The Toxicity Testing of Cyanobacterial Toxins In vivo and In vitro by
Mouse Bioassay: A Review

Hamed       Ahari; Bahareh      Nowruzi; Amir    Ali    Anvar; Samaneh    Jafari    Porzani
doi:10.2174/1389557521666211101162030
Abstract

Different biological methods based on bioactivity are available to detect cyanotoxins, including neurotoxicity, immunological interactions, hepatotoxicity, cytotoxicity, and enzymatic activity. The mouse bioassay is the first test employed in laboratory cultures, cell extracts, and water bloom materials to detect toxins. It is also used as a traditional method to estimate the LD50. Concerning the ease of access and low cost, it is the most common method for this purpose. In this method, a sample is injected intraperitoneally into adult mice, and accordingly, they are assayed and monitored for about 24 hours for toxic symptoms. The toxin can be detected using this method from minutes to a few hours; its type, e.g., hepatotoxin, neurotoxin, etc., can also be determined. However, this method is nonspecific, fails to detect low amounts, and cannot distinguish between homologues. Although the mouse bioassay is gradually replaced with new chemical and immunological methods, it is still the main technique to detect the bioactivity and efficacy of cyanotoxins using LD50 determined based on the survival time of animals exposed to the toxin. In addition, some countries oppose animal use in toxicity studies. However, high cost, ethical considerations, low-sensitivity, non-specificity, and prolonged processes persuade researchers to employ chemical and functional analysis techniques. The qualitative and quantitative analyses, as well as high specificity and sensitivity, are among the advantages of cytotoxicity tests to investigate cyanotoxins. The present study aimed at reviewing the results obtained from in vitro and in vivo investigations of the mouse bioassay to detect cyanotoxins, including microcystins, cylindrospermopsin, saxitoxins, etc.
Keywords: Cyanotoxins, mouse bioassay, in vivo and in vitro conditions, toxicity tests, cyanobacterial toxins, cytotoxicity tests.
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[1] 
Msagati, T.A.; Siame, B.A.; Shushu, D.D. Evaluation of methods for the isolation, detection and quantification of cyanobacterial hepatotoxins. Aquat. Toxicol.,  2006, 78(4), 382-397.
[http://dx.doi.org/10.1016/j.aquatox.2006.03.011] [PMID: 16757036] 
[2] 
Lawton, L.A.; Metcalf, J.S.; Žegura, B.; Junek, R.; Welker, M.; Törökné, A.; Bláha, L. Laboratory analysis of cyanobacterial toxins and bioassays. In: Toxic Cyanobacteria in Water; , 2021; pp. 745-800.
[http://dx.doi.org/10.1201/9781003081449-14] 
[3] 
Imam, T.S.; Tsagero, M.H.; Hadiza, A.A.; Aminu, S.B.; Ugya, A.Y. Emerging approach to uncover cyanotoxins in aquatic environment: A concise review. Curr. World Environ.,  2020, 15(1), 100.
[http://dx.doi.org/10.12944/CWE.15.1.13] 
[4] 
Bartram, J.; Chorus, I. Toxic cyanobacteria in water: A guide to their public health consequences, monitoring and management; CRC Press: New York, 1999. 
[http://dx.doi.org/10.1201/9781482295061] 
[5] 
Falconer, I.R.; Smith, J.V.; Jackson, A.R.; Jones, A.; Runnegar, M.T. Oral toxicity of a bloom of the Cyanobacterium Microcystis aeruginosa administered to mice over periods up to 1 year. J. Toxicol. Environ. Health,  1988, 24(3), 291-305.
[http://dx.doi.org/10.1080/15287398809531163] [PMID: 3135416] 
[6] 
Falconer, I.R. Measurement of toxins from blue-green algae in water and foodstuffs. Algal Toxins Seafood Drink. Water,  1993, 1, 165-175.
[7] 
Falconer, I.; Jackson, R.; Langley, B.; Runnegar, M. Liver pathology in mice in poisoning by the blue-green alga Microcystis aeruginosa. Aust. J. Biol. Sci.,  1981, 34(2), 179-188.
[http://dx.doi.org/10.1071/BI9810179] 
[8] 
Fawell, J.K.; Mitchell, R.E.; Everett, D.J.; Hill, R.E. The toxicity of cyanobacterial toxins in the mouse: I microcystin-LR. Hum. Exp. Toxicol.,  1999, 18(3), 162-167.
[http://dx.doi.org/10.1177/096032719901800305] [PMID: 10215106] 
[9] 
Hermansky, S.J.; Markin, R.S.; Fowler, E.H.; Stohs, S.J. Hepatic ultrastructural changes induced by the toxin Microcystin-LR (MCLR) in mice. J. Environ. Pathol. Toxicol. Oncol.,  1993, 12(2), 101-106.
[PMID: 8189358] 
[10] 
Masango, M.G. A comparative analysis of the cytotoxicity of cyanotoxins using in vitro (cell culture) and in vivo (mouse) assays; University of Pretoria, 2008. 
[11] 
Nagata, S.; Tsutsumi, T.; Hasegawa, A.; Yoshida, F.; Ueno, Y.; Watanabe, M.F. Enzyme immunoassay for direct determination of microcystins in environmental water. J. AOAC Int.,  1997, 80(2), 408-417.
[http://dx.doi.org/10.1093/jaoac/80.2.408] 
[12] 
Ramya, M.; Umamaheswari, A.; Elumalai, S. Global health concern of cyanotoxins in surface water and its various detection methods. Curr. Bot.,  2020, 65-74.
[13] 
Stoner, R.D.; Adams, W.H.; Slatkin, D.N.; Siegelman, H.W. The effects of single L-amino acid substitutions on the lethal potencies of the microcystins. Toxicon,  1989, 27(7), 825-828.
[http://dx.doi.org/10.1016/0041-0101(89)90051-2] [PMID: 2506678] 
[14] 
Dawson, R.M. The toxicology of microcystins. Toxicon,  1998, 36(7), 953-962.
[http://dx.doi.org/10.1016/S0041-0101(97)00102-5] [PMID: 9690788] 
[15] 
Oberholster, P.; Botha, A.; Grobbelaar, J. Microcystis aeruginosa: source of toxic microcystins in drinking water. Afr. J. Biotechnol.,  2004, 3(3), 159-168.
[http://dx.doi.org/10.5897/AJB2004.000-2029] 
[16] 
Chernoff, N.; Hill, D.; Lang, J.; Schmid, J.; Farthing, A.; Huang, H. Dose-Response Study of Microcystin Congeners MCLA, MCLR, MCLY, MCRR, and MCYR Administered Orally to Mice. Toxins (Basel),  2021, 13(2), 86.
[http://dx.doi.org/10.3390/toxins13020086] [PMID: 33498948] 
[17] 
Caderni, G.; Giannini, A.; Lancioni, L.; Luceri, C.; Biggeri, A.; Dolara, P. Characterisation of aberrant crypt foci in carcinogen-treated rats: Association with intestinal carcinogenesis. Br. J. Cancer,  1995, 71(4), 763-769.
[http://dx.doi.org/10.1038/bjc.1995.148] [PMID: 7710942] 
[18] 
McLellan, E.A.; Medline, A.; Bird, R.P. Sequential analyses of the growth and morphological characteristics of aberrant crypt foci: Putative preneoplastic lesions. Cancer Res.,  1991, 51(19), 5270-5274.
[PMID: 1913650] 
[19] 
Takayama, T.; Katsuki, S.; Takahashi, Y.; Ohi, M.; Nojiri, S.; Sakamaki, S.; Kato, J.; Kogawa, K.; Miyake, H.; Niitsu, Y. Aberrant crypt foci of the colon as precursors of adenoma and cancer. N. Engl. J. Med.,  1998, 339(18), 1277-1284.
