Microcystins: Occurrence and Human Health Effects
Franca M. Buratti, Maura Manganelli, Meriç Albay, Simona Scardala, Emanuela TestaiMicrocystins (MCs) are among the most widespread and studied cyanobacterial toxins. More than 300 different MCs congeners have been identified so far, of which MC-LR is the most well-known and is considered as one of the most acutely toxic. Chemically, MCs are cyclic heptapeptides produced through nonribosomal peptide synthases by a number of different cyanobacteria. Microcystin-containing ‘blooms’ occur worldwide and have caused numerous cases of animals poisoning (many of which were lethal) and a small number of well-evidenced non fatal cases of human poisoning. While acute fatal human intoxication would require ingestion of unlikely high amounts of scum, long-term effects from repeated exposure to low doses (e.g. contained in drinking or recreational waters, in food and feed) can be anticipated. Based on the increasing occurrence of cyanobacteria due to climate change, MCs can be considered an emerging risk for animal, human and the environment and represent a good example of the One Health approach. Here we give a critical review of information on MCs’ producing organisms, biosynthesis and genes encoding it, occurrence and toxicological profile, with a focus on kinetics, systemic toxicity, mode of action and human health effects, including the derivation of limit values for their concentration in water to which humans are exposed and recommendations by International Organizations and/ or regulatory limits across the globe.
References
- Akçaalan, R., Devesa-Garriga, R., Dietrich, A., Steinhaus, M., Dunkel, A., Mall, V., . . . & Kaloudis, T. (2022). Water taste and odor (T&O): Challenges, gaps and solutions from a perspective of the WaterTOP network. Chemical Engineering Journal Advances, 12, 100409. https://doi.org/10.1016/j.ceja.2022.100409 google scholar
- Altaner, S., Jaeger, S., Fotler, R., Zemskov, I., Wittmann, V., Schreiber, F., & Dietrich, D. R. (2020). Machine learning prediction of cyanobacterial toxin (microcystin) toxicodynamics in humans. Altex-Alternatives to Animal Experimentation, 37(1), 24-36. https://doi.org/10.14573/altex.1904031 google scholar
- Anderson, M., Valera, M., & Schnetzer, A. (2023). Co-occurrence of freshwater and marine phycotoxins: A record of microcystins and domoic acid in Bogue Sound, North Carolina (2015 to 2020). Harmful Algae, 125, 102412. https://doi.org/10.1016/j.hal.2023.102412 google scholar
- Annadotter, H., Cronberg, G., Lawton, L., Hansson, H. B., Göthe, U., & Skulberg, O. (2001). 5.3.1 An extensive outbreak of gastroenteritis associated with the toxic cyanobacterium Planktothrix agardhii (Oscillatoriales, Cyanophyceae) in Scania, South Sweden. In: Chorus I (ed) Cyanotoxins: Occurrence, Causes, Consequen-ces. Springer-Verlag, p 200-208 google scholar
- Arman, T., & Clarke, J. D. (2021). Microcystin Toxicokinetics, Molecular Toxicology, and Pathophysiology in Preclinical Rodent Models and Humans. Toxins (Basel), 13(8). https://doi.org/10.3390/toxins13080537 google scholar
- Arnich, N. (2012). France: regulation, risk management, risk assessment and research on cyanobacteria and cyanotoxins. In: Chorus I (ed) Current approaches to cyanotoxin risk assessment, risk management and regulations in different countries. Umweltbundesamt, Berlin. pp. 63-70 google scholar
- Azevedo, S., Carmichael, W. W., Jochimsen, E. M., Rinehart, K. L., Lau, S., Shaw, G. R., & Eaglesham, G. K. (2002). Human intoxication by microcystins during renal dialysis treatment in Caruaru-Brazil. Toxicology, 181, 441-446. https://doi.org/10.1016/s0300-483x(02)00491-2 google scholar
- Backer, L. C., Landsberg, J. H., Miller, M., Keel, K., & Taylor, T. K. (2013). Canine cyanotoxin poisonings in the United States (1920s-2012): review of suspected and confirmed cases from three data sources. Toxins (Basel), 5(9), 1597-1628. https://doi.org/10.3390/toxins5091597 google scholar
- Backer, L. C., Manassaram-Baptiste, D., LePrell, R., & Bolton, B. (2015). Cyanobacteria and algae blooms: Re-view of health and environmental data from the Harmful Algal Bloom-Related Illness Surveillance System (HABISS) 2007-2011. Toxins (Basel), 7(4), 1048-1064. https://doi.org/10.3390/toxins7041048 google scholar
- Backer, L. C., McNeel, S. V., Barber, T., Kirkpatrick, B., Williams, C., Irvin, M., . . .& Cheng, Y. S. (2010). Recreational exposure to microcystins during algal blooms in two California lakes. Toxicon, 55(5), 909-921. https://doi.org/10.1016/j.toxicon.2009.07.006 google scholar
- Belykh, O. I., Sorokovikova, E. G., Tomberg, I. V., Fedorova, G. A., Kuzmin, A. V., Krasnopeev, A. Y., . . .& Tikhonova, I. V. (2023). Water Quality, Toxicity and Diversity of Planktonic and Benthic Cyanobacteria in Pristine Ancient Lake Khubsugul (Hövsgöl), Mongolia. Toxins (Basel), 15(3). https://doi.org/10.3390/ toxins15030213 google scholar
- Bouhaddada, R., Nelieu, S., Nasri, H., Delarue, G., & Bouaıcha, N. (2016). High diversity of microcystins in a Microcystis bloom from an Algerian lake. Environ Pollut, 216, 836-844. https://doi.org/10.1016/j. envpol.2016.06.055 google scholar
- Bourke, A. T. C., Hawes, R. B., Neilson, A., & Stallman, N. D. (1983). An outbreak of hepato-enteritis (the Palm Island mystery disease) possibly caused by algal intoxication. Toxicon, 21, 45-48. https://doi. org/10.1016/0041-0101(83)90151-4 google scholar
- Bte Sukarji, N. H., He, Y., Te, S. H., & Gin, K. Y. (2022). Application of a Mechanistic Model for the Prediction of Microcystin Production by Microcystis in Lab Cultures and Tropical Lake. Toxins (Basel), 14(2). https:// doi.org/10.3390/toxins14020103 google scholar
- Buley, R. P., Gladfelter, M. F., Fernandez-Figueroa, E. G., & Wilson, A. E. (2022). Can correlational analyses help determine the drivers of microcystin occurrence in freshwater ecosystems? A meta-analysis of micro-cystin and associated water quality parameters. Environmental Monitoring and Assessment, 194(7), 493. https://doi.org/10.1007/s10661-022-10114-8 google scholar
- Buratti, F. M., & Testai, E. (2015). Species- and congener-differences in microcystin-LR and -RR GSH conjuga-tion in human, rat, and mouse hepatic cytosol. Toxicology Letters, 232(1), 133-140. https://doi.org/10.1016/j. toxlet.2014.10.020 google scholar
- Buratti, F. M., Manganelli, M., Vichi, S., Stefanelli, M., Scardala, S., Testai, E., & Funari, E. (2017). Cyano-toxins: producing organisms, occurrence, toxicity, mechanism of action and human health toxicological risk evaluation. Archives of Toxicology, 91(3), 1049-1130. https://doi.org/10.1007/s00204-016-1913-6 google scholar
- Buratti, F. M., Scardala, S., Funari, E., & Testai, E. (2011). Human glutathione transferases catalyzing the con-jugation of the hepatoxin microcystin-LR. Chemical Research in Toxicology, 24(6), 926-933. https://doi. org/10.1021/tx2000976 google scholar
