Microcystin Explained

Microcystins—or cyanoginosins—are a class of toxins produced by certain freshwater cyanobacteria, commonly known as blue-green algae.[1] Over 250[2] different microcystins have been discovered so far, of which microcystin-LR is the most common. Chemically they are cyclic heptapeptides produced through nonribosomal peptide synthases.[3]

Cyanobacteria can produce microcystins in large quantities during algal blooms which then pose a major threat to drinking and irrigation water supplies, and the environment at large.[4] [5]

Characteristics

Microcystins—or cyanoginosins—are a class of toxins[6] produced by certain freshwater cyanobacteria; primarily Microcystis aeruginosa but also other Microcystis, as well as members of the Planktothrix, Anabaena, Oscillatoria and Nostoc genera.

Microcystin-LR (i.e. X = leucine, Z = arginine) is the most toxic form of over 80 known toxic variants, and is also the most studied by chemists, pharmacologists, biologists, and ecologists. Microcystin-containing 'blooms' are a problem worldwide, including China, Brazil, Australia, South Africa,[7] [8] [9] [10] [11] [12] [13] [14] the United States and much of Europe. Hartebeespoort Dam in South Africa is one of the most contaminated sites in Africa, and possibly in the world.

Chemistry

Microcystins have a common structural framework of D-Ala1-X2-3-Z4-Adda5-D-γ-Glu6-7, where X and Z are variable amino acids; the systematic name "microcystin-XZ" (MC-XZ in short) is then assigned based on the one letter codes (if available; longer codes otherwise) of the amino acids.[2] If the molecule show any other modification, the differences are noted in square brackets before "MC".[2] Of these, several are uncommon non-proteinogenic amino acids:[15]

Mechanism of action

Microcystins covalently bond to and inhibit protein phosphatases PP1 and PP2A and can thus cause pansteatitis.[15] The ADDA residue is key to this functionality: greatly simplified synthetic analogues consisting of ADDA and one additional amino acid can show the same inhibiting function.[17]

Factors affecting production

The microcystin-producing Microcystis is a genus of freshwater cyanobacteria and thrives in warm water conditions, especially in stagnant waters. The EPA predicted in 2013 that climate change and changing environmental conditions may lead to harmful algae growth and may negatively impact human health.[18] Algal growth is also encouraged through the process of eutrophication (oversupply of nutrients). In particular, dissolved reactive phosphorus promotes algal growth.[19]

Microcystins may have evolved as a way to deal with low iron supply in cyanobacteria: the molecule binds iron, and non-producing strains are significantly worse at coping with low iron levels.[20] Low iron supply up-regulates McyD, one of the microcystin synthetic operons.[21] Sufficient iron supply, however, can still boost microcystin production by making the bacterium better at photosynthesis, therefore producing sufficient ATP for MC biosynthesis.[22]

Microcystin production is also positively correlated with temperature.[23] Bright light and red light increases transcription of McyD, but blue light reduces it.[24] A wide range of other factors such as pH may also affect MC production, but comparison is complicated due to a lack of standard testing conditions.[25]

Exposure pathways

There are several ways of exposure to these hepatotoxins that humans can encounter one of which is through recreational activities like swimming, surfing, fishing, and other activities involving direct contact with contaminated water.[26] Another rare, yet extremely toxic, route of exposure that has been identified by scientists is through hemodialysis surgeries. One of the fatal cases for microcystic intoxication through hemodialysis was studied in Brazil where 48% of patients that received the surgery in a specific period of time died because the water used in the procedure was found to be contaminated.[27]

Microcystins are chemically stable over a wide range of temperature and pH, possibly as a result of their cyclic structure.[28] Microcystin-LR water contamination is resistant to boiling and microwave treatments.[29] Microcystin-producing bacteria algal blooms can overwhelm the filter capacities of water treatment plants. Some evidence shows the toxin can be transported by irrigation into the food chain.[30] [31]

Lake Erie blooms

In 2011, a record outbreak of blooming microcystis occurred in Lake Erie, in part related to the wettest spring on record, and expanded lake bottom dead zones, reduced fish populations, fouled beaches, and damaged the local tourism industry, which generates more than $10 billion in revenue annually.