[http://dx.doi.org/10.1056/NEJM199810293391803] [PMID: 9791143] 
[20] 
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(6), 420-424.
[http://dx.doi.org/10.1007/BF01629424] [PMID: 1618889] 
[21] 
Falconer, I.R. Tumor promotion and liver injury caused by oral consumption of cyanobacteria. Environ. Toxicol. Water Qual.,  1991, 6(2), 177-184.
[http://dx.doi.org/10.1002/tox.2530060207] 
[22] 
Kondo, F.; Ikai, Y.; Oka, H.; Okumura, M.; Ishikawa, N.; Harada, K.; Matsuura, K.; Murata, H.; Suzuki, M. Formation, characterization, and toxicity of the glutathione and cysteine conjugates of toxic heptapeptide microcystins. Chem. Res. Toxicol.,  1992, 5(5), 591-596.
[http://dx.doi.org/10.1021/tx00029a002] [PMID: 1445998] 
[23] 
Fitzgeorge, R.; Clark, S.; Keevil, C. Routes of intoxication. Spec. Publ. R. Soc. Chem.,  1994, 149, 69-74.
[24] 
Funari, E.; Testai, E. Human health risk assessment related to cyanotoxins exposure. Crit. Rev. Toxicol.,  2008, 38(2), 97-125.
[http://dx.doi.org/10.1080/10408440701749454] [PMID: 18259982] 
[25] 
Fromme, H.; Köhler, A.; Krause, R.; Führling, D. Occurrence of cyanobacterial toxins-microcystins and anatoxin‐a-in Berlin water bodies with implications to human health and regulations. Environ. Toxicol.,  2000, 15(2), 120-130.
[http://dx.doi.org/10.1002/(SICI)1522-7278(2000)15:2<120::AID-TOX8>3.0.CO;2-X] 
[26] 
Gehringer, M.M. Microcystin-LR and okadaic acid-induced cellular effects: a dualistic response. FEBS Lett.,  2004, 557(1-3), 1-8.
[http://dx.doi.org/10.1016/S0014-5793(03)01447-9] [PMID: 14741332] 
[27] 
Schaeffer, D.J.; Malpas, P.B.; Barton, L.L. Risk assessment of microcystin in dietary Aphanizomenon flos-aquae. Ecotoxicol. Environ. Saf.,  1999, 44(1), 73-80.
[http://dx.doi.org/10.1006/eesa.1999.1816] [PMID: 10499991] 
[28] 
He, J.; Chen, J.; Wu, L.; Li, G.; Xie, P. Metabolic response to oral microcystin-LR exposure in the rat by NMR-based metabonomic study. J. Proteome Res.,  2012, 11(12), 5934-5946.
[http://dx.doi.org/10.1021/pr300685g] [PMID: 23145862] 
[29] 
Sedan, D.; Laguens, M.; Copparoni, G.; Aranda, J.O.; Giannuzzi, L.; Marra, C.A.; Andrinolo, D. Hepatic and intestine alterations in mice after prolonged exposure to low oral doses of Microcystin-LR. Toxicon,  2015, 104, 26-33.
[http://dx.doi.org/10.1016/j.toxicon.2015.07.011] [PMID: 26210502] 
[30] 
Metcalf, J.S.; Codd, G.A. Co-occurrence of cyanobacteria and cyanotoxins with other environmental health hazards: impacts and implications. Toxins (Basel),  2020, 12(10), 629.
[http://dx.doi.org/10.3390/toxins12100629] [PMID: 33019550] 
[31] 
Benson, J.M.; Hutt, J.A.; Rein, K.; Boggs, S.E.; Barr, E.B.; Fleming, L.E. The toxicity of microcystin LR in mice following 7 days of inhalation exposure. Toxicon,  2005, 45(6), 691-698.
[http://dx.doi.org/10.1016/j.toxicon.2005.01.004] [PMID: 15804518] 
[32] 
Qin, W.; Zhang, X.; Yang, L.; Xu, L.; Zhang, Z.; Wu, J.; Wang, Y. Microcystin-LR altered mRNA and protein expression of endoplasmic reticulum stress signaling molecules related to hepatic lipid metabolism abnormalities in mice. Environ. Toxicol. Pharmacol.,  2015, 40(1), 114-121.
[http://dx.doi.org/10.1016/j.etap.2015.05.002] [PMID: 26093960] 
[33] 
Zhang, B.; Liu, Y.; Li, X. Alteration in the expression of cytochrome P450s (CYP1A1, CYP2E1, and CYP3A11) in the liver of mouse induced by microcystin-LR. Toxins (Basel),  2015, 7(4), 1102-1115.
[http://dx.doi.org/10.3390/toxins7041102] [PMID: 25831226] 
[34] 
Chernoff, N.; Hill, D.; Lang, J.; Schmid, J.; Le, T.; Farthing, A.; Huang, H. The comparative toxicity of 10 microcystin congeners administered orally to mice: Clinical effects and organ toxicity. Toxins (Basel),  2020, 12(6), 403.
[http://dx.doi.org/10.3390/toxins12060403] [PMID: 32570788] 
[35] 
Zhao, S.; Li, G.; Chen, J. A proteomic analysis of prenatal transfer of microcystin-LR induced neurotoxicity in rat offspring. J. Proteome.,  2015, 114, 197-213.
[http://dx.doi.org/10.1016/j.jprot.2014.11.015] [PMID: 25479203] 
[36] 
Zhao, Y.; Xue, Q.; Su, X.; Xie, L.; Yan, Y.; Steinman, A.D. Microcystin-LR induced thyroid dysfunction and metabolic disorders in mice. Toxicology,  2015, 328, 135-141.
[http://dx.doi.org/10.1016/j.tox.2014.12.007] [PMID: 25497113] 
[37] 
Soares, R.M.; Cagido, V.R.; Ferraro, R.B.; Meyer-Fernandes, J.R.; Rocco, P.R.; Zin, W.A.; Azevedo, S.M. Effects of microcystin-LR on mouse lungs. Toxicon,  2007, 50(3), 330-338.
[http://dx.doi.org/10.1016/j.toxicon.2007.04.003] [PMID: 17521692] 
[38] 
Carvalho, G.M.C.; Oliveira, V.R.; Casquilho, N.V.; Araujo, A.C.P.; Soares, R.M.; Azevedo, S.M.F.; 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.
[http://dx.doi.org/10.1016/j.toxicon.2016.01.066] [PMID: 26844922] 
[39] 
Oliveira, V.R.; Avila, M.B.; Carvalho, G.M.C.; Azevedo, S.M.F.; Lima, L.M.; Barreiro, E.J.; Carvalho, A.R.; Zin, W.A. Investigating the therapeutic effects of LASSBio-596 in an in vivo model of cylindrospermopsin-induced lung injury. Toxicon,  2015, 94, 29-35.
[http://dx.doi.org/10.1016/j.toxicon.2014.12.004] [PMID: 25528385] 
[40] 
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.
[http://dx.doi.org/10.1016/j.toxicon.2016.03.007] [PMID: 26995211] 
[41] 
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.
[http://dx.doi.org/10.1016/j.envpol.2015.12.001] [PMID: 26706032] 
[42] 
Ueno, Y.; Makita, Y.; Nagata, S.; Tsutsumi, T.; Yoshida, F.; Tamura, S.I.; Sekijima, M.; Tashiro, F.; Harada, T.; Yoshida, T. No chronic oral toxicity of a low dose of microcystin‐LR, a cyanobacterial hepatotoxin, in female BALB/c mice. Environ. Toxicol.,  1999, 14(1), 45-55.
[http://dx.doi.org/10.1002/(SICI)1522-7278(199902)14:1<45::AID-TOX8>3.0.CO;2-T] 
[43] 
Bouaïcha, N.; Maatouk, I.; Plessis, M.J.; Périn, F. Genotoxic potential of Microcystin-LR and nodularin in vitro in primary cultured rat hepatocytes and in vivo in rat liver. Environ. Toxicol.,  2005, 20(3), 341-347.