- Buratti, F. M., Scardala, S., Funari, E., & Testai, E. (2013). The conjugation of microcystin-RR by human recombinant GSTs and hepatic cytosol. Toxicology Letters, 219(3), 231-238. https://doi.org/10.1016/j.tox-let.2013.03.015 google scholar
- Carmichael, W. W., & Boyer, G. L. (2016). Health impacts from cyanobacteria harmful algae blooms: Imp-lications for the North American Great Lakes. Harmful Algae, 54, 194-212. https://doi.org/10.1016/j. hal.2016.02.002 google scholar
- Catherine, Q., Susanna, W., Isidora, E. S., Mark, H., Aurelie, V., & Jean-François, H. (2013). A review of current knowledge on toxic benthic freshwater cyanobacteria--ecology, toxin production and risk management. Water Research, 47(15), 5464-5479. https://doi.org/10.1016/j.watres.2013.06.042 google scholar
- Chen, J., Xie, P., Li, L., & Xu, J. (2009). First identification of the hepatotoxic microcystins in the serum of a chronically exposed human population together with indication of hepatocellular damage. Toxicological Sciences, 108(1), 81-89. https://doi.org/10.1093/toxsci/kfp009 google scholar
- Chen, L., & Xie, P. (2016). Mechanisms of Microcystin-induced Cytotoxicity and Apoptosis. Mini Reviews in Medicinal Chemistry, 16(13), 1018-1031. https://doi.org/10.2174/1389557516666160219130407 google scholar
- Chen, L., Giesy, J. P., & Xie, P. (2018). The dose makes the poison. Science of The Total Environment, 621, 649-653. https://doi.org/10.1016/j.scitotenv.2017.11.218 google scholar
- Chen, Y. M., Lee, T. H., Lee, S. J., Huang, H. B., Huang, R., & Chou, H. N. (2006). Comparison of protein phosphatase inhibition activities and mouse toxicities of microcystins. Toxicon, 47(7), 742-746. https://doi. org/10.1016/j.toxicon.2006.01.026 google scholar
- Chen, Y., Xu, J., Li, Y., & Han, X. (2011). Decline of sperm quality and testicular function in male mice du-ring chronic low-dose exposure to microcystin-LR. Reproductive Toxicology, 31(4), 551-557. https://doi. org/10.1016/j.reprotox.2011.02.006 google scholar
- Chorus, I., & Welker, M. (eds) (2021). Toxic cyanobacteria in water: A guide to their public health consequen-ces, monitoring and management. 2nd edition. CRC Press, Boca Raton (FL), on behalf of the World Health Organization, Geneva, CH google scholar
- Codd, G. A., Morrison, L. F., & Metcalf, J. S. (2005). Cyanobacterial toxins: Risk management for health protection. Toxicology and Applied Pharmacology, 203(3 SPEC. ISS.), 264-272. https://doi.org/10.1016/j. taap.2004.02.016 google scholar
- Codd, G. A., Testai, E., Funari, E., & Svircev, Z. (2020). Cyanobacteria, Cyanotoxins, and Human Health Water Treatment for Purification from Cyanobacteria and Cyanotoxins (pp. 37-68). google scholar
- De Pace, R., Vita, V., Bucci, M.S., Gallo, P., & Bruno, M. (2014). Microcystin Contamination in Sea Mussel Farms from the Italian Southern Adriatic Coast following Cyanobacterial Blooms in an Artificial Reservoir. Journal of Ecosystems, 2014:374027, http://dx.doi.org/10.1155/2014/374027. google scholar
- DIRECTIVE (EU) 2020/2184 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 December 2020 on the quality of water intended for human consumption google scholar
- Dick, G. J., Duhaime, M. B., Evans, J. T., Errera, R. M., Godwin, C. M., Kharbush, J. J., . . .& Denef, V. J. (2021). The genetic and ecophysiological diversity of Microcystis. Environmental Microbiology, 23(12), 7278-7313. https://doi.org/10.1111/1462-2920.15615 google scholar
- Dlg.s 23 febbraio 2023, n. 18 . National actuation of the DIRECTIVE (EU) 2020/2184 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 December 2020 on the quality of water intended for human consumption google scholar
- Dreher, T. W., Davis, E. W., 2nd, Mueller, R. S., & Otten, T. G. (2021). Comparative genomics of the ADA clade within the Nostocales. Harmful Algae, 104, 102037. https://doi.org/10.1016/j.hal.2021.102037 google scholar
- Dreher, T. W., Davis, E. W., Wilhelm, F. M., Burnet, S. H., & Mueller, R. S. (2022). Genome sequence of freshwater nontoxigenic Limnoraphis associated with microcystin-producing blooms. Harmful Algae, 118, 102309. https://doi.org/10.1016/j.hal.2022.102309 google scholar
- Eguzozie, K., Mavumengwana, V., Nkosi, D., Kayitesi, E., & Nnabuo-Eguzozie, E. C. (2016). Bioaccumulation and Quantitative Variations of Microcystins in the Swartspruit River, South Africa. Archives of Environmen-tal Contamination and Toxicology, 71, 286-296. https://doi.org/10.1007/s00244-016-0269-5 google scholar
- Esterhuizen-Londt, M., Hertel, S., & Pflugmacher, S. (2017). Uptake and biotransformation of pure commercial microcystin-LR versus microcystin-LR from a natural cyanobacterial bloom extract in the aquatic fungus Mucor hiemalis. Biotechnology Letters, 39(10), 1537-1545. https://doi.org/10.1007/s10529-017-2378-2 google scholar
- EUROPEAN UNION (DRINKING WATER) REGULATIONS 2023 S.I. No. 99 of 2023 google scholar
- Falconer, I. R., Beresford, A. M., & Runnegar, M. T. (1983). Evidence of liver damage by toxin from a bloom of the blue-green alga, Microcystis aeruginosa. Medical Journal of Australia, 1(11), 511-514. https://doi. org/10.5694/j.1326-5377.1983.tb136192.x google scholar
- Fastner, J., & Humpage, A. (2021). 2.1 Hepatotoxıc cyclıc peptıdes - mıcrocystıns and nodularıns. In : Chorus, google scholar
- I., Welker, M. (eds) Toxic cyanobacteria in water: A guide to their public health consequences, monitoring and management. 2nd edition. CRC Press, Boca Raton (FL), on behalf of the World Health Organization, Geneva, CH google scholar
- Fastner, J., Teikari, J., Hoffmann, A., Köhler, A., Hoppe, S., Dittmann, E., & Welker, M. (2023). Cyanotoxins associated with macrophytes in Berlin (Germany) water bodies - Occurrence and risk assessment. Science of The Total Environment, 858(Pt 1), 159433. https://doi.org/10.1016/j.scitotenv.2022.159433 google scholar
- Fawell, J. K., Mitchell, R. E., Everett, D. J., & Hill, R. E. (1999). The toxicity of cyanobacterial toxins in the mouse: I microcystin-LR. Human & Experimental Toxicology, 18(3), 162-167. google scholar
- Fawell, J. K., James, C. P., & James, H. (1994). Toxins From Blue-Green Algae: Toxicological Assessment of Microcystin-LR and a Method for its Determination in Water. Medmenham, Marlow, Bucks, Water Research Centre, pp. 1-46. google scholar
- Feng, L. J., Sun, X. D., Zhu, F. P., Feng, Y., Duan, J. L., Xiao, F., . . .& Yuan, X. Z. (2020). Nanoplastics Promote Microcystin Synthesis and Release from Cyanobacterial Microcystis aeruginosa. Environmental Science & Technology, 54(6), 3386-3394. https://doi.org/10.1021/acs.est.9b06085 google scholar
- Fischer, A., Hoeger, S. J., Stemmer, K., Feurstein, D. J., Knobeloch, D., Nussler, A., & Dietrich, D. R. (2010). 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. Toxi-cology and Applied Pharmacology, 245(1), 9-20. https://doi.org/S0041-008X(10)00057-8 [pii] google scholar
