňky účinky léků metabolismus MeSH
- extracelulárním signálem regulované MAP kinasy metabolismus MeSH
- lidé MeSH
- mikrocystiny toxicita MeSH
- mitogenem aktivované proteinkinasy p38 metabolismus MeSH
- mořské toxiny toxicita MeSH
- přenašeče organických aniontů genetika MeSH
- signální transdukce účinky léků MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cyanoginosin LR MeSH Prohlížeč
- extracelulárním signálem regulované MAP kinasy MeSH
- mikrocystiny MeSH
- mitogenem aktivované proteinkinasy p38 MeSH
- mořské toxiny MeSH
- přenašeče organických aniontů MeSH
Changes in ecological and environmental factors lead to an increased occurrence of cyanobacterial water blooms, while secondary metabolites-producing cyanobacteria pose a threat to both environmental and human health. Apart from oral and dermal exposure, humans may be exposed via inhalation and/or swallowing of contaminated water and aerosols. Although many studies deal with liver toxicity, less information about the effects in the respiratory system is available. We investigated the effects of a prevalent cyanotoxin, microcystin-LR (MC-LR), using respiratory system-relevant human bronchial epithelial (HBE) cells. The expression of specific organic-anion-transporting polypeptides was evaluated, and the western blot analysis revealed the formation and accumulation of MC-LR protein adducts in exposed cells. However, MC-LR up to 20 μM neither caused significant cytotoxic effects according to multiple viability endpoints after 48-h exposure, nor reduced impedance (cell layer integrity) over 96 h. Time-dependent increase of putative MC-LR adducts with protein phosphatases was not associated with activation of mitogen-activated protein kinases ERK1/2 and p38 during 48-h exposure in HBE cells. Future studies addressing human health risks associated with inhalation of toxic cyanobacteria and cyanotoxins should focus on complex environmental samples of cyanobacterial blooms and alterations of additional non-cytotoxic endpoints while adopting more advanced in vitro models.
Zobrazit více v PubMed
Lee J., Lee S., Jiang X. Cyanobacterial toxins in freshwater and food: Important sources of exposure to humans. Annu. Rev. Food Sci. Technol. 2017;8:281–304. doi: 10.1146/annurev-food-030216-030116. PubMed DOI
Codd G.A., Morrison L.F., Metcalf J.S. Cyanobacterial toxins: Risk management for health protection. Toxicol. Appl. Pharmacol. 2005;203:264–272. doi: 10.1016/j.taap.2004.02.016. PubMed DOI
Paerl H.W., Otten T.G. Harmful cyanobacterial blooms: Causes, consequences, and controls. Microb. Ecol. 2013;65:995–1010. doi: 10.1007/s00248-012-0159-y. PubMed DOI
Buratti F.M., Manganelli M., Vichi S., Stefanelli M., Scardala S., Testai E., Funari E. Cyanotoxins: Producing organisms, occurrence, toxicity, mechanism of action and human health toxicological risk evaluation. Arch. Toxicol. 2017;91:1049–1130. doi: 10.1007/s00204-016-1913-6. PubMed DOI
Grosse Y., Baan R., Straif K., Secretan B., El Ghissassi F., Cogliano V., Cantor K.P., Falconer I.R., Levallois P., Verger P., et al. Carcinogenicity of nitrate, nitrite, and cyanobacterial peptide toxins. Lancet Oncol. 2006;7:628–629. doi: 10.1016/S1470-2045(06)70789-6. PubMed DOI
Giannuzzi L., Krock B., Minaglia M.C.C., Rosso L., Houghton C., Sedan D., Malanga G., Espinosa M., Andrinolo D., Hernando M. Growth, toxin production, active oxygen species and catalase activity of Microcystis aeruginosa (Cyanophyceae) exposed to temperature stress. Comp. Biochem. Physiol. Part C Toxicol. Pharmacol. 2016;189:22–30. doi: 10.1016/j.cbpc.2016.07.001. PubMed DOI