[http://dx.doi.org/10.1002/tox.20110] [PMID: 15892058] 
[44] 
Li, X.; Zhao, Q.; Zhou, W.; Xu, L.; Wang, Y. Effects of chronic exposure to microcystin-LR on hepatocyte mitochondrial DNA replication in mice. Environ. Sci. Technol.,  2015, 49(7), 4665-4672.
[http://dx.doi.org/10.1021/es5059132] [PMID: 25723732] 
[45] 
Wang, X.; Huang, P.; Liu, Y.; Du, H.; Wang, X.; Wang, M.; Wang, Y.; Hei, T.K.; Wu, L.; Xu, A. Role of nitric oxide in the genotoxic response to chronic microcystin-LR exposure in human-hamster hybrid cells. J. Environ. Sci. (China),  2015, 29, 210-218.
[http://dx.doi.org/10.1016/j.jes.2014.07.036] [PMID: 25766030] 
[46] 
Filipič, M.; Žegura, B.; Sedmak, B.; Horvat-Žnidaršic, I.; Milutinovič, A.; Šuput, D. Subchronic exposure of rats to sublethal dose of microcystin-YR induces DNA damage in multiple organs. Radiol. Oncol.,  2007, 41(1), 15-22.
[http://dx.doi.org/10.2478/v10019-007-0003-z] 
[47] 
Žegura, B.; Filipič, M.; Šuput, D.; Lah, T.; Sedmak, B. In vitro genotoxicity of microcystin-RR on primary cultured rat hepatocites and Hep G2 cell line detected by Comet assay. Radiol. Oncol.,  2002, 36(2), 159-161.
[48] 
Žegura, B.; Štraser, A.; Filipič, M. Genotoxicity and potential carcinogenicity of cyanobacterial toxins - a review. Mutat. Res.,  2011, 727(1-2), 16-41.
[http://dx.doi.org/10.1016/j.mrrev.2011.01.002] [PMID: 21277993] 
[49] 
Ito, E.; Kondo, F.; Terao, K.; Harada, K. Neoplastic nodular formation in mouse liver induced by repeated intraperitoneal injections of microcystin-LR. Toxicon,  1997, 35(9), 1453-1457.
[http://dx.doi.org/10.1016/S0041-0101(97)00026-3] [PMID: 9403968] 
[50] 
Lian, M.; Liu, Y.; Yu, S-Z.; Qian, G-S.; Wan, S-G.; Dixon, K.R. Hepatitis B virus x gene and cyanobacterial toxins promote aflatoxin B1-induced hepatotumorigenesis in mice. World J. Gastroenterol.,  2006, 12(19), 3065-3072.
[http://dx.doi.org/10.3748/wjg.v12.i19.3065] [PMID: 16718789] 
[51] 
Labine, M.; Minuk, G.Y. Long-term, low-dose exposure to microcystin toxin does not increase the risk of liver tumor development or growth in mice. Hepatol. Res.,  2015, 45(6), 683-692.
[http://dx.doi.org/10.1111/hepr.12394] [PMID: 25052518] 
[52] 
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(12), 28077-28086.
[http://dx.doi.org/10.3390/ijms161226083] [PMID: 26602924] 
[53] 
Chen, Y.; Xu, J.; Li, Y.; Han, X. Decline of sperm quality and testicular function in male mice during chronic low-dose exposure to microcystin-LR. Reprod. Toxicol.,  2011, 31(4), 551-557.
[http://dx.doi.org/10.1016/j.reprotox.2011.02.006] [PMID: 21338672] 
[54] 
Wu, J.; Yuan, M.; Song, Y.; Sun, F.; Han, X. MC-LR Exposure leads to subfertility of female mice and induces oxidative stress in granulosa cells. Toxins (Basel),  2015, 7(12), 5212-5223.
[http://dx.doi.org/10.3390/toxins7124872] [PMID: 26633508] 
[55] 
Wu, J.; Shao, S.; Zhou, F.; Wen, S.; Chen, F.; Han, X. Reproductive toxicity on female mice induced by microcystin-LR. Environ. Toxicol. Pharmacol.,  2014, 37(1), 1-6.
[http://dx.doi.org/10.1016/j.etap.2013.10.012] [PMID: 24280256] 
[56] 
Cardellina, J.H., II; Marner, F-J.; Moore, R.E. Seaweed dermatitis: Structure of lyngbyatoxin A. Science,  1979, 204(4389), 193-195.
[http://dx.doi.org/10.1126/science.107586] [PMID: 107586] 
[57] 
Moore, R.E. Toxins, anticancer agents, and tumor promoters from marine prokaryotes. Pure Appl. Chem.,  1982, 54(10), 1919-1934.
[http://dx.doi.org/10.1351/pac198254101919] 
[58] 
Pfaller, W.; Gstraunthaler, G. Nephrotoxicity testing in vitro-what we know and what we need to know. Environ. Health Perspect.,  1998, 106(Suppl. 2), 559-569.
[PMID: 9599703] 
[59] 
Jennings, P. Clinical Nephrotoxins; Springer, 2003, pp. 115-147.
[http://dx.doi.org/10.1007/1-4020-2586-6_7] 
[60] 
Milutinović, A.; Sedmak, B.; Horvat-Žnidaršić, I.; Šuput, D. Renal injuries induced by chronic intoxication with microcystins. Cell. Mol. Biol. Lett.,  2002, 7(1), 139-141.
[PMID: 11944069] 
[61] 
Milutinović, A.; Živin, M.; Zorc-Pleskovič, R.; Sedmak, B.; Šuput, D. Nephrotoxic effects of chronic administration of microcystins -LR and -YR. Toxicon,  2003, 42(3), 281-288.
[http://dx.doi.org/10.1016/S0041-0101(03)00143-0] [PMID: 14559079] 
[62] 
Ding, W-X.; Shen, H-M.; Zhu, H-G.; Lee, B-L.; Ong, C-N. Genotoxicity of microcystic cyanobacteria extract of a water source in China. Mutat. Res.,  1999, 442(2), 69-77.
[http://dx.doi.org/10.1016/S1383-5718(99)00064-9] [PMID: 10393275] 
[63] 
Abramsson-Zetterberg, L.; Sundh, U.B.; Mattsson, R. Cyanobacterial extracts and microcystin-LR are inactive in the micronucleus assay in vivo and in vitro. Mutat. Res.,  2010, 699(1-2), 5-10.
[http://dx.doi.org/10.1016/j.mrgentox.2010.04.001] [PMID: 20381641] 
[64] 
Zhan, L.; Honma, M.; Wang, L.; Hayashi, M.; Wu, D-S.; Zhang, L-S.; Rajaguru, P.; Suzuki, T. Microcystin-LR is not Mutagenic in vivo in the λ/lacZ Transgenic Mouse (MutaTMMouse). Genes Environ.,  2006, 28(2), 68-73.
[http://dx.doi.org/10.3123/jemsge.28.68] 
[65] 
Falconer, I.R.; Buckley, T.H. Tumour promotion by Microcystis sp., a blue-green alga occurring in water supplies. Med. J. Aust.,  1989, 150(6), 351-351.
[http://dx.doi.org/10.5694/j.1326-5377.1989.tb136517.x] [PMID: 2497311] 
[66] 
Falconer, I.R.; Humpage, A.R. Tumour promotion by cyanobacterial toxins. Phycologia,  1996, 35(Sup 6), 74-79.
[http://dx.doi.org/10.2216/i0031-8884-35-6S-74.1] 
[67] 
Humpage, A.R.; Hardy, S.J.; Moore, E.J.; Froscio, S.M.; Falconer, I.R. Microcystins (cyanobacterial toxins) in drinking water enhance the growth of aberrant crypt foci in the mouse colon. J. Toxicol. Environ. Health A,  2000, 61(3), 155-165.