- Fischer, W. J., Altheimer, S., Cattori, V., Meier, P. J., Dietrich, D. R., & Hagenbuch, B. (2005). Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin. Toxicology and App-lied Pharmacology, 203(3), 257-263. https://doi.org/S0041-008X(04)00406-5 [pii] google scholar
- Fitzgeorge, R. B., Clark, S. A., & Keevil, C. W. (1994). Routes of intoxication. In: Detection Methods for Cya-nobacterial Toxins. Ed. Codd, G. A., Jefferies, T. M., Keevil, C. W., Potter, E. Royal Society of Chemistry, Cambridge, UK, pp. 69-74. google scholar
- Fleming, L. E., Rivero, C., Burns, J., Williams, C., Bean, J. A., Shea, K. A., & Stinn, J. (2002). Blue green algal (cyanobacterial) toxins, surface drinking water, and liver cancer in Florida. Harmful Algae, 1(2), 157-168. https://doi.org/10.1016/S1568-9883(02)00026-4 google scholar
- Funari, E., & Testai, E. (2008). Human health risk assessment related to cyanotoxins exposure. Critical Reviews in Toxicology, 38(2), 97-125. https://doi.org/10.1080/10408440701749454 google scholar
- Funari, E., Manganelli, M., Buratti, F. M., & Testai, E. (2017). Cyanobacteria blooms in water: Italian guidelines to assess and manage the risk associated to bathing and recreational activities. Science of The Total Envi-ronment, 598, 867-880. https://doi.org/10.1016/j.scitotenv.2017.03.232 google scholar
- Gaget, V., Humpage, A. R., Huang, Q., Monis, P., & Brookes, J. D. (2017). Benthic cyanobacteria: A source of cylindrospermopsin and microcystin in Australian drinking water reservoirs. Water Research, 124, 454-464. https://doi.org/10.1016/j.watres.2017.07.073 google scholar
- GB (2006) GB5749-2006-Standards for drinking water quality in China. google scholar
- Gehringer, M. M. (2004). Microcystin-LR and okadaic acid-induced cellular effects: a dualistic response. FEBS Letters, 557(1-3), 1-8. https://doi.org/S0014579303014479 [pii] google scholar
- Ger, K. A., Faassen, E. J., Pennino, M. G. & Lürling, M. (2016). Effect of the toxin (microcystin) content of Microcystis on copepod grazing. Harmful Algae, 52, 34-45. https://doi.org/10.1016/j.hal.2015.12.008 google scholar
- Giannuzzi, L., Sedan, D., Echenique, R. & Andrinolo, D. (2011). An acute case of intoxication with cyanobacte-ria and cyanotoxins in recreational water in Salto Grande Dam, Argentina. Marine Drugs, 9(11), 2164-2175. https://doi.org/10.3390/md9112164 google scholar
- Gilroy, D. J., Kauffman, K. W., Hall, R. A., Huang, X., & Chu, F. S. (2000). Assessing potential health risks from microcystin toxins in blue-green algae dietary supplements. Environmental Health Perspectives, 108(5), 435-439. google scholar
- Harada, K., Imanishi, S., Kato, H., Mizuno, M., Ito, E., & Tsuji, K. (2004). Isolation of Adda from microcys-tin-LR by microbial degradation. Toxicon, 44(1), 107-109. https://doi.org/10.1016/j.toxicon.2004.04.003 google scholar
- Harke, M. J., Steffen, M. M., Gobler, C. J., Otten, T. G., Wilhelm, S. W., Wood, S. A., & Paerl, H. W. (2016). A review of the global ecology, genomics, and biogeography of the toxic cyanobacterium, Microcystis spp. Harmful Algae, 54, 4-20. https://doi.org/10.1016/j.hal.2015.12.007 google scholar
- Hastie, C. J., Borthwick, E. B., Morrison, L. F., Codd, G. A., & Cohen, P. T. (2005). Inhibition of several protein phosphatases by a non-covalently interacting microcystin and a novel cyanobacterial peptide, nostocyclin. Biochimica et Biophysica Acta, 1726(2), 187-193. https://doi.org/10.1016/j.bbagen.2005.06.005 google scholar
- He, J., Chen, J., Wu, L., Li, G., & Xie, P. (2012). Metabolic response to oral microcystin-LR exposure in the rat by NMR-based metabonomic study. Journal of Proteome Research, 11(12), 5934-5946. https://doi. org/10.1021/pr300685g google scholar
- He, J., Li, G., Chen, J., Lin, J., Zeng, C., Chen, J., . . .& Xie, P. (2017). Prolonged exposure to low-dose micro-cystin induces nonalcoholic steatohepatitis in mice: a systems toxicology study. Archive Toxicology, 91(1), 465-480. https://doi.org/10.1007/s00204-016-1681-3 google scholar
- Health Canada. (2016). Cyanobacterial toxins in drinking water. Federal-Provincial-Territorial Committee on Drinking Water, Ottawa. https://www.canada.ca/content/dam/canada/health-canada/migration/healthy-ca-nadians/health-system-systeme-sante/consultations/cyanobacteria-cyanobacterie/alt/cyanobacteria-cyano-bacterie-eng.pdf (last access 20/07/2023) google scholar
- Health Canada (2020). Guidelines for Canadian Drinking Water Quality—Summary Table. Water and Air Quality Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario https://www. canada.ca/en/health-canada/services/environmental-workplace-health/reports-publications/water-quality/ guidelines-canadian-drinking-water-quality-summary-table.html (last access 20/07/2023) google scholar
- Health Canada (2022). Guidelines for Canadian Recreational Water Quality Cyanobacteria and their Toxins https://www.canada.ca/content/dam/hc-sc/documents/services/publications/healthy-living/guidance-cana-dian-recreational-water-quality-cyanobacteria-toxins/water-quality-cyanobacteria-toxins-en.pdf (last access 20/07/2023) google scholar
- Heinze, R. (1999). Toxicity of the cyanobacterial toxin microcystin-LR to rats after 28 days intake with the drinking water. Environmental Toxicology, 14(1), 57-60. https://doi.org/10.1002/(SICI)1522-7278(199902 )14:1<57::AID-TOX9>3.0.CO;2-J google scholar
- Hilborn, E. D., & Beasley, V. R. (2015). One health and cyanobacteria in freshwater systems: animal illnesses and deaths are sentinel events for human health risks. Toxins (Basel), 7(4), 1374-1395. https://doi.org/10.3390/ toxins7041374 google scholar
- Hilborn, E. D., & Ward, R. A. (2016). The Risk of Cyanobacterial Toxins in Dialysate: What Do We Know? Seminars in Dialysis, 29(1), 15-18. https://doi.org/10.1111/sdi.12420 google scholar
- Hilborn, E. D., Roberts, V. A., Backer, L., Deconno, E., Egan, J. S., Hyde, J. B., . . .& Hlavsa, M. C. (2014). Algal bloom-associated disease outbreaks among users of freshwater lakes--United States, 2009-2010. MMWR The Morbidity and Mortality Weekly Report, 63(1), 11-15. google scholar
- Hilborn, E. D., Soares, R. M., Servaites, J. C., Delgado, A. G., Magalhâes, V F., Carmichael, W. W., & Azevedo, S. M. (2013). Sublethal microcystin exposure and biochemical outcomes among hemodialysis patients. PLoS One, 8(7), e69518. https://doi.org/10.1371/journal.pone.0069518 google scholar
- Hinojosa, M. G., Gutierrez-Praena, D., Prieto, A. I., Guzman-Guillen, R., Jos, A., & Camean, A. M. (2019). Neurotoxicity induced by microcystins and cylindrospermopsin: A review. Science of The Total Environ-ment, 668, 547-565. https://doi.org/10.1016/j.scitotenv.2019.02.426 google scholar
- Honkanen, R. E., Zwiller, J., Moore, R. E., Daily, S. L., Khatra, B. S., Dukelow, M., & Boynton, A. L. (1990). Characterization of microcystin-LR, a potent inhibitor of type 1 and type 2A protein phosphatases. Journal of Biological Chemistry, 265(32), 19401-19404. google scholar