Visser P.M., Verspagen J.M.H., Sandrini G., Stal L.J., Matthijs H.C.P., Davis T.W., Paerl H.W., Huisman J. How rising CO2 and global warming may stimulate harmful cyanobacterial blooms. Harmful Algae. 2016;54:145–159. doi: 10.1016/j.hal.2015.12.006. PubMed DOI
Carmichael W.W. Health effects of toxin-producing cyanobacteria: “The CyanoHABs”. Hum. Ecol. Risk Assess. An. Int. J. 2001;7:1393–1407. doi: 10.1080/20018091095087. DOI
Zhou M., Tu W.W., Xu J. Mechanisms of microcystin-LR-induced cytoskeletal disruption in animal cells. Toxicon. 2015;101:92–100. doi: 10.1016/j.toxicon.2015.05.005. PubMed DOI
Wiśniewska K., Lewandowska A.U., Śliwińska-Wilczewska S. The importance of cyanobacteria and microalgae present in aerosols to human health and the environment—Review study. Environ. Int. 2019;131:104964. doi: 10.1016/j.envint.2019.104964. PubMed DOI
Facciponte D.N., Bough M.W., Seidler D., Carroll J.L., Ashare A., Andrew A.S., Tsongalis G.J., Vaickus L.J., Henegan P.L., Butt T.H., et al. Identifying aerosolized cyanobacteria in the human respiratory tract: A proposed mechanism for cyanotoxin-associated diseases. Sci. Total Environ. 2018;645:1003–1013. doi: 10.1016/j.scitotenv.2018.07.226. PubMed DOI PMC
Lewandowska A.U., Śliwińska-Wilczewska S., Woźniczka D. Identification of cyanobacteria and microalgae in aerosols of various sizes in the air over the Southern Baltic Sea. Mar. Pollut. Bull. 2017;125:30–38. doi: 10.1016/j.marpolbul.2017.07.064. PubMed DOI
May N.W., Olson N.E., Panas M., Axson J.L., Tirella P.S., Kirpes R.M., Craig R.L., Gunsch M.J., Laskin A., Ault A.P., et al. Aerosol emissions from Great lakes harmful algal blooms. Environ. Sci. Technol. 2018;52:397–405. doi: 10.1021/acs.est.7b03609. PubMed DOI
Backer L.C., McNeel S.V., Barber T., Kirkpatrick B., Williams C., Irvin M., Zhou Y., Johnson T.B., Nierenberg K., Aubel M., et al. Recreational exposure to microcystins during algal blooms in two California lakes. Toxicon. 2010;55:909–921. doi: 10.1016/j.toxicon.2009.07.006. PubMed DOI
Scherer P.I., Raeder U., Geist J., Zwirglmaier K. Influence of temperature, mixing, and addition of microcystin-LR on microcystin gene expression in Microcystis aeruginosa. Microbiologyopen. 2017;6:1–10. doi: 10.1002/mbo3.393. PubMed DOI PMC
Nishiwaki-Matsushima R., Ohta T., Nishiwaki S., Suganuma M., Kohyama K., Ishikawa T., Carmichael W.W., Fujiki H. Liver tumor promotion by the cyanobacterial cyclic peptide toxin microcystin-LR. J. Cancer Res. Clin. Oncol. 1992;118:420–424. doi: 10.1007/BF01629424. PubMed DOI
Svirčev Z., Drobac D., Tokodi N., Mijović B., Codd G.A., Meriluoto J. Toxicology of microcystins with reference to cases of human intoxications and epidemiological investigations of exposures to cyanobacteria and cyanotoxins. Arch. Toxicol. 2017;91:621–650. doi: 10.1007/s00204-016-1921-6. PubMed DOI
McLellan N.L., Manderville R.A. Toxic mechanisms of microcystins in mammals. Toxicol. Res. 2017;6:391–405. doi: 10.1039/C7TX00043J. PubMed DOI PMC
Bouaïcha N., Miles C.O., Beach D.G., Labidi Z., Djabri A., Benayache N.Y., Nguyen-Quang T. Structural diversity, characterization and toxicology of microcystins. Toxins. 2019;11:714. doi: 10.3390/toxins11120714. PubMed DOI PMC
Li Y., Huang H., Xue L., Zhuang D. Effects of MC-LR on ROS level in human bronchial epithelia cells and Chinese hamster ovary cells. Life Sci. J. 2015;12:170–173.