[http://dx.doi.org/10.1080/00984100050131305] [PMID: 11036504] 
[68] 
Ohta, T.; Sueoka, E.; Iida, N.; Komori, A.; Suganuma, M.; Nishiwaki, R.; Tatematsu, M.; Kim, S-J.; Carmichael, W.W.; Fujiki, H. Nodularin, a potent inhibitor of protein phosphatases 1 and 2A, is a new environmental carcinogen in male F344 rat liver. Cancer Res.,  1994, 54(24), 6402-6406.
[PMID: 7527297] 
[69] 
Sekijima, M.; Tsutsumi, T.; Yoshida, T.; Harada, T.; Tashiro, F.; Chen, G.; Yu, S-Z.; Ueno, Y. Enhancement of glutathione S-transferase placental-form positive liver cell foci development by microcystin-LR in aflatoxin B1-initiated rats. Carcinogenesis,  1999, 20(1), 161-165.
[http://dx.doi.org/10.1093/carcin/20.1.161] [PMID: 9934864] 
[70] 
Ito, N.; Tsuda, H.; Tatematsu, M.; Inoue, T.; Tagawa, Y.; Aoki, T.; Uwagawa, S.; Kagawa, M.; Ogiso, T.; Masui, T. Enhancing effect of various hepatocarcinogens on induction of preneoplastic glutathione S-transferase placental form positive foci in rats-an approach for a new medium-term bioassay system. Carcinogenesis,  1988, 9(3), 387-394.
[http://dx.doi.org/10.1093/carcin/9.3.387] [PMID: 3345580] 
[71] 
Sueoka, E.; Sueoka, N.; Okabe, S.; Kozu, T.; Komori, A.; Ohta, T.; Suganuma, M.; Kim, S.J.; Lim, I.K.; Fujiki, H. Expression of the tumor necrosis factor α gene and early response genes by nodularin, a liver tumor promoter, in primary cultured rat hepatocytes. J. Cancer Res. Clin. Oncol.,  1997, 123(8), 413-419.
[PMID: 9292703] 
[72] 
Komori, A.; Yatsunami, J.; Suganuma, M.; Okabe, S.; Abe, S.; Sakai, A.; Sasaki, K.; Fujiki, H. Tumor necrosis factor acts as a tumor promoter in BALB/3T3 cell transformation. Cancer Res.,  1993, 53(9), 1982-1985.
[PMID: 8481899] 
[73] 
Li, H.; Xie, P.; Li, G.; Hao, L.; Xiong, Q. In vivo study on the effects of microcystin extracts on the expression profiles of proto-oncogenes (c-fos, c-jun and c-myc) in liver, kidney and testis of male Wistar rats injected i.v. with toxins. Toxicon,  2009, 53(1), 169-175.
[http://dx.doi.org/10.1016/j.toxicon.2008.10.027] [PMID: 19041662] 
[74] 
Szremska, A.P.; Kenner, L.; Weisz, E.; Ott, R.G.; Passegué, E.; Artwohl, M.; Freissmuth, M.; Stoxreiter, R.; Theussl, H-C.; Parzer, S.B.; Moriggl, R.; Wagner, E.F.; Sexl, V. JunB inhibits proliferation and transformation in B-lymphoid cells. Blood,  2003, 102(12), 4159-4165.
[http://dx.doi.org/10.1182/blood-2003-03-0915] [PMID: 12907453] 
[75] 
Verde, P.; Casalino, L.; Talotta, F.; Yaniv, M.; Weitzman, J.B. Deciphering AP-1 function in tumorigenesis: Fra-ternizing on target promoters. Cell Cycle,  2007, 6(21), 2633-2639.
[http://dx.doi.org/10.4161/cc.6.21.4850] [PMID: 17957143] 
[76] 
Toivola, D.M.; Eriksson, J.E. Toxins affecting cell signalling and alteration of cytoskeletal structure. Toxicol. in vitro,  1999, 13(4-5), 521-530.
[http://dx.doi.org/10.1016/S0887-2333(99)00024-7] [PMID: 20654510] 
[77] 
Amstad, P.A.; Krupitza, G.; Cerutti, P.A. Mechanism of c-fos induction by active oxygen. Cancer Res.,  1992, 52(14), 3952-3960.
[PMID: 1617671] 
[78] 
Yoshida, T.; Takeda, M.; Tsutsumi, T.; Nagata, S.; Yoshida, F.; Maita, K.; Harada, T.; Ueno, Y. Tumor necrosis factor-α expression and Kupffer cell activation in hepatotoxicity caused by microcystin-LR in mice. J. Toxicol. Pathol.,  2001, 14(4), 259-259.
[http://dx.doi.org/10.1293/tox.14.259] 
[79] 
Shi, Q.; Cui, J.; Zhang, J.; Kong, F.X.; Hua, Z.C.; Shen, P.P. Expression modulation of multiple cytokines in vivo by cyanobacteria blooms extract from Taihu Lake, China. Toxicon,  2004, 44(8), 871-879.
[http://dx.doi.org/10.1016/j.toxicon.2004.08.010] [PMID: 15530969] 
[80] 
Žegura, B.; Zajc, I.; Lah, T.T.; Filipič, M. Patterns of microcystin-LR induced alteration of the expression of genes involved in response to DNA damage and apoptosis. Toxicon,  2008, 51(4), 615-623.
[http://dx.doi.org/10.1016/j.toxicon.2007.11.009] [PMID: 18191168] 
[81] 
Chen, T.; Wang, Q.; Cui, J.; Yang, W.; Shi, Q.; Hua, Z.; Ji, J.; Shen, P. Induction of apoptosis in mouse liver by microcystin-LR: A combined transcriptomic, proteomic, and simulation strategy. Mol. Cell. Proteom.,  2005, 4(7), 958-974.
[http://dx.doi.org/10.1074/mcp.M400185-MCP200] [PMID: 15863401] 
[82] 
Zhang, J.; Chen, J.; Xia, Z. Microcystin-LR exhibits immunomodulatory role in mouse primary hepatocytes through activation of the NF-κB and MAPK signaling pathways. Toxicol. Sci.,  2013, 136(1), 86-96.
[83] 
Clark, I.M.; Swingler, T.E.; Sampieri, C.L.; Edwards, D.R. The regulation of matrix metalloproteinases and their inhibitors. Int. J. Biochem. Cell Biol.,  2008, 40(6-7), 1362-1378.
[http://dx.doi.org/10.1016/j.biocel.2007.12.006] [PMID: 18258475] 
[84] 
Itoh, Y.; Nagase, H.; Nagase, H. Matrix metalloproteinases in cancer. Essays Biochem.,  2002, 38, 21-36.
[http://dx.doi.org/10.1042/bse0380021] [PMID: 12463159] 
[85] 
Yan, C.; Boyd, D.D. Regulation of matrix metalloproteinase gene expression. J. Cell. Physiol.,  2007, 211(1), 19-26.
[http://dx.doi.org/10.1002/jcp.20948] [PMID: 17167774] 
[86] 
Weng, C-J.; Chau, C-F.; Hsieh, Y-S.; Yang, S-F.; Yen, G-C. Lucidenic acid inhibits PMA-induced invasion of human hepatoma cells through inactivating MAPK/ERK signal transduction pathway and reducing binding activities of NF-kappaB and AP-1. Carcinogenesis,  2008, 29(1), 147-156.
[http://dx.doi.org/10.1093/carcin/bgm261] [PMID: 18024477] 
[87] 
St Amand, A. Cylindrospermopsis: an invasive toxic alga. Lake Line,  2002, 22(1), 36-37.