- Howard, M. D. A., Kudela, R. M., Hayashi, K., Tatters, A. O., Caron, D. A., Theroux, S., . . .& Laughrey, Z. (2021). Multiple co-occurring and persistently detected cyanotoxins and associated cyanobacteria in adjacent California lakes. Toxicon, 192, 1-14. https://doi.org/10.1016/j.toxicon.2020.12.019 google scholar
- Hu, Y., Chen, J., Fan, H., Xie, P., & He, J. (2016). A review of neurotoxicity of microcystins. Environmental Science and Pollution Research International, 23(8), 7211-7219. https://doi.org/10.1007/s11356-016-6073-y google scholar
- Humpage, A. R., & Cunliffe, D. A. (2021). 5.1 Drinking-water. In: Chorus, I., Welker, M.; (eds) Toxic cyanobac-teria in water: A guide to their public health consequences, monitoring and management. 2nd edition. CRC Press, Boca Raton (FL), on behalf of the World Health Organization, Geneva, CH. p 305-332. google scholar
- IARC (International Agency for Research on Cancer) (2010) Ingested nitrate and nitrite, and cyanobacterial pep-tide toxins. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. WHO Press, Geneva. google scholar
- Ibelings, B. W., Backer, L. C., Kardinaal, W. E., & Chorus, I. (2015). Current approaches to cyanotoxin risk assessment and risk management around the globe. Harmful Algae, 49, 63-74. https://doi.org/10.1016/j. hal.2014.10.002 google scholar
- Ibelings, B. W, Foss, A., & Chorus, I. (2021a) 5.3 Food. In: Chorus, I., Welker, M.; (eds) Toxic cyanobacteria in water: A guide to their public health consequences, monitoring and management. 2nd edition. CRC Press, Boca Raton (FL), on behalf of the World Health Organization, Geneva, CH. p 305-332. google scholar
- Ibelings, B. W., Kurmayer, R., Azevedo, S. M. F., Wood, S. A., Chorus, I., & Welker, M. (2021b) 4 Understanding the occurrence of cyanobacteria and cyanotoxins. In: Chorus, I., Welker, M.; (eds) Toxic cyanobacteria in water: A guide to their public health consequences, monitoring and management. 2nd edition. CRC Press, Boca Raton (FL), on behalf of the World Health Organization, Geneva, CH. p 213-294 google scholar
- Ito, E., Kondo, F., & Harada, K. (2000). First report on the distribution of orally administered microcystin-LR in mouse tissue using an immunostaining method. Toxicon, 38(1), 37-48. https://doi.org/S0041010199000847 [pii] google scholar
- Ito, E., Takai, A., Kondo, F., Masui, H., Imanishi, S., & Harada, K. (2002). Comparison of protein phosphatase inhibitory activity and apparent toxicity of microcystins and related compounds. Toxicon, 40(7), 1017-1025. https://doi.org/10.1016/s0041-0101(02)00099-5 google scholar
- Izaguirre, G., Jungblut, A. D., & Neilan, B. A. (2007). Benthic cyanobacteria (Oscillatoriaceae) that produce microcystin-LR, isolated from four reservoirs in southern California. Water Research, 41(2), 492-498. htt-ps://doi.org/S0043-1354(06)00565-3 [pii] google scholar
- Jochimsen, E. M., Carmichael, W. W., An, J. S., Cardo, D. M., Cookson, S. T., Holmes, C. E., . . .& Jarvis, W. R. (1998). Liver failure and death after exposure to microcystins at a hemodialysis center in Brazil. The New England Journal of Medicine, 338(13), 873-878. https://doi.org/10.1056/nejm199803263381304 google scholar
- Kadiri, M. O., Isagba, S., Ogbebor, J. U., Omoruyi, O. A., Unusiotame-Owolagba, T. E., Lorenzi, A. S., . . .& Chia, M. A. (2020). The presence of microcystins in the coastal waters of Nigeria, from the Bights of Bonny google scholar
- and Benin, Gulf of Guinea. Environmental Science and Pollution Research, 27(28), 35284-35293. https:// doi.org/10.1007/s11356-020-09740-x google scholar
- Kaur, G., Fahrner, R., Wittmann, V., Stieger, B., & Dietrich, D. R. (2019). Human MRP2 exports MC-LR but not the glutathione conjugate. Chemico-Biological Interaction, 311, 108761. https://doi.org/10.1016/j. cbi.2019.108761 google scholar
- Komarek, J. (2003). 3 - Coccoıd and colonıal cyanobacterıa. In J. D. Wehr & R. G. Sheath (Eds.), Freshwater Algae of North America (pp. 59-116). Burlington: Academic Press. google scholar
- Kondo, F., Ikai, Y., Oka, H., Okumura, M., Ishikawa, N., Harada, K., . . .& Suzuki, M. (1992). Formation, cha-racterization, and toxicity of the glutathione and cysteine conjugates of toxic heptapeptide microcystins. Chemical Research in Toxicology, 5(5), 591-596. google scholar
- Kruk, C., Martmez, A., Martmez de la Escalera, G., Trinchin, R., Manta, G., Segura, A. M., . . .& Calliari, D. (2021). Rapid freshwater discharge on the coastal ocean as a mean of long distance spreading of an unprece-dented toxic cyanobacteria bloom. Science of The Total Environment, 754, 142362. https://doi.org/10.1016/j. scitotenv.2020.142362 google scholar
- Kujbida, P., Hatanaka, E., Vinolo, M. A., Waismam, K., Cavalcanti, D. M., Curi, R., . . .& Pinto, E. (2009). Microcystins -LA, -YR, and -LR action on neutrophil migration. Biochem Biophys Res Commun, 382(1), 9-14. https://doi.org/10.1016/j.bbrc.2009.02.009 google scholar
- Kurmayer, R., & Christiansen, G. (2009). The Genetic Basis of Toxin Production in Cyanobacteria. Freshwater Reviews, 2(1), 31-50, https://doi.org/10.1608/FRJ-2.1.2 google scholar
- Kurmayer, R., & Kutzenberger, T. (2003). Application of real-time PCR for quantification of microcystin genot-ypes in a population of the toxic cyanobacterium Microcystis sp. Applied and Environmental Microbiology, 69(11), 6723-6730. https://doi.org/10.1128/aem.69.11.6723-6730.2003 google scholar
- Kurmayer, R., Christiansen, G., Fastner, J., & Börner, T. (2004). Abundance of active and inactive microcystin genotypes in populations of the toxic cyanobacterium Planktothrix spp. Environmental Microbiology, 6(8), 831-841. https://doi.org/10.1111/j.1462-2920.2004.00626.x google scholar
- Kurmayer, R., Deng, L., & Entfellner, E. (2016). Role of toxic and bioactive secondary metabolites in coloni-zation and bloom formation by filamentous cyanobacteria Planktothrix. Harmful Algae, 54, 69-86. https:// doi.org/10.1016/j.hal.2016.01.004 google scholar
- Lehman, P. W., Kurobe, T., Lesmeister, S., Baxa, D., Tung, A., & Teh, S. J. (2017). Impacts of the 2014 severe drought on the Microcystis bloom in San Francisco Estuary. Harmful Algae, 63, 94-108. https://doi. org/10.1016/j.hal.2017.01.011 google scholar
- Levesque, B., Gervais, M. C., Chevalier, P., Gauvin, D., Anassour-Laouan-Sidi, E., Gingras, S., . . . & Bird, D. (2014). Prospective study of acute health effects in relation to exposure to cyanobacteria. Science of The Total Environment, 466-467, 397-403. https://doi.org/10.1016/j.scitotenv.2013.07.045 google scholar
- Li, X., Dreher, T. W., & Li, R. (2016a). An overview of diversity, occurrence, genetics and toxin production of bloom-forming Dolichospermum (Anabaena) species. Harmful Algae, 54, 54-68. https://doi.org/10.1016/j. hal.2015.10.015 google scholar