Fischer A., Hoeger S.J., Stemmer K., Feurstein D.J., Knobeloch D., Nussler A., Dietrich D.R. The role of organic anion transporting polypeptides (OATPs/SLCOs) in the toxicity of different microcystin congeners in vitro: A comparison of primary human hepatocytes and OATP-transfected HEK293 cells. Toxicol. Appl. Pharmacol. 2010;245:9–20. doi: 10.1016/j.taap.2010.02.006. PubMed DOI
He X., Liu Y.L., Conklin A., Westrick J., Weavers L.K., Dionysiou D.D., Lenhart J.J., Mouser P.J., Szlag D., Walker H.W. Toxic cyanobacteria and drinking water: Impacts, detection, and treatment. Harmful Algae. 2016;54:174–193. doi: 10.1016/j.hal.2016.01.001. PubMed DOI
International Agency for Research on Cancer (IARC) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Ingested Nitrate and Nitrite, and Cyanobacterial Peptide Toxins. Volume 94. International Agency for Research on Cancer (IARC); Lyon, France: 2010. PubMed PMC
Liu J., Wang B., Huang P., Wang H., Xu K., Wang X., Xu L., Guo Z. Microcystin-LR promotes cell proliferation in the mice liver by activating Akt and p38/ERK/JNK cascades. Chemosphere. 2016;163:14–21. doi: 10.1016/j.chemosphere.2016.08.002. PubMed DOI
Wang H., Xu K., Wang B., Liu J., Wang X., Xing M., Huang P., Guo Z., Xu L. Microcystin-LR induces a wide variety of biochemical changes in the A549 human non-small cell lung cancer cell line: Roles for protein phosphatase 2A and its substrates. Environ. Toxicol. 2017;32:1065–1078. doi: 10.1002/tox.22305. PubMed DOI
Zegura B. An Overview of the mechanisms of Microcystin-LR genotoxicity and potential carcinogenicity. Mini Rev. Med. Chem. 2016;16:1042–1062. doi: 10.2174/1389557516666160308141549. PubMed DOI
Zhang X., Xie P., Zhang X., Zhou W., Zhao S., Zhao Y., Cai Y. Toxic effects of microcystin-LR on the HepG2 cell line under hypoxic and normoxic conditions. J. Appl. Toxicol. 2013;33:1180–1186. doi: 10.1002/jat.2749. PubMed DOI
Žegura B., Sedmak B., Filipič M. Microcystin-LR induces oxidative DNA damage in human hepatoma cell line HepG2. Toxicon. 2003;41:41–48. doi: 10.1016/S0041-0101(02)00207-6. PubMed DOI
Li Y., Li J., Huang H., Yang M., Zhuang D., Cheng X., Zhang H., Fu X. Microcystin-LR induces mitochondria-mediated apoptosis in human bronchial epithelial cells. Exp. Ther. Med. 2016;12:633–640. doi: 10.3892/etm.2016.3423. PubMed DOI PMC
Lone Y., Bhide M., Koiri R.K. Microcystin-LR induced immunotoxicity in mammals. J. Toxicol. 2016;2016:1–5. doi: 10.1155/2016/8048125. PubMed DOI PMC
Adamovsky O., Moosova Z., Pekarova M., Basu A., Babica P., Svihalkova Sindlerova L., Kubala L., Blaha L. Immunomodulatory potency of microcystin, an important water-polluting cyanobacterial toxin. Environ. Sci. Technol. 2015;49:12457–12464. doi: 10.1021/acs.est.5b02049. PubMed DOI
Chen L., Chen J., Zhang X., Xie P. A review of reproductive toxicity of microcystins. J. Hazard. Mater. 2016;301:381–399. doi: 10.1016/j.jhazmat.2015.08.041. PubMed DOI
Wu Q., Yan W., Liu C., Li L., Yu L., Zhao S., Li G. Microcystin-LR exposure induces developmental neurotoxicity in zebrafish embryo. Environ. Pollut. 2016;213:793–800. doi: 10.1016/j.envpol.2016.03.048. PubMed DOI