[88] 
Hawkins, P.R.; Chandrasena, N.R.; Jones, G.J.; Humpage, A.R.; Falconer, I.R. Isolation and toxicity of Cylindrospermopsis raciborskii from an ornamental lake. Toxicon,  1997, 35(3), 341-346.
[http://dx.doi.org/10.1016/S0041-0101(96)00185-7] [PMID: 9080590] 
[89] 
Li, R.; Carmichael, W.W.; Brittain, S.; Eaglesham, G.K.; Shaw, G.R.; Mahakhant, A.; Noparatnaraporn, N.; Yongmanitchai, W.; Kaya, K.; Watanabe, M.M. Isolation and identification of the cyanotoxin cylindrospermopsin and deoxy-cylindrospermopsin from a Thailand strain of Cylindrospermopsis raciborskii (Cyanobacteria). Toxicon,  2001, 39(7), 973-980.
[http://dx.doi.org/10.1016/S0041-0101(00)00236-1] [PMID: 11223086] 
[90] 
Bazin, E.; Huet, S.; Jarry, G.; Le Hégarat, L.; Munday, J.S.; Humpage, A.R.; Fessard, V. Cytotoxic and genotoxic effects of cylindrospermopsin in mice treated by gavage or intraperitoneal injection. Environ. Toxicol.,  2012, 27(5), 277-284.
[http://dx.doi.org/10.1002/tox.20640] [PMID: 20725938] 
[91] 
Sibaldo de Almeida, C.; Costa de Arruda, A.C.; Caldas de Queiroz, E.; Matias de Lima Costa, H.T.; Barbosa, P.F.; Araújo Moura Lemos, T.M.; Oliveira, C.N.; Pinto, E.; Schwarz, A.; Kujbida, P. Oral exposure to cylindrospermopsin in pregnant rats: Reproduction and foetal toxicity studies. Toxicon,  2013, 74, 127-129.
[http://dx.doi.org/10.1016/j.toxicon.2013.08.051] [PMID: 23988391] 
[92] 
Rogers, E.H.; Zehr, R.D.; Gage, M.I.; Humpage, A.R.; Falconer, I.R.; Marr, M.; Chernoff, N. The cyanobacterial toxin, cylindrospermopsin, induces fetal toxicity in the mouse after exposure late in gestation. Toxicon,  2007, 49(6), 855-864.
[http://dx.doi.org/10.1016/j.toxicon.2006.12.009] [PMID: 17292934] 
[93] 
Chernoff, N.; Rogers, E.H.; Zehr, R.D.; Gage, M.I.; Malarkey, D.E.; Bradfield, C.A.; Liu, Y.; Schmid, J.E.; Jaskot, R.H.; Richards, J.H.; Wood, C.R.; Rosen, M.B. Toxicity and recovery in the pregnant mouse after gestational exposure to the cyanobacterial toxin, cylindrospermopsin. J. Appl. Toxicol.,  2011, 31(3), 242-254.
[http://dx.doi.org/10.1002/jat.1586] [PMID: 20936652] 
[94] 
Chernoff, N.; Rogers, E.H.; Zehr, R.D.; Gage, M.I.; Travlos, G.S.; Malarkey, D.E.; Brix, A.; Schmid, J.E.; Hill, D. The course of toxicity in the pregnant mouse after exposure to the cyanobacterial toxin cylindrospermopsin: Clinical effects, serum chemistries, hematology, and histopathology. J. Toxicol. Environ. Health A,  2014, 77(17), 1040-1060.
[http://dx.doi.org/10.1080/15287394.2014.919838] [PMID: 25072824] 
[95] 
Reid, K.J.; Lang, K.; Froscio, S.; Humpage, A.J.; Young, F.M. Undifferentiated murine embryonic stem cells used to model the effects of the blue-green algal toxin cylindrospermopsin on preimplantation embryonic cell proliferation. Toxicon,  2015, 106, 79-88.
[http://dx.doi.org/10.1016/j.toxicon.2015.09.022] [PMID: 26403865] 
[96] 
Runnegar, M.T.; Kong, S-M.; Zhong, Y-Z.; Ge, J-L.; Lu, S.C. The role of glutathione in the toxicity of a novel cyanobacterial alkaloid cylindrospermopsin in cultured rat hepatocytes. Biochem. Biophys. Res. Commun.,  1994, 201(1), 235-241.
[http://dx.doi.org/10.1006/bbrc.1994.1694] [PMID: 8198579] 
[97] 
Chong, M.W.; Wong, B.S.; Lam, P.K.; Shaw, G.R.; Seawright, A.A. Toxicity and uptake mechanism of cylindrospermopsin and lophyrotomin in primary rat hepatocytes. Toxicon,  2002, 40(2), 205-211.
[http://dx.doi.org/10.1016/S0041-0101(01)00228-8] [PMID: 11689242] 
[98] 
Humpage, A.R.; Fontaine, F.; Froscio, S.; Burcham, P.; Falconer, I.R. Cylindrospermopsin genotoxicity and cytotoxicity: Role of cytochrome P-450 and oxidative stress. J. Toxicol. Environ. Health A,  2005, 68(9), 739-753.
[http://dx.doi.org/10.1080/15287390590925465] [PMID: 16020200] 
[99] 
Terao, K.; Ohmori, S.; Igarashi, K.; Ohtani, I.; Watanabe, M.F.; Harada, K.I.; Ito, E.; Watanabe, M. Electron microscopic studies on experimental poisoning in mice induced by cylindrospermopsin isolated from blue-green alga Umezakia natans. Toxicon,  1994, 32(7), 833-843.
[http://dx.doi.org/10.1016/0041-0101(94)90008-6] [PMID: 7940590] 
[100] 
Seawright, A.A.; Nolan, C.C.; Shaw, G.R.; Chiswell, R.K.; Norris, R.L.; Moore, M.R.; Smith, M.J. The oral toxicity for mice of the tropical cyanobacterium Cylindrospermopsis raciborskii (Woloszynska). Environm. Toxicol.,  1999, 14(1), 135-142.
[http://dx.doi.org/10.1002/(SICI)1522-7278(199902)14:1<135::AID-TOX17>3.0.CO;2-L] 
[101] 
Řezanka, T.; Dembitsky, V.M. Metabolites produced by cyanobacteria belonging to several species of the family Nostocaceae. Folia Microbiol. (Praha),  2006, 51(3), 159-182.
[http://dx.doi.org/10.1007/BF02932119] [PMID: 17004647] 
[102] 
Sukenik, A.; Reisner, M.; Carmeli, S.; Werman, M. Oral toxicity of the cyanobacterial toxin cylindrospermopsin in mice: Long-term exposure to low doses. Environ. Toxicol.,  2006, 21(6), 575-582.
[http://dx.doi.org/10.1002/tox.20220] [PMID: 17091501] 
[103] 
Humpage, A.R.; Falconer, I.R. Oral toxicity of the cyanobacterial toxin cylindrospermopsin in male Swiss albino mice: Determination of no observed adverse effect level for deriving a drinking water guideline value. Environ. Toxicol.,  2003, 18(2), 94-103.
[http://dx.doi.org/10.1002/tox.10104] [PMID: 12635097] 
[104] 
Shaw, G.R.; Seawright, A.A.; Moore, M.R.; Lam, P.K. Cylindrospermopsin, a cyanobacterial alkaloid: Evaluation of its toxicologic activity. Ther. Drug Monit.,  2000, 22(1), 89-92.
[http://dx.doi.org/10.1097/00007691-200002000-00019] [PMID: 10688267] 
[105] 
Norris, R.L.; Seawright, A.A.; Shaw, G.R.; Smith, M.J.; Chiswell, R.K.; Moore, M.R. Distribution of 14C cylindrospermopsin in vivo in the mouse. Environ. Toxicol.,  2001, 16(6), 498-505.