- Li, X., Xu, L., Zhou, W., Zhao, Q., & Wang, Y. (2016). Chronic exposure to microcystin-LR affected mitochond-rial DNA maintenance and caused pathological changes of lung tissue in mice. Environmental Pollution, 210, 48-56. https://doi.org/10.1016/j.envpol.2015.12.001 google scholar
- Li, X., Zhao, Q., Zhou, W., Xu, L., & Wang, Y. (2015). Effects of chronic exposure to microcystin-LR on hepa-tocyte mitochondrial DNA replication in mice. Environmental Science and Technology, 49(7), 4665-4672. https://doi.org/10.1021/es5059132 google scholar
- Li, Y., Chen, J. A., Zhao, Q., Pu, C., Qiu, Z., Zhang, R., & Shu, W. (2011). A cross-sectional investigation of chronic exposure to microcystin in relationship to childhood liver damage in the Three Gorges Reservoir Re-gion, China. Environmental Health Perspective, 119(10), 1483-1488. https://doi.org/10.1289/ehp.1002412 google scholar
- Lin, C. J., Wade, T. J., Sams, E. A., Dufour, A. P., Chapman, A. D., & Hilborn, E. D. (2016). A Prospective Study of Marine Phytoplankton and Reported Illness Among Recreational Beachgoers in Puerto Rico, 2009. Environmental Health Perspective, 124(4), 477-483. https://doi.org/10.1289/ehp.1409558 google scholar
- Liu, J., & Sun, Y. (2015). The role of PP2A-associated proteins and signal pathways in microcystin-LR toxicity. Toxicology Letters, 236(1), 1-7. https://doi.org/10.1016/j.toxlet.2015.04.010 google scholar
- MacKeigan, P. W., Zastepa, A., Taranu, Z. E., Westrick, J. A., Liang, A., Pick, F. R., . . .& Gregory-Eaves, I. (2023). Microcystin concentrations and congener composition in relation to environmental variables across 440 north-temperate and boreal lakes. Science of The Total Environment, 884, 163811. https://doi. org/10.1016/j.scitotenv.2023.163811 google scholar
- MacKintosh, C., Beattie, K. A., Klumpp, S., Cohen, P., & Codd, G. A. (1990). Cyanobacterial microcystin-LR is a potent and specific inhibitor of protein phosphatases 1 and 2A from both mammals and higher plants. FEBS Letters, 264(2), 187-192. https://doi.org/0014-5793(90)80245-E google scholar
- Magalhâes, V. F., Soares, R. M., & Azevedo, S. M. (2001). Microcystin contamination in fish from the Jaca-repagua Lagoon (Rio de Janeiro, Brazil): ecological implication and human health risk. Toxicon, 39(7), 1077-1085. https://doi.org/10.1016/s0041-0101(00)00251-8 google scholar
- Manganelli, M. (2016). Blooms of toxic microorganisms in aquatic environments: marine microalgae and fres-hwater cyanobacteria. A brief review with a particular focus on the Italian situation. Rendiconti Lincei, 27(1), 135-143. https://doi.org/10.1007/s12210-015-0488-0 google scholar
- Manganelli, M., Scardala, S., Stefanelli, M., Vichi, S., Mattei, D., Bogialli, S., . . .& Funari, E. (2010). Health risk evaluation associated to Planktothrix rubescens: An integrated approach to design tailored monitoring programs for human exposure to cyanotoxins. Water Research, 44(5), 1297-1306. https://doi.org/10.1016/j. watres.2009.10.045 google scholar
- Manganelli, M., Stefanelli, M., Vichi, S., Andreani, P., Nascetti, G., Scialanca, F., . . .& Funari, E. (2016). Cya-nobacteria biennal dynamic in a volcanic mesotrophic lake in central Italy: Strategies to prevent dangerous human exposures to cyanotoxins. Toxicon, 115, 28-40. https://doi.org/10.1016/j.toxicon.2016.03.004 google scholar
- Manganelli, M., Testai, E., Tazart, Z., Scardala, S., & Codd, G. A. (2023). Co-Occurrence of Taste and Odor Compounds and Cyanotoxins in Cyanobacterial Blooms: Emerging Risks to Human Health? Microorga-nisms, 11(4). https://doi.org/10.3390/microorganisms11040872 google scholar
- McCarty, C. L., Nelson, L., Eitniear, S., Zgodzinski, E., Zabala, A., Billing, L., & DiOrio, M. (2016). Com-munity Needs Assessment After Microcystin Toxin Contamination of a Municipal Water Supply - Lucas County, Ohio, September 2014. MMWR Morbidity and Mortality Weekly Report, 65(35), 925-929. https:// doi.org/10.15585/mmwr.mm6535a1 google scholar
- McCord, J., Lang, J. R., Hill, D., Strynar, M., & Chernoff, N. (2018). pH dependent octanol-water partitioning coefficients of microcystin congeners. Journal of Water Health, 16(3), 340-345. https://doi.org/10.2166/ wh.2018.257 google scholar
- Metcalf, J. S., & Codd, G. A. (2020). Co-Occurrence of Cyanobacteria and Cyanotoxins with Other Envi-ronmental Health Hazards: Impacts and Implications. Toxins (Basel), 12(10). https://doi.org/10.3390/ toxins12100629 google scholar
- Metcalf, J. S., Banack, S. A., Wessel, R. A., Lester, M., Pim, J. G., Cassani, J. R., & Cox, P. A. (2021). Toxin Analysis of Freshwater Cyanobacterial and Marine Harmful Algal Blooms on the West Coast of Florida and Implications for Estuarine Environments. Neurotoxicity Research, 39(1), 27-35. https://doi.org/10.1007/ s12640-020-00248-3 google scholar
- Metcalf, J. S., Beattie, K. A., Pflugmacher, S., & Codd, G. A. (2000). Immuno-crossreactivity and toxicity as-sessment of conjugation products of the cyanobacterial toxin, microcystin-LR. FEMS Microbiology Letters, 189(2), 155-158. https://doi.org/S0378-1097(00)00270-6 google scholar
- MHD (Minnesota Departement of Health), (2015). Microcystin-LR in Drinking Water. https://www.health.state. mn.us/communities/environment/risk/docs/guidance/gw/mclrinfo.pdf (last access 07/20/2023) google scholar
- Miller, M. A., Kudela, R. M., Mekebri, A., Crane, D., Oates, S.C., Tinker, M. T., ... & Jessup, D. A. (2010). Evidence for a Novel Marine Harmful Algal Bloom: Cyanotoxin (Microcystin) Transfer from Land to Sea Otters. PLoS One 5(9): e12576. https://doi.org/10.1371/journal.pone.0012576 google scholar
- Mohamed, Z. A. (2008). Toxic cyanobacteria and cyanotoxins in public hot springs in Saudi Arabia. Toxicon, 51(1), 17-27. https://doi.org/10.1016/j.toxicon.2007.07.007 google scholar
- Mohamed, Z. A., Deyab, M. A., Abou-Dobara, M. I., El-Sayed, A. K., & El-Raghi, W. M. (2015). Occurrence of cyanobacteria and microcystin toxins in raw and treated waters of the Nile River, Egypt: implication for water treatment and human health. Environmental Science and Pollution Research, 22(15), 11716-11727. https://doi.org/10.1007/s11356-015-4420-z google scholar
- Mulvenna, V., Dale, K., Priestly, B., Mueller, U., Humpage, A., Shaw, G., . . .& Falconer, I. (2012). Health risk assessment for cyanobacterial toxins in seafood. International Journal of Environmental Research and Public Health, 9(3), 807-820. https://doi.org/10.3390/ijerph9030807 google scholar
- Mulvenna, V., & Orr, P. T. (2012) Australia: guidelines, legislation and management frameworks. In: Chorus, I. (ed) Current approaches to cyanotoxin risk assessment, risk management and regulations in different countries. Umweltbundesamt, Berlin. pp. 21-28. google scholar
- Murby, A. L., & Haney, J. F. (2016). Field and laboratory methods to monitor lake aerosols for cyanobacteria and microcystins. Aerobiologia, 32(3), 395-403. https://doi.org/10.1007/s10453-015-9409-z google scholar