Stebbing J., Lit L.C., Zhang H., Darrington R.S., Melaiu O., Rudraraju B., Giamas G. The regulatory roles of phosphatases in cancer. Oncogene. 2014;33:939–953. doi: 10.1038/onc.2013.80. PubMed DOI
Martínez Hernández J., López-Rodas V., Costas E. Microcystins from tap water could be a risk factor for liver and colorectal cancer: A risk intensified by global change. Med. Hypotheses. 2009;72:539–540. doi: 10.1016/j.mehy.2008.11.041. PubMed DOI
Kubickova B., Babica P., Hilscherová K., Šindlerová L. Effects of cyanobacterial toxins on the human gastrointestinal tract and the mucosal innate immune system. Environ. Sci. Eur. 2019;31 doi: 10.1186/s12302-019-0212-2. DOI
Carvalho G.M.C., Oliveira V.R., Soares R.M., Azevedo S.M.F.O., Lima L.M., Barreiro E.J., dos Santos Valenca S., Saldiva P.H.N., Faffe D.S., Zin W.A. Can LASSBio 596 and dexamethasone treat acute lung and liver inflammation induced by microcystin-LR? Toxicon. 2010;56:604–612. doi: 10.1016/j.toxicon.2010.06.005. PubMed DOI
Gupta N., Pant S.C., Vijayaraghavan R., Rao P.V.L. Comparative toxicity evaluation of cyanobacterial cyclic peptide toxin microcystin variants (LR, RR, YR) in mice. Toxicology. 2003;188:285–296. doi: 10.1016/S0300-483X(03)00112-4. PubMed DOI
Soares R.M., Cagido V.R., Ferraro R.B., Meyer-Fernandes J.R., Rocco P.R.M., Zin W.A., Azevedo S.M.F.O. Effects of microcystin-LR on mouse lungs. Toxicon. 2007;50:330–338. doi: 10.1016/j.toxicon.2007.04.003. PubMed DOI
Zhao S., Sun H., Yan W., Xu D., Shen T. A proteomic study of the pulmonary injury induced by microcystin-LR in mice. Toxicon. 2018;150:304–314. doi: 10.1016/j.toxicon.2018.06.072. PubMed DOI
Carvalho G.M.C., Oliveira V.R., Casquilho N.V., Araujo A.C.P., Soares R.M., Azevedo S.M.F.O., Pires K.M.P., Valença S.S., Zin W.A. Pulmonary and hepatic injury after sub-chronic exposure to sublethal doses of microcystin-LR. Toxicon. 2016;112:51–58. doi: 10.1016/j.toxicon.2016.01.066. PubMed DOI
Oliveira V.R., Mancin V.G.L., Pinto E.F., Soares R.M., Azevedo S.M.F.O., Macchione M., Carvalho A.R., Zin W.A. Repeated intranasal exposure to microcystin-LR affects lungs but not nasal epithelium in mice. Toxicon. 2015;104:14–18. doi: 10.1016/j.toxicon.2015.07.331. PubMed DOI
Li X., Xu L., Zhou W., Zhao Q., Wang Y. Chronic exposure to microcystin-LR affected mitochondrial DNA maintenance and caused pathological changes of lung tissue in mice. Environ. Pollut. 2016;210:48–56. doi: 10.1016/j.envpol.2015.12.001. PubMed DOI
Benson M.J., Hutt A.J., Rein K., Boggs E.S., Barr B.E., Fleming E.L. The toxicity of microcystin LR in mice following 7 days of inhalation exposure. Toxicon. 2005;45:691–698. doi: 10.1016/j.toxicon.2005.01.004. PubMed DOI PMC
Wang C., Gu S., Yin X., Yuan M., Xiang Z., Li Z., Cao H., Meng X., Hu K., Han X. The toxic effects of microcystin-LR on mouse lungs and alveolar type II epithelial cells. Toxicon. 2016;115:81–88. doi: 10.1016/j.toxicon.2016.03.007. PubMed DOI PMC