[http://dx.doi.org/10.1002/tox.10008] [PMID: 11769247] 
[106] 
Chiswell, R.K.; Shaw, G.R.; Eaglesham, G.; Smith, M.J.; Norris, R.L.; Seawright, A.A.; Moore, M.R. Stability of cylindrospermopsin, the toxin from the cyanobacterium, Cylindrospermopsis raciborskii: Effect of pH, temperature, and sunlight on decomposition. Environm. Toxicol.,  1999, 14(1), 155-161.
[http://dx.doi.org/10.1002/(SICI)1522-7278(199902)14:1<155::AID-TOX20>3.0.CO;2-Z] 
[107] 
Banker, R.; Carmeli, S.; Werman, M.; Teltsch, B.; Porat, R.; Sukenik, A. Uracil moiety is required for toxicity of the cyanobacterial hepatotoxin cylindrospermopsin. J. Toxicol. Environ. Health A,  2001, 62(4), 281-288.
[http://dx.doi.org/10.1080/009841001459432] [PMID: 11245397] 
[108] 
Runnegar, M.T.; Xie, C.; Snider, B.B.; Wallace, G.A.; Weinreb, S.M.; Kuhlenkamp, J. In vitro hepatotoxicity of the cyanobacterial alkaloid cylindrospermopsin and related synthetic analogues. Toxicol. Sci.,  2002, 67(1), 81-87.
[http://dx.doi.org/10.1093/toxsci/67.1.81] [PMID: 11961219] 
[109] 
Devlin, J.; Edwards, O.; Gorham, P.; Hunter, N.; Pike, R.; Stavric, B. Anatoxin-a, a toxic alkaloid from Anabaena flos-aquae NRC-44h. Cancer J. Chem.,  1977, 55(8), 1367-1371.
[http://dx.doi.org/10.1139/v77-189] 
[110] 
Campbell, H.F.; Edwards, O.E.; Elder, J.W.; Kolt, R.J. ChemInform Abstract: Total synthesis of DL-Anatoxin-A and DL-Isoanatoxin-A; Chemischer Informationsdienst, 1978. 
[111] 
Sivonen, K.; Himberg, K.; Luukkainen, R.; Niemelä, S.; Poon, G.; Codd, G. Preliminary characterization of neurotoxic cyanobacteria blooms and strains from Finland. Toxicity Assessment,  1989, 4(3), 339-352.
[http://dx.doi.org/10.1002/tox.2540040310] 
[112] 
Shams, S.; Capelli, C.; Cerasino, L.; Ballot, A.; Dietrich, D.R.; Sivonen, K.; Salmaso, N. Anatoxin-a producing Tychonema (Cyanobacteria) in European waterbodies. Water Res.,  2015, 69, 68-79.
[http://dx.doi.org/10.1016/j.watres.2014.11.006] [PMID: 25437339] 
[113] 
Aronstam, R.S.; Witkop, B. Anatoxin-a interactions with cholinergic synaptic molecules. Proc. Natl. Acad. Sci. USA,  1981, 78(7), 4639-4643.
[http://dx.doi.org/10.1073/pnas.78.7.4639] [PMID: 6270690] 
[114] 
Campos, F.; Durán, R.; Vidal, L.; Faro, L.R.; Alfonso, M. In vivo effects of the anatoxin-a on striatal dopamine release. Neurochem. Res.,  2006, 31(4), 491-501.
[http://dx.doi.org/10.1007/s11064-006-9042-x] [PMID: 16758357] 
[115] 
Stevens, D.K.; Krieger, R.I. Effect of route of exposure and repeated doses on the acute toxicity in mice of the cyanobacterial nicotinic alkaloid anatoxin-a. Toxicon,  1991, 29(1), 134-138.
[http://dx.doi.org/10.1016/0041-0101(91)90047-U] [PMID: 1903000] 
[116] 
Valentine, W.M.; Schaeffer, D.J.; Beasley, V.R. Electromyographic assessment of the neuromuscular blockade produced in vivo by anatoxin-a in the rat. Toxicon,  1991, 29(3), 347-357.
[http://dx.doi.org/10.1016/0041-0101(91)90288-3] [PMID: 1904660] 
[117] 
Fawell, J.K.; Mitchell, R.E.; Hill, R.E.; Everett, D.J. The toxicity of cyanobacterial toxins in the mouse: II anatoxin-a. Hum. Exp. Toxicol.,  1999, 18(3), 168-173.
[http://dx.doi.org/10.1177/096032719901800306] [PMID: 10215107] 
[118] 
Astrachan, N.B.; Archer, B.G.; Hilbelink, D.R. Evaluation of the subacute toxicity and teratogenicity of anatoxin-a. Toxicon,  1980, 18(5-6), 684-688.
[http://dx.doi.org/10.1016/0041-0101(80)90100-2] [PMID: 6784276] 
[119] 
Mahmood, N.A.; Carmichael, W.W. Anatoxin-a(s), an anticholinesterase from the cyanobacterium Anabaena flos-aquae NRC-525-17. Toxicon,  1987, 25(11), 1221-1227.
[http://dx.doi.org/10.1016/0041-0101(87)90140-1] [PMID: 3124299] 
[120] 
Cook, W.O.; Beasley, V.R.; Dahlem, A.M.; Dellinger, J.A.; Harlin, K.S.; Carmichael, W.W. Comparison of effects of anatoxin-a(s) and paraoxon, physostigmine and pyridostigmine on mouse brain cholinesterase activity. Toxicon,  1988, 26(8), 750-753.
[http://dx.doi.org/10.1016/0041-0101(88)90282-6] [PMID: 3188065] 
[121] 
Carmichael, W.W. Cyanobacteria secondary metabolites--the cyanotoxins. J. Appl. Bacteriol.,  1992, 72(6), 445-459.
[http://dx.doi.org/10.1111/j.1365-2672.1992.tb01858.x] [PMID: 1644701] 
[122] 
Mann, S.; Cohen, M.; Chapuis-Hugon, F.; Pichon, V.; Mazmouz, R.; Méjean, A.; Ploux, O. Synthesis, configuration assignment, and simultaneous quantification by liquid chromatography coupled to tandem mass spectrometry, of dihydroanatoxin-a and dihydrohomoanatoxin-a together with the parent toxins, in axenic cyanobacterial strains and in environmental samples. Toxicon,  2012, 60(8), 1404-1414.
[http://dx.doi.org/10.1016/j.toxicon.2012.10.006] [PMID: 23085422] 
[123] 
Skulberg, O.M.; Skulberg, R.; Carmichael, W.W.; Andersen, R.A.; Matsunaga, S.; Moore, R.E. Investigations of a neurotoxic oscillatorialean strain (Cyanophyceae) and its toxin. Isolation and characterization of homoanatoxin‐a. Environ. Toxicol. Chem.,  1992, 11(3), 321-329.
[http://dx.doi.org/10.1002/etc.5620110306] 
[124] 
Wood, S.A.; Smith, F.M.; Heath, M.W.; Palfroy, T.; Gaw, S.; Young, R.G.; Ryan, K.G. Within-mat variability in anatoxin-a and homoanatoxin-a production among benthic Phormidium (cyanobacteria) strains. Toxins (Basel),  2012, 4(10), 900-912.
[http://dx.doi.org/10.3390/toxins4100900] [PMID: 23162704] 
[125] 
Borison, H.L.; McCarthy, L.E. Respiratory and circulatory effects of saxitoxin in the cerebrospinal fluid. Br. J. Pharmacol.,  1977, 61(4), 679-689.
[http://dx.doi.org/10.1111/j.1476-5381.1977.tb07561.x] [PMID: 597670] 
[126] 
Wiberg, G.S.; Stephenson, N.R. Toxicologic studies on paralytic shellfish poison. Toxicol. Appl. Pharmacol.,  1960, 2(6), 607-615.