- Naselli-Flores, L., Barone, R., Chorus, I., & Kurmayer, R. (2007). Toxic cyanobacterial blooms in reservoirs under a semiarid mediterranean climate: the magnification of a problem. Environmental Toxicology, 22(4), 399-404. https://doi.org/10.1002/tox.20268 google scholar
- Niedermeyer, T. H., Daily, A., Swiatecka-Hagenbruch, M., & Moscow, J. A. (2014). Selectivity and potency of microcystin congeners against OATP1B1 and OATP1B3 expressing cancer cells. PLoS One, 9(3), e91476. https://doi.org/10.1371/journal.pone.0091476 google scholar
- Nishiwaki, R., Ohta, T., Sueoka, E., Suganuma, M., Harada, K., Watanabe, M. F., & Fujiki, H. (1994). Two sig-nificant aspects of microcystin-LR: specific binding and liver specificity. Cancer Letters, 83(1-2), 283-289. https://doi.org/10.1016/0304-3835(94)90331-X google scholar
- NJDEP (New Jersey Department of Environmental Protection), (2021). Cyanobacterial Harmful Algal Bloom (HAB) Freshwater Recreational Response Strategy https://www.state.nj.us/dep/hab/download/HAB2021St-rategyFinal.pdf (last access 07/20/2023) google scholar
- NRMMC (National Resource Management Ministerial Council), (2008). Guidelines for managing risks in recre-ational water https://www.nhmrc.gov.au/about-us/publications/guidelines-managing-risks-recreational-wa-ter (last access 07/20/2023) google scholar
- NRMMC (National Resource Management Ministerial Council), (2011). Update 2022 Australian Drinking Water Guidelines Paper 6 National Water Quality Management Strategy https://www.nhmrc.gov.au/about-us/publications/australian-drinking-water-guidelines#block-views-block-file-attachments-content-block-1 (last access 07/20/2023) google scholar
- O’Neil, J. M., Davis, T. W., Burford, M. A., & Gobler, C. J. (2012). The rise of harmful cyanobacteria blo-oms: The potential roles of eutrophication and climate change. Harmful Algae, 14, 313-334. https://doi. org/10.1016/j.hal.2011.10.027 google scholar
- OHA (Oregon Health Authority), (2021). Advisory Guidelines Cyanobacteria Blooms in Recreational Waters. https://www.oregon.gov/oha/PH/HEALTHYENVIRONMENTS/RECREATION/HARMFULALGAEBLO-OMS/Documents/Advisory%20Guidelines%20for%20Harmful%20Cyanobacteria%20Blooms%20in%20 Recreational%20Waters.pdf (last access 07/20/2023) google scholar
- Okello, W., Portmann, C., Erhard, M., Gademann, K., & Kurmayer, R. (2010). Occurrence of microcystin-pro-ducing cyanobacteria in Ugandan freshwater habitats. Environmental Toxicology, 25(4), 367-380. https:// doi.org/10.1002/tox.20522 google scholar
- Ostermaier, V., Schanz, F., Köster, O., & Kurmayer, R. (2012). Stability of toxin gene proportion in red-pigmen-ted populations of the cyanobacterium Planktothrix during 29 years of re-oligotrophication of Lake Zürich. BMC Biology, 10(1), 100. https://doi.org/10.1186/1741-7007-10-100 google scholar
- Österholm, J., Popin, R. V., Fewer, D. P., & Sivonen, K. (2020). Phylogenomic Analysis of Secondary Metabo-lism in the Toxic Cyanobacterial Genera Anabaena, Dolichospermum and Aphanizomenon. Toxins (Basel), 12(4). https://doi.org/10.3390/toxins12040248 google scholar
- Paerl, H. W. (2014). Mitigating harmful cyanobacterial blooms in a human- and climatically-impacted world. Life (Basel), 4(4), 988-1012. https://doi.org/10.3390/life4040988 google scholar
- Pan, C., Chen, Y., Xu, T., Wang, J., Li, D., & Han, X. (2018). Chronic exposure to microcystin-leucine-arginine promoted proliferation of prostate epithelial cells resulting in benign prostatic hyperplasia. Environmental Pollution, 242(Pt B), 1535-1545. https://doi.org/10.1016/j.envpol.2018.08.024 google scholar
- Pancrace, C., Barny, M. A., Ueoka, R., Calteau, A., Scalvenzi, T., Pedron, J., . . .& Gugger, M. (2017). Insights into the Planktothrix genus: Genomic and metabolic comparison of benthic and planktic strains. Science Report, 7, 41181. https://doi.org/10.1038/srep41181 google scholar
- Peacock, M. B., Gibble, C. M., Senn, D. B., Cloern, J. E., & Kudela, R. M. (2018). Blurred lines: Multiple fres-hwater and marine algal toxins at the land-sea interface of San Francisco Bay, California. Harmful Algae, 73, 138-147. https://doi.org/10.1016/j.hal.2018.02.005 google scholar
- Pflugmacher, S. (2016). Biotransformation of Microcystins in Eukaryotic Cells - Possible Future Research Directions. Mini-Reviews in Medicinal Chemistry, 16(13), 1078-1083. https://doi.org/10.2174/13895575 16666160219130837 google scholar
- Pflugmacher, S., Wiegand, C., Oberemm, A., Beattie, K. A., Krause, E., Codd, G. A., & Steinberg, C. E. (1998). Identification of an enzymatically formed glutathione conjugate of the cyanobacterial hepatotoxin micro-cystin-LR: the first step of detoxication. Biochimica et Biophysica Acta, 1425(3), 527-533. https://doi.org/ S0304-4165(98)00107-X google scholar
- Plaas, H. E., Paerl, R. W., Baumann, K., Karl, C., Popendorf, K. J., Barnard, M. A., . . .& Paerl, H. W. (2022). Harmful cyanobacterial aerosolization dynamics in the airshed of a eutrophic estuary. Science of The Total Environment, 852, 158383. https://doi.org/10.1016/j.scitotenv.2022.158383 google scholar
- Ploug, H. (2008). Cyanobacterial Surface Blooms Formed by Aphanizomenon sp. and Nodularia spumigena in the Baltic Sea: Small-Scale Fluxes, pH, and Oxygen Microenvironments. Limnology and Oceanography, 53, 914-921. https://doi.org/10.2307/40058207 google scholar
- Pouria, S., de Andrade, A., Barbosa, J., Cavalcanti, R. L., Barreto, V. T., Ward, C. J., . . .& Codd, G. A. (1998). Fatal microcystin intoxication in haemodialysis unit in Caruaru, Brazil. Lancet, 352(9121), 21-26. https:// doi.org/S0140673697122851 google scholar
- Preece, E. P., Hardy, F. J., Moore, B. C., & Bryan, M. (2017). A review of microcystin detections in Estuarine and Marine waters: Environmental implications and human health risk. Harmful Algae, 61, 31-45. https:// doi.org/10.1016/j.hal.2016.11.006 google scholar
- Quiblier, C., Wood, S., Echenique-Subiabre, I., Heath, M., Villeneuve, A., & Humbert, J. F. (2013). A review of current knowledge on toxic benthic freshwater cyanobacteria-ecology, toxin production and risk manage-ment. WaterResearch, 47(15):5464-5479. https://doi.org/10.1016Zj.watres.2013.06.042 google scholar
- Roberts, V. A., Vigar, M., Backer, L., Veytsel, G. E., Hilborn, E. D., Hamelin, E. I., . . .& Yoder, J. S. (2020). Surveillance for Harmful Algal Bloom Events and Associated Human and Animal Illnesses - One He-alth Harmful Algal Bloom System, United States, 2016-2018. MMWR Morbidity Mortality Weekly Report, 69(50), 1889-1894. https://doi.org/10.15585/mmwr.mm6950a2 google scholar
- Sabart, M., Misson, B., Descroix, A., Duffaud, E., Combourieu, B., Salençon, M. J., & Latour, D. (2013). The importance of small colonies in sustaining Microcystis population exposed to mixing conditions: an explo-ration through colony size, genotypic composition and toxic potential. Environmental Microbiology Report, 5(5), 747-756. https://doi.org/10.1111/1758-2229.12077 google scholar