Wang P.J., Chien M.S., Wu F.J., Chou H.N., Lee S.J. Inhibition of embryonic development by microcystin-LR in zebrafish, Danio Rerio. Toxicon. 2005;45:303–308. doi: 10.1016/j.toxicon.2004.10.016. PubMed DOI
Overgaard C.E., Mitchell L.A., Koval M. Roles for claudins in alveolar epithelial barrier function. Ann. N. Y. Acad. Sci. 2012;1257:167–174. doi: 10.1111/j.1749-6632.2012.06545.x. PubMed DOI PMC
Repetto G., Peso A., Zurita J.L. Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nat. Protoc. 2008;3:1125–1131. doi: 10.1038/nprot.2008.75. PubMed DOI
Organisation for Economic Co-Operation and Development (OECD) Test No. 432: In Vitro 3T3 NRU Phototoxicity Test. Organisation for Economic Co-Operation and Development (OECD); Paris, France: 2019. OECD Guidelines for the Testing of Chemicals, Section 4.
Fischer W.J., Altheimer S., Cattori V., Meier P.J., Dietrich D.R., Hagenbuch B. Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin. Toxicol. Appl. Pharmacol. 2005;203:257–263. doi: 10.1016/j.taap.2004.08.012. PubMed DOI
Bleasby K., Castle J.C., Roberts C.J., Cheng C., Bailey W.J., Sina J.F., Kulkarni A.V., Hafey M.J., Evers R., Johnson J.M., et al. Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: A resource for investigations into drug disposition. Xenobiotica. 2006;36:963–988. doi: 10.1080/00498250600861751. PubMed DOI
Tamai I., Nezu J., Uchino H., Sai Y., Oku A., Shimane M., Tsuji A. molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem. Biophys. Res. Commun. 2000;273:251–260. doi: 10.1006/bbrc.2000.2922. PubMed DOI
Sakamoto A., Matsumaru T., Yamamura N., Uchida Y., Tachikawa M., Ohtsuki S., Terasaki T. Quantitative expression of human drug transporter proteins in lung tissues: Analysis of regional, gender, and interindividual differences by liquid chromatography-tandem mass spectrometry. J. Pharm. Sci. 2013;102:3395–3406. doi: 10.1002/jps.23606. PubMed DOI
Kreft M.E., Jerman U.D., Lasič E., Hevir-Kene N., Rižner T.L., Peternel L., Kristan K. The characterization of the human cell line Calu-3 under different culture conditions and its use as an optimized in vitro model to investigate bronchial epithelial function. Eur. J. Pharm. Sci. 2015;69:1–9. doi: 10.1016/j.ejps.2014.12.017. PubMed DOI
Endter S., Francombe D., Gumbleton M., Ehrhardt C. RT-PCR analysis of ABC, SLC and SLCO drug transporters in human lung epithelial cell models. J. Pharm. Pharmacol. 2009;61:583–591. doi: 10.1211/jpp.61.05.0006. PubMed DOI
Raska J., Ctverackova L., Dydowiczova A., Sovadinova I., Blaha L., Babica P. Tumor-Promoting cyanotoxin microcystin-LR does not induce procarcinogenic events in adult human liver stem cells. Toxicol. Appl. Pharmacol. 2018;345:103–113. doi: 10.1016/j.taap.2018.03.011. PubMed DOI
MacKintosh C., Beattie K.A., Klumpp S., Cohen P., Codd G.A. Cyanobacterial microcystin-LR is a potent and specific inhibitor of protein phosphatases 1 and 2A from both mammals and higher plants. FEBS Lett. 1990;264:187–192. doi: 10.1016/0014-5793(90)80245-E. PubMed DOI
Mikhailov A., Härmälä-Braskén A.-S., Hellman J., Meriluoto J., Eriksson J.E. Identification of ATP-synthase as a novel intracellular target for microcystin-LR. Chem. Biol. Interact. 2003;142:223–237. doi: 10.1016/S0009-2797(02)00075-3. PubMed DOI