[http://dx.doi.org/10.1016/0041-008X(60)90078-8] [PMID: 13784983] 
[127] 
Munday, R.; Thomas, K.; Gibbs, R.; Murphy, C.; Quilliam, M.A. Acute toxicities of saxitoxin, neosaxitoxin, decarbamoyl saxitoxin and gonyautoxins 1&4 and 2&3 to mice by various routes of administration. Toxicon,  2013, 76, 77-83.
[http://dx.doi.org/10.1016/j.toxicon.2013.09.013] [PMID: 24060374] 
[128] 
Testai, E.; Scardala, S.; Vichi, S.; Buratti, F.M.; Funari, E. Risk to human health associated with the environmental occurrence of cyanobacterial neurotoxic alkaloids anatoxins and saxitoxins. Crit. Rev. Toxicol.,  2016, 46(5), 385-419.
[http://dx.doi.org/10.3109/10408444.2015.1137865] [PMID: 26923223] 
[129] 
Stal, L.J.; Albertano, P.; Bergman, B.; von Bröckel, K.; Gallon, J.R.; Hayes, P.K.; Sivonen, K.; Walsby, A.E. BASIC: Baltic Sea cyanobacteria. An investigation of the structure and dynamics of water blooms of cyanobacteria in the Baltic Sea-responses to a changing environment. Cont. Shelf Res.,  2003, 23(17-19), 1695-1714.
[http://dx.doi.org/10.1016/j.csr.2003.06.001] 
[130] 
Lankoff, A.; Kołątaj, A. Influence of microcystine-YR and nodularin on the activity of some glucosidases in mouse liver. Toxicology,  2000, 146(2-3), 177-185.
[http://dx.doi.org/10.1016/S0300-483X(00)00173-6] [PMID: 10814850] 
[131] 
Namikoshi, M.; Choi, B.W.; Sun, F.; Rinehart, K.L.; Evans, W.R.; Carmichael, W.W. Chemical characterization and toxicity of dihydro derivatives of nodularin and microcystin-LR, potent cyanobacterial cyclic peptide hepatotoxins. Chem. Res. Toxicol.,  1993, 6(2), 151-158.
[http://dx.doi.org/10.1021/tx00032a003] [PMID: 8477005] 
[132] 
Carmichael, W.W.; Eschedor, J.T.; Patterson, G.M.; Moore, R.E. Toxicity and partial structure of a hepatotoxic peptide produced by the cyanobacterium Nodularia spumigena Mertens emend. L575 from New Zealand. Appl. Environ. Microbiol.,  1988, 54(9), 2257-2263.
[http://dx.doi.org/10.1128/aem.54.9.2257-2263.1988] [PMID: 3142356] 
[133] 
Eriksson, J.E.; Meriluoto, J.A.; Kujari, H.P.; Österlund, K.; Fagerlund, K.; Hällbom, L. Preliminary characterization of a toxin isolated from the cyanobacterium Nodularia spumigena. Toxicon,  1988, 26(2), 161-166.
[http://dx.doi.org/10.1016/0041-0101(88)90168-7] [PMID: 3129825] 
[134] 
Runnegar, M.T.; Jackson, A.R.; Falconer, I.R. Toxicity of the cyanobacterium Nodularia spumigena Mertens. Toxicon,  1988, 26(2), 143-151.
[http://dx.doi.org/10.1016/0041-0101(88)90166-3] [PMID: 3129824] 
[135] 
Yea, S.S.; Kim, H.M.; Jeon, Y.J.; Oh, H-M.; Jeong, H.G.; Yang, K-H. Suppression of IL-2 and IL-4 gene expression by nodularin through the reduced NF-AT binding activity. Toxicol. Lett.,  2000, 114(1-3), 215-224.
[http://dx.doi.org/10.1016/S0378-4274(99)00299-4] [PMID: 10713487] 
[136] 
Lankoff, A.; Kolataj, A. Influence of microcystin-YR and nodularin on the activity of some proteolytic enzymes in mouse liver. Toxicon,  2001, 39(2-3), 419-423.
[http://dx.doi.org/10.1016/S0041-0101(00)00140-9] [PMID: 10978764] 
[137] 
Song, K.Y.; Lim, I.K.; Park, S.C.; Lee, S.O.; Park, H.S.; Choi, Y.K.; Hyun, B.H. Effect of nodularin on the expression of glutathione S-transferase placental form and proliferating cell nuclear antigen in N-nitrosodiethylamine initiated hepatocarcinogenesis in the male Fischer 344 rat. Carcinogenesis,  1999, 20(8), 1541-1548.
[http://dx.doi.org/10.1093/carcin/20.8.1541] [PMID: 10426804] 
[138] 
Park, T.J.; Song, K.Y.; Sohn, S.H.; Lim, I.K. Marked inhibition of testosterone biosynthesis by the hepatotoxin nodularin due to apoptosis of Leydig cells. Mol. Carcinog.,  2002, 34(3), 151-163.
[139] 
Maatouk, I.; Bouaïcha, N.; Plessis, M.J.; Périn, F. Detection by 32P-postlabelling of 8-oxo-7,8-dihydro-2′-deoxyguanosine in DNA as biomarker of microcystin-LR- and nodularin-induced DNA damage in vitro in primary cultured rat hepatocytes and in vivo in rat liver. Mutat. Res.,  2004, 564(1), 9-20.
[http://dx.doi.org/10.1016/j.mrgentox.2004.06.010] [PMID: 15474406] 
[140] 
Shaw, G.; Kamen, R. A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell,  1986, 46(5), 659-667.
[http://dx.doi.org/10.1016/0092-8674(86)90341-7] [PMID: 3488815] 
[141] 
Sandström, A.; Glemarec, C.; Meriluoto, J.A.; Eriksson, J.E.; Chattopadhyaya, J. Structure of a hepatotoxic pentapeptide from the cyanobacterium Nodularia spumigena. Toxicon,  1990, 28(5), 535-540.
[http://dx.doi.org/10.1016/0041-0101(90)90297-K] [PMID: 2117781] 
[142] 
Bernard, C.; Froscio, S.; Campbell, R.; Monis, P.; Humpage, A.; Fabbro, L. Novel toxic effects associated with a tropical Limnothrix/Geitlerinema-like cyanobacterium. Environ. Toxicol.,  2011, 26(3), 260-270.
[http://dx.doi.org/10.1002/tox.20552] [PMID: 19950362] 
[143] 
Torres-Arino, A.; Mora-Heredia, E. Isolation and characterization of potentially toxic or harmful cyanobacteria from Oaxaca and Chiapas, Mexico. J. Environ. Sci. Health Part A Tox. Hazard. Subst. Environ. Eng.,  2010, 45(1), 128-136.
[http://dx.doi.org/10.1080/10934520903388483] [PMID: 20390852] 
[144] 
Humpage, A.; Falconer, I.; Bernard, C.; Froscio, S.; Fabbro, L. Toxicity of the cyanobacterium Limnothrix AC0243 to male Balb/c mice. Water Res.,  2012, 46(5), 1576-1583.
[http://dx.doi.org/10.1016/j.watres.2011.11.019] [PMID: 22119368] 
[145] 
Li, W.I.; Marquez, B.L.; Okino, T.; Yokokawa, F.; Shioiri, T.; Gerwick, W.H.; Murray, T.F. Characterization of the preferred stereochemistry for the neuropharmacologic actions of antillatoxin. J. Nat. Prod.,  2004, 67(4), 559-568.
[http://dx.doi.org/10.1021/np0303409] [PMID: 15104484] 
[146] 
Han, B.; Gross, H.; Goeger, D.E.; Mooberry, S.L.; Gerwick, W.H. Aurilides B and C, cancer cell toxins from a papua new guinea collection of the marine cyanobacterium Lyngbya majuscula. J. Nat. Prod.,  2006, 69(4), 572-575.