- Salmaso, N., Buzzi, F., Garibaldi, L., Morabito, G., & Simona, M. (2012). Effects of nutrient availability and temperature on phytoplankton development: a case study from large lakes south of the Alps. Aquatic Scien-ces 74, 555-570. https://doi.org/10.1007/s00027-012-0248-5 google scholar
- Sandrini, G., Ji, X., Verspagen, J. M., Tann, R. P., Slot, P. C., Luimstra, V. M., . . .& Huisman, J. (2016). Rapid adaptation of harmful cyanobacteria to rising CO2. Proceedings of National Academy of Sciences, 113(33), 9315-9320. https://doi.org/10.1073/pnas.1602435113 google scholar
- Santori, N., Buratti, F. M., Scardala, S., Dorne, J.-L. C. M., & Testai, E. (2020). In vitro detoxication of micro-cystins in human samples: variability among variants with different hydrophilicity and structure. Toxicology Letters 322, 131-139. https://doi.org/10.1016/j.toxlet.2020.01.007 google scholar
- Schaeffer, D. J., Malpas, P. B., & Barton, L. L. (1999). Risk assessment of microcystin in dietary Aphanizomenon flos-aquae. Ecotoxicology and Environmental Safety, 44(1), 73-80. https://doi.org/10.1006/eesa.1999.1816 google scholar
- Sedan, D., Laguens, M., Copparoni, G., Aranda, J. O., Giannuzzi, L., Marra, C. A., & Andrinolo, D. (2015). Hepatic and intestine alterations in mice after prolonged exposure to low oral doses of Microcystin-LR. Toxicon, 104, 26-33. https://doi.org/10.1016/j.toxicon.2015.07.011 google scholar
- Shapiro, J. (1997). The role of carbon dioxide in the initiation and maintenance of blue-green dominance in lakes. Freshwater Biology 37: 307-323. https://doi.org/10.1046/j.1365-2427.1997.00164.x google scholar
- Shartau, R. B., Turcotte, L. D. M., Bradshaw, J. C., Ross, A. R. S., Surridge, B. D., Nemcek, N., & Johnson, S. C. (2023). Dissolved Algal Toxins along the Southern Coast of British Columbia Canada. Toxins (Basel), 15(6), 395. https://doi.org/10.3390/toxins15060395 google scholar
- Skafi, M., Vo Duy, S., Munoz, G., Dinh, Q. T., Simon, D. F., Juneau, P., & Sauve, S. (2021). Occurrence of microcystins, anabaenopeptins and other cyanotoxins in fish from a freshwater wildlife reserve impacted by harmful cyanobacterial blooms. Toxicon, 194, 44-52. https://doi.org/10.1016/j.toxicon.2021.02.004 google scholar
- Soares, R. M., Yuan, M., Servaites, J. C., Delgado, A., Magalhâes, V. F., Hilborn, E. D., . . .& Azevedo, S. M. (2006). Sublethal exposure from microcystins to renal insufficiency patients in Rio de Janeiro, Brazil. En-vironmental Toxicology, 21(2), 95-103. https://doi.org/10.1002/tox.20160 google scholar
- Suda, S., Watanabe, M. M., Otsuka, S., Mahakahant, A., Yongmanitchai, W., Nopartnaraporn, N., . . .& Day, J. G. (2002). Taxonomic revision of water-bloom-forming species of oscillatorioid cyanobacteria. International Journal of Systematic and Evolutionary Microbiology, 52(5), 1577-1595. https://doi.org/10.1099/00207713-52-5-1577 google scholar
- Svircev, Z., Krstic, S., Miladinov-Mikov, M., Baltic, V., & Vidovic, M. (2009). Freshwater cyanobacterial blooms and primary liver cancer epidemiological studies in Serbia. Journal of Environmental Science and Health, Part C Environmental Carcinogenesis and Ecotoxicology Reviews, 27(1), 36-55. https://doi. org/10.1080/10590500802668016 google scholar
- Svircev, Z., Lalic, D., Bojadzija Savic, G., Tokodi, N., Drobac Backovic, D., Chen, L., . . .& Codd, G. A. (2019). Global geographical and historical overview of cyanotoxin distribution and cyanobacterial poisonings. Arc-hive of Toxicology, 93(9), 2429-2481. https://doi.org/10.1007/s00204-019-02524-4 google scholar
- Takenaka, S. (2001). Covalent glutathione conjugation to cyanobacterial hepatotoxin microcystin LR by F344 rat cytosolic and microsomal glutathione S-transferases. Environmental Toxicology and Pharmacology, 9(4), 135-139. https://doi.org/10.1016/s1382-6689(00)00049-1 google scholar
- Tatters, A. O., Smith, J., Kudela, R. M., Hayashi, K., Howard, M. D., Donovan, A. R., . . .& Caron, D. A. (2021). The tide turns: Episodic and localized cross-contamination of a California coastline with cyanotoxins. Har-mful Algae, 103, 102003. https://doi.org/10.1016/j.hal.2021.102003 google scholar
- Teixeira Mda, G., Costa Mda, C., de Carvalho, V. L., Pereira Mdos, S., & Hage, E. (1993). Gastroenteritis epi-demic in the area of the Itaparica Dam, Bahia, Brazil. Bulletin of the Pan Amerincan Health Organization, 27(3), 244-253. google scholar
- Testai, E., Buratti, F. M., Funari, E., Manganelli, M., Vichi, S., Arnich, N., . . .& Sialehaamoa, A. (2016). Re-view and analysis of occurrence, exposure and toxicity of cyanobacteria toxins in food. EFSA Supporting Publications, 13(2), 998E. https://doi.org/10.2903/sp.efsa.2016.EN-998 google scholar
- Tooming-Klunderud, A., Sogge, H., Rounge, T. B., Nederbragt, A. J., Lagesen, K., Glöckner, G., . . .& Jakob-sen, K. S. (2013). From green to red: horizontal gene transfer of the phycoerythrin gene cluster between Planktothrix strains. Applied and Environmental Microbiology, 79(21), 6803-6812. https://doi.org/10.1128/ aem.01455-13 google scholar
- Trevino-Garrison, I., DeMent, J., Ahmed, F. S., Haines-Lieber, P., Langer, T., Menager, H., . . .& Edward, C. (2015). Human Illnesses and Animal Deaths Associated with Freshwater Harmful Algal Blooms—Kansas. Toxins (Basel), 7(2), 353-366. https://doi.org/10.3390/toxins7020353 google scholar
- Turco, L., Santori, N., Buratti, F. M., Dorne, J. C. M., & Testai, E. (2022). Congeners-Specific Intestinal Absorp-tion Of Microcystins In An In Vitro 3D Human Intestinal Epithelium: The Role Of Influx/Efflux Transpor-ters. Frontiers in Toxicology, 4, 883063. https://doi.org/10.3389/ftox.2022.883063 google scholar
- Turner, P. C., Gammie, A. J., Hollinrake, K., & Codd, G. A. (1990). Pneumonia associated with contact with cyanobacteria. British Medical Journal, 300(6737), 1440-1441. https://doi.org/10.1136/bmj.300.6737.1440 google scholar
- Ueno, Y., Nagata, S., Tsutsumi, T., Hasegawa, A., Watanabe, M. F., Park, H. D., . . .& Yu, S. Z. (1996). Detection of microcystins, a blue-green algal hepatotoxin, in drinking water sampled in Haimen and Fusui, endemic areas of primary liver cancer in China, by highly sensitive immunoassay. Carcinogenesis, 17(6), 1317-1321 google scholar
- US EPA, (United States Environmental Protection Agency). (2019). Recommended Human Health Recreational Ambient Water Quality Criteria or Swimming Advisories for Microcystins and Cylindrospermopsin EPA 822-R-19-001 Washington, DC, https://www.epa.gov/sites/production/files/2019-05/documents/hh-rec-cri-teria-habs-document-2019.pdf (last access 20/07/2023) google scholar
- US EPA, (United States Environmental Protection Agency). (2021). Final Technical Support Document: Imple-menting the National Clean Water Act Section 304(a) Recommended Human Health Recreational Ambient Water Quality Criteria or Swimming Advisories for Microcystins and Cylindrospermopsin https://www. epa.gov/system/files/documents/2021-08/final-tsd-implement-2019-rwqc.pdf.pdf (last access 20/07/2023) google scholar