Chen T., Cui J., Liang Y., Xin X., Owen Young D., Chen C., Shen P. Identification of human liver mitochondrial aldehyde dehydrogenase as a potential target for microcystin-LR. Toxicology. 2006;220:71–80. doi: 10.1016/j.tox.2005.12.001. PubMed DOI
Zhu Z., Zhang L., Shi G. Proteasome as a molecular target of microcystin-LR. Toxins. 2015;7:2221–2231. doi: 10.3390/toxins7062221. PubMed DOI PMC
Huang H., Liu C., Fu X., Zhang S., Xin Y., Li Y., Xue L., Cheng X., Zhang H. Microcystin-LR induced apoptosis in rat sertoli cells via the mitochondrial caspase-dependent pathway: Role of reactive oxygen species. Front. Physiol. 2016;7:1–10. doi: 10.3389/fphys.2016.00397. PubMed DOI PMC
Takser L., Benachour N., Husk B., Cabana H., Gris D. Cyanotoxins at low doses induce apoptosis and inflammatory effects in murine brain cells: Potential implications for neurodegenerative diseases. Toxicol. Rep. 2016;3:180–189. doi: 10.1016/j.toxrep.2015.12.008. PubMed DOI PMC
Basu A., Dydowiczová A., Čtveráčková L., Jaša L., Trosko J.E., Bláha L., Babica P. Assessment of hepatotoxic potential of cyanobacterial toxins using 3D In Vitro model of adult human liver stem cells. Environ. Sci. Technol. 2018;52:10078–10088. doi: 10.1021/acs.est.8b02291. PubMed DOI
Menezes C., Alverca E., Dias E., Sam-Bento F., Pereira P. Involvement of endoplasmic reticulum and autophagy in microcystin-LR toxicity in Vero-E6 and HepG2 cell lines. Toxicol. Vitr. 2013;27:138–148. doi: 10.1016/j.tiv.2012.09.009. PubMed DOI
Chong M.W.K., Gu K.D., Lam P.K.S., Yang M., Fong W.F. Study on the cytotoxicity of microcystin-LR on cultured cells. Chemosphere. 2000;41:143–147. doi: 10.1016/S0045-6535(99)00402-6. PubMed DOI
Huguet A., Henri J., Petitpas M., Hogeveen K., Fessard V. Comparative cytotoxicity, oxidative stress, and cytokine secretion induced by two cyanotoxin variants, microcystin-LR and-RR, in human intestinal Caco-2 cells. J. Biochem. Mol. Toxicol. 2013;27:253–258. doi: 10.1002/jbt.21482. PubMed DOI
Kubickova B., Laboha P., Hildebrandt J.P., Hilscherová K., Babica P. Effects of cylindrospermopsin on cultured immortalized human airway epithelial cells. Chemosphere. 2019;220:620–628. doi: 10.1016/j.chemosphere.2018.12.157. PubMed DOI
Zihni C., Mills C., Matter K., Balda M.S. Tight junctions: From simple barriers to multifunctional molecular gates. Nat. Rev. Mol. Cell Biol. 2016;17:564–580. doi: 10.1038/nrm.2016.80. PubMed DOI
Zhou Y., Geng X., Chen Y., Shi H., Yang Y., Zhu C., Yu G., Tang Z. Essential roles of Akt/Snail pathway in microcystin-LR-induced tight junction toxicity in Sertoli cell. Food Chem. Toxicol. 2018;112:290–298. doi: 10.1016/j.fct.2018.01.004. PubMed DOI
Upadhyay S., Palmberg L. Air-Liquid interface: Relevant In Vitro models for investigating air pollutant-induced pulmonary toxicity. Toxicol. Sci. 2018;164:21–30. doi: 10.1093/toxsci/kfy053. PubMed DOI