[http://dx.doi.org/10.1021/np0503911] [PMID: 16643028] 
[147] 
Medina, R.A.; Goeger, D.E.; Hills, P.; Mooberry, S.L.; Huang, N.; Romero, L.I.; Ortega-Barría, E.; Gerwick, W.H.; McPhail, K.L. Coibamide A, a potent antiproliferative cyclic depsipeptide from the Panamanian marine cyanobacterium Leptolyngbya sp. J. Am. Chem. Soc.,  2008, 130(20), 6324-6325.
[http://dx.doi.org/10.1021/ja801383f] [PMID: 18444611] 
[148] 
Han, B.; McPhail, K.L.; Gross, H.; Goeger, D.E.; Mooberry, S.L.; Gerwick, W.H. Isolation and structure of five lyngbyabellin derivatives from a Papua New Guinea collection of the marine cyanobacterium Lyngbya majuscula. Tetrahedron,  2005, 61(49), 11723-11729.
[http://dx.doi.org/10.1016/j.tet.2005.09.036] 
[149] 
Maru, N. Lyngbyacyclamides A and B, novel cytotoxic peptides from marine cyanobacteria Lyngbya sp. Tetrahedron Lett.,  2010, 51(49), 6384-6387.
[http://dx.doi.org/10.1016/j.tetlet.2010.06.105] 
[150] 
Horgen, F.D.; Kazmierski, E.B.; Westenburg, H.E.; Yoshida, W.Y.; Scheuer, P.J.; Malevamide, D. Malevamide D: isolation and structure determination of an isodolastatin H analogue from the marine cyanobacterium Symploca hydnoides. J. Nat. Prod.,  2002, 65(4), 487-491.
[http://dx.doi.org/10.1021/np010560r] [PMID: 11975485] 
[151] 
Pereira, A.; Cao, Z.; Murray, T.F.; Gerwick, W.H. Hoiamide a, a sodium channel activator of unusual architecture from a consortium of two papua new Guinea cyanobacteria. Chem. Biol.,  2009, 16(8), 893-906.
[http://dx.doi.org/10.1016/j.chembiol.2009.06.012] [PMID: 19716479] 
[152] 
Manger, R.L.; Leja, L.S.; Lee, S.Y.; Hungerford, J.M.; Hokama, Y.; Dickey, R.W.; Granade, H.R.; Lewis, R.; Yasumoto, T.; Wekell, M.M. Detection of sodium channel toxins: directed cytotoxicity assays of purified ciguatoxins, brevetoxins, saxitoxins, and seafood extracts. J. AOAC Int.,  1995, 78(2), 521-527.
[http://dx.doi.org/10.1093/jaoac/78.2.521] [PMID: 7756868] 
[153] 
Han, B.; Goeger, D.; Maier, C.S.; Gerwick, W.H. The wewakpeptins, cyclic depsipeptides from a Papua New Guinea collection of the marine cyanobacterium Lyngbya semiplena. J. Org. Chem.,  2005, 70(8), 3133-3139.
[http://dx.doi.org/10.1021/jo0478858] [PMID: 15822975] 
[154] 
Edwards, D.J.; Marquez, B.L.; Nogle, L.M.; McPhail, K.; Goeger, D.E.; Roberts, M.A.; Gerwick, W.H. Structure and biosynthesis of the jamaicamides, new mixed polyketide-peptide neurotoxins from the marine cyanobacterium Lyngbya majuscula. Chem. Biol.,  2004, 11(6), 817-833.
[http://dx.doi.org/10.1016/j.chembiol.2004.03.030] [PMID: 15217615] 
[155] 
Doan, N.T.; Rickards, R.W.; Rothschild, J.M.; Smith, G.D. Allelopathic actions of the alkaloid 12-epi-hapalindole E isonitrile and calothrixin A from cyanobacteria of the genera Fischerella and Calothrix. J. Appl. Phycol.,  2000, 12(3-5), 409-416.
[http://dx.doi.org/10.1023/A:1008170007044] 
[156] 
Liu, S.Q.; Saijo, K.; Todoroki, T.; Ohno, T. Induction of human autologous cytotoxic T lymphocytes on formalin-fixed and paraffin-embedded tumour sections. Nat. Med.,  1995, 1(3), 267-271.
[http://dx.doi.org/10.1038/nm0395-267] [PMID: 7585045] 
[157] 
Fujii, K.; Sivonen, K.; Kashiwagi, T.; Hirayama, K.; Harada, K-i. Nostophycin, a novel cyclic peptide from the toxic cyanobacterium Nostoc sp. 152. J. Org. Chem.,  1999, 64(16), 5777-5782.
[http://dx.doi.org/10.1021/jo982306i] 
[158] 
Schwartz, R.E.; Hirsch, C.F.; Sesin, D.F.; Flor, J.E.; Chartrain, M.; Fromtling, R.E.; Harris, G.H.; Salvatore, M.J.; Liesch, J.M.; Yudin, K. Pharmaceuticals from cultured algae. J. Ind. Microbiol.,  1990, 5(2-3), 113-123.
[http://dx.doi.org/10.1007/BF01573860] 
[159] 
Trimurtulu, G.; Ohtani, I.; Patterson, G.M.; Moore, R.E.; Corbett, T.H.; Valeriote, F.A.; Demchik, L. Total structures of cryptophycins, potent antitumor depsipeptides from the blue-green alga Nostoc sp. strain GSV 224. J. Am. Chem. Soc.,  1994, 116(11), 4729-4737.
[http://dx.doi.org/10.1021/ja00090a020] 
[160] 
Kerksiek, K.; Mejillano, M.R.; Schwartz, R.E.; Georg, G.I.; Himes, R.H. Interaction of cryptophycin 1 with tubulin and microtubules. FEBS Lett.,  1995, 377(1), 59-61.
[http://dx.doi.org/10.1016/0014-5793(95)01271-0] [PMID: 8543019] 
[161] 
Panda, D.; Himes, R.H.; Moore, R.E.; Wilson, L.; Jordan, M.A. Mechanism of action of the unusually potent microtubule inhibitor cryptophycin 1. Biochemistry,  1997, 36(42), 12948-12953.
[http://dx.doi.org/10.1021/bi971302p] [PMID: 9335554] 
[162] 
Mooberry, S.L.; Busquets, L.; Tien, G. Induction of apoptosis by cryptophycin 1, a new antimicrotubule agent. Int. J. Cancer,  1997, 73(3), 440-448.
[http://dx.doi.org/10.1002/(SICI)1097-0215(19971104)73:3<440::AID-IJC20>3.0.CO;2-F] [PMID: 9359493] 
[163] 
Liang, J.; Moore, R.E.; Moher, E.D.; Munroe, J.E.; Al-awar, R.S.; Hay, D.A.; Varie, D.L.; Zhang, T.Y.; Aikins, J.A.; Martinelli, M.J.; Shih, C.; Ray, J.E.; Gibson, L.L.; Vasudevan, V.; Polin, L.; White, K.; Kushner, J.; Simpson, C.; Pugh, S.; Corbett, T.H. Cryptophycins-309, 249 and other cryptophycin analogs: Preclinical efficacy studies with mouse and human tumors. Invest. New Drugs,  2005, 23(3), 213-224.
[http://dx.doi.org/10.1007/s10637-005-6729-9] [PMID: 15868377] 
[164] 
Nowruzi, B.; Khavari-Nejad, R-A.; Sivonen, K.; Kazemi, B.; Najafi, F.; Nejadsattari, T. Identification and toxigenic potential of a Nostoc sp. Algae,  2012, 27(4), 303.
[http://dx.doi.org/10.4490/algae.2012.27.4.303] 
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DOI https://dx.doi.org/10.2174/1389557521666211101162030	Print ISSN 1389-5575
Publisher Name Bentham Science Publisher	Online ISSN 1875-5607
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