- US EPA, (United States Environmental Protection Agency). (2015). Drinking water health advisory for the cyanobacterial microcystin toxin, EPA-820R15100. 75 pages. https://www.epa.gov/sites/production/fi-les/2017-06/documents/microcystins-report-2015.pdf (last access 20/07/2023) google scholar
- Usman, A. S., Merican, F., Zaki, S., Broady, P., Convey, P., & Muangmai, N. (2022). Microcystin production by oscillatorialean cyanobacteria isolated from cryopreserved Antarctic mats. Harmful Algae, 120, 102336. doi:10.1016/j.hal.2022.102336 google scholar
- Van Wichelen, J., Vanormelingen, P., Codd, G. A., & Vyverman, W. (2016). The common bloom-forming cyano-bacterium Microcystis is prone to a wide array of microbial antagonists. Harmful Algae, 55, 97-111. https:// doi.org/10.1016/j.hal.2016.02.009 google scholar
- VDH, (Virginia Department of Health). (2021). Guidance for Cyanobacteria Bloom Recreational Advisory Management 2021 https://www.vdh.virginia.gov/content/uploads/sites/178/2021/03/Guidance_for_Cyano-bacteria_Recreational_Advisory_Mgt.pdf (last access 20/07/2023) google scholar
- Vichi, S., Buratti, F. M., & Testai, E. (2016). Microcystins: Toxicological Profile. In P. Gopalakrishnakone, V. Haddad Jr, A. Tubaro, E. Kim, & W. R. Kem (Eds.), Marine and Freshwater Toxins (pp. 219-238). Dord-recht: Springer Netherlands. google scholar
- Vidal, F., Sedan, D., D’Agostino, D., Cavalieri, M. L., Mullen, E., Parot Varela, M. M., . . .& Andrinolo, D. (2017). Recreational Exposure during Algal Bloom in Carrasco Beach, Uruguay: A Liver Failure Case Report. Toxins (Basel), 9(9). https://doi.org/10.3390/toxins9090267 google scholar
- Wang, X., Xu, L., Li, X., Chen, J., Zhou, W., Sun, J., & Wang, Y. (2018). The differential effects of microcys-tin-LR on mitochondrial DNA in the hippocampus and cerebral cortex. Environmental Pollution, 240, 68-76. https://doi.org/10.1016/j.envpol.2018.04.103 google scholar
- Whitton, B. A., & Potts, M. (2012). Introduction to the cyanobacteria. In: Whitton, B. A. (Ed.) Ecology of Cya-nobacteria II Their Diversity in Space and Time. Wiley, Chichester, UK, pp. 1-13. google scholar
- WHO. (2020). Cyanobacterial toxins: microcystins - Background document for development of WHO Guideli-nes for drinking-water quality and Guidelines for safe recreational water environments. WHO/HEP/ECH/ WSH/2020.6. google scholar
- WHO. (2021). Guidelines on recreational water quality. Volume 1: coastal and fresh waters. Geneva: World Health Organization. Licence: CC BY-NC-SA 3.0 IGO. google scholar
- WHO. (2022). Guidelines for drinking-water quality: fourth edition incorporating the first and second addenda google scholar
- Wood, S. A., Heath, M. W., Holland, P. T., Munday, R., McGregor, G. B., & Ryan, K. G. (2010). Identification of a benthic microcystin-producing filamentous cyanobacterium (Oscillatoriales) associated with a dog poisoning in New Zealand. Toxicon, 55(4), 897-903. https://doi.org/S0041-0101(09)00588-1 google scholar
- Wood, S. A., Dietrich, D. R., Cary, S. C., & Hamilton, D. P. (2012a). Increasing Microcystis cell density enhances microcystin synthesis: a mesocosm study. Inland Waters, 2(1), 17-22. https://doi.org/10.5268/IW-2.1.424 google scholar
- Wood, S. A., Kuhajek, J. M., de Winton, M., & Phillips, N. R. (2012b). Species composition and cyanotoxin production in periphyton mats from three lakes of varying trophic status. FEMS Microbiology Ecology, 79(2), 312-326. https://doi.org/10.1111/j.1574-6941.2011.01217.x google scholar
- Wood, S. A., Kelly, L., Bouma-Gregson, K., Humbert, J. F., Laughinghouse, H. D. t., Lazorchak, J., . . .& Davis, T. W. (2020). Toxic benthic freshwater cyanobacterial proliferations: Challenges and solutions for enhancing knowledge and improving monitoring and mitigation. Freshwater Biology, 65(10), 1824-1842. https://doi. org/10.1111/fwb.13532 google scholar
- Wood, S. A., Puddick, J., Hawes, I., Steiner, K., Dietrich, D. R., & Hamilton, D. P. (2021). Variability in mic-rocystin quotas during a Microcystis bloom in a eutrophic lake. PLoS One, 16(7), e0254967. https://doi. org/10.1371/journal.pone.0254967 google scholar
- Wu, J., Hilborn, E. D., Schaeffer, B. A., Urquhart, E., Coffer, M. M., Lin, C. J., & Egorov, A. I. (2021). Acute health effects associated with satellite-determined cyanobacterial blooms in a drinking water source in Massachusetts. Environmental Health, 20(1), 83. https://doi.org/10.1186/s12940-021-00755-6 google scholar
- Wu, J., Yuan, M., Song, Y., Sun, F., & Han, X. (2015). MC-LR Exposure Leads to Subfertility of Female Mice and Induces Oxidative Stress in Granulosa Cells. Toxins (Basel), 7(12), 5212-5223. https://doi.org/10.3390/ toxins7124872 google scholar
- Yancey, C. E., Smith, D. J., Den Uyl, P. A., Mohamed, O. G., Yu, F., Ruberg, S. A., . . .& Dick, G. J. (2022). Metagenomic and Metatranscriptomic Insights into Population Diversity of Microcystis Blooms: Spatial and Temporal Dynamics of mcy Genotypes, Including a Partial Operon That Can Be Abundant and Expressed. Applied and Environmental Microbiology, 88(9), e0246421. https://doi.org/10.1128/aem.02464-21 google scholar
- Yoshizawa, S., Matsushima, R., Watanabe, M. F., Harada, K., Ichihara, A., Carmichael, W. W., & Fujiki, H. (1990). Inhibition of protein phosphatases by microcystins and nodularin associated with hepatotoxicity. Journal of Cancer Research and Clinical Oncology, 116(6), 609-614. https://doi.org/10.1007/bf01637082 google scholar
- Yu, L., Kong, F., Zhang, M., Yang, Z., Shi, X., & Du, M. (2014). The dynamics of Microcystis genotypes and microcystin production and associations with environmental factors during blooms in Lake Chaohu, China. Toxins (Basel), 6(12), 3238-3257. https://doi.org/10.3390/toxins6123238 google scholar
- Zegura, B., Straser, A., & Filipic, M. (2011). Genotoxicity and potential carcinogenicity of cyanobacterial toxins - a review. Mutation Research, 727(1-2), 16-41. https://doi.org/10.1016/j.mrrev.2011.01.002 google scholar
- Zheng, C., Zeng, H., Lin, H., Wang, J., Feng, X., Qiu, Z., . . .& Shu, W. (2017). Serum microcystin levels posi-tively linked with risk of hepatocellular carcinoma: A case-control study in southwest China. Hepatology, 66(5), 1519-1528. https://doi.org/10.1002/hep.29310 google scholar
- Zhou, L., Yu, H., & Chen, K. (2002). Relationship between microcystin in drinking water and colorectal cancer. Biomedical and Environmental Sciences, 15(2), 166-171. google scholar
- Zhou, Y., Sun, M., Tang, Y., Chen, Y., Zhu, C., Yang, Y., . . .& Tang, Z. (2020). Responses of the proteome in testis of mice exposed chronically to environmentally relevant concentrations of Microcystin-LR. Ecotoxi-cology and Environmental Safety, 187, 109824. https://doi.org/10.1016/j.ecoenv.2019.109824 google scholar