Qian F., Deng J., Wang G., Ye R.D., Christman J.W. Pivotal role of mitogen-activated protein kinase-activated protein kinase 2 in inflammatory pulmonary diseases. Curr. Protein Pept. Sci. 2016;17:332–342. doi: 10.2174/1389203716666150629121324. PubMed DOI PMC
Sun Y., Yu X., Li M., Liu J. P44/42 MAPK signal pathway-mediated hyperphosphorylation of paxillin and redistribution of E-cadherin was involved in microcystin-LR-reduced cellular adhesion in a human liver cell line. Chemosphere. 2018;200:594–602. doi: 10.1016/j.chemosphere.2018.02.170. PubMed DOI
Díez-Quijada L., Prieto A.I., Guzmán-Guillén R., Jos A., Cameán A.M. Occurrence and toxicity of microcystin congeners other than MC-LR and MC-RR: A review. Food Chem. Toxicol. 2019;125:106–132. doi: 10.1016/j.fct.2018.12.042. PubMed DOI
Faassen E.J., Lürling M. Occurrence of the microcystins MC-LW and MC-LF in dutch surface waters and their contribution to total microcystin toxicity. Mar. Drugs. 2013;11:2643–2654. doi: 10.3390/md11072643. PubMed DOI PMC
Mantzouki E., Lürling M., Fastner J., de Senerpont Domis L., Wilk-Woźniak E., Koreivienė J., Seelen L., Teurlincx S., Verstijnen Y., Krztoń W., et al. Temperature effects explain continental scale distribution of cyanobacterial toxins. Toxins. 2018;10:156. doi: 10.3390/toxins10040156. PubMed DOI PMC
World Health Organization (WHO) Guidelines for Safe Recreational Water Environments. 1st-Coasta ed. World Health Organization (WHO); Geneva, Switzerland: 2003.
United States Environmental Protection Agency (EPA) Recommended Human Health Recreational Ambient Water Quality Criteria or Swimming Advisories for Microcystins and Cylindrospermopsin. United States Environmental Protection Agency (EPA); Washington, DC, USA: 2019. (EPA 822-R-19-001)
Pilotto L.S., Douglas R.M., Burch M.D., Cameron S. Health effects of exposure to cyanobacteria (blue-green algae ) during recreational water-related activities. Aust. N. Z. J. Public Health. 1997;21:562–566. doi: 10.1111/j.1467-842X.1997.tb01755.x. PubMed DOI
Stewart I., Webb P.M., Schluter P.J., Fleming L.E., Burns J.W., Gantar M., Backer L.C., Shaw G.R. Epidemiology of recreational exposure to freshwater cyanobacteria—An international prospective cohort study. BMC Public Health. 2006;6:93. doi: 10.1186/1471-2458-6-93. PubMed DOI PMC
Yankaskas J.R., Haizlip J.E., Conrad M., Koval D., Lazarowski E., Paradiso A.M., Rinehart C.A., Sarkadi B., Schlegel R., Boucher R.C. Papilloma-Virus immortalized tracheal epithelial cells retail a well-differentiated phenotype. Am. J. Physiol. 1993;264:C1219–C1230. doi: 10.1152/ajpcell.1993.264.5.C1219. PubMed DOI
Gruenert D.C., Willems M., Cassiman J.J., Frizzell R.A. Established cell lines used in cystic fibrosis research. J. Cyst. Fibros. 2004;3:191–196. doi: 10.1016/j.jcf.2004.05.040. PubMed DOI
Cozens A.L., Yezzi M.J., Kunzelmann K., Ohrui T., Chin L., Eng K., Finkbeiner W.E., Widdicombe J.H., Gruenert D.C. CFTR expression and chloride secretion in polarized immortal human bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 1994;10:38–47. doi: 10.1165/ajrcmb.10.1.7507342. PubMed DOI
ACEA Biosciences . Calculation Principles of RTCA Software. ACEA Biosciences; San Diego, CA, USA: 2016.