In August 2014, the City of Toledo, Ohio detected unsafe levels of microcystin in its water supply due to harmful algal blooms in Lake Erie, the shallowest of the Great Lakes. The city issued an advisory to approximately 500,000 people that the water was not safe for drinking or cooking.[32] [33] An Ohio state task force found that Lake Erie received more phosphorus than any other Great Lake, both from crop land, due to the farming practices, and from urban water-treatment centres.[19]

San Francisco Bay Area

In 2016, microcystin had been found in San Francisco Bay Area shellfish in seawater, apparently from freshwater runoff, exacerbated by drought.[34]

Iowa

In 2018, the Iowa Department of Natural Resources found microcystins at levels of 0.3 µg/L, or micrograms per liter (ppb), in the raw water supplies of 15 out of 26 public water systems tested.[35]

Oregon

In 2023, the Oregon Department of Environmental Quality (DEQ) and Oregon Health Authority issued a cyanobacteria advisory for much of the Willamette River as it runs through Portland.[36] The advisory affected the Willamette from the Ross Island Lagoon through Cathedral Park.[37] Testing by the DEQ showed microcystin levels at 549 ppb.

Human health effects upon exposure

Microcystins cannot be broken down by standard proteases like pepsin, trypsin, collagenase, and chymotrypsin due to their cyclic chemical nature.[28] They are hepatotoxic, i.e., able to cause serious damage to the liver. Once ingested, microcystin travels to the liver via the bile acid transport system, where most is stored, though some remains in the blood stream and may contaminate tissue.[38] [39] Acute health effects of Microcystin-LR are abdominal pain, vomiting and nausea, diarrhea, headache, blistering around the mouth, and after inhalation sore throat, dry cough, and pneumonia.[40]

Studies suggest that the absorption of microcystins occurs in the gastrointestinal tract. Furthermore, it was found that these hepatotoxins inhibit the activity of protein enzymes phosphatase PP1 and PP2A causing hemorrhagic shock and were found to kill within 45 minutes in mice studies.[41]

There appears to be inadequate information to assess the carcinogenic potential of microcystins by applying EPA Guidelines for Carcinogen Risk Assessment. A few studies suggest a relationship may exist between liver and colorectral cancers and the occurrence of cyanobacteria in drinking water in China.[42] [43] [44] [45] [46] [47] Evidence is, however, limited due to limited ability to accurately assess and measure exposure.

Regulation

In the US, the EPA issued a health advisory in 2015.[48] A ten day Health Advisory was calculated for different ages which is considered protective of non-carcinogenic adverse health effects over a ten-day exposure to microcystins in drinking water: 0.3 μg/L for bottle-fed infants and young children of pre-school age and 1.6 μg/L for children of school age through adults.[48]

See also

Further reading

External links

Notes and References

  1. Web site: Cyanobacterial Harmful Algal Blooms (CyanoHABs) & Water. Mass.gov. 9 June 2022.
  2. Bouaïcha . Noureddine . Miles . Christopher . Beach . Daniel . Labidi . Zineb . Djabri . Amina . Benayache . Naila . Nguyen-Quang . Tri . 3. Structural Diversity, Characterization and Toxicology of Microcystins . Toxins . 7 December 2019 . 11 . 12 . 714 . 10.3390/toxins11120714 . 31817927 . 6950048 . free.
  3. Limited Stability of Microcystins in Oligopeptide Compositions of Microcystis aeruginosa (Cyanobacteria): Implications in the Definition of Chemotypes. 2013. Toxins. 5. 6. 1089–1104. Ramsy Agha . Samuel Cirés . Lars Wörmer . Antonio Quesada . 10.3390/toxins5061089. 23744054. 3717771. free.
  4. Paerl HW, Huisman J . Climate change: a catalyst for global expansion of harmful cyanobacterial blooms . Environmental Microbiology Reports . 1 . 1 . 27–37 . February 2009 . 23765717 . 10.1111/j.1758-2229.2008.00004.x. 2009EnvMR...1...27P .
  5. Web site: October 24, 2013 . Oregon State University . Increasing toxicity of algal blooms tied to nutrient enrichment and climate change .
  6. Dawson. R.M. the toxicology of microcystins. Toxicon. 36. 7. 953–962. 10.1016/S0041-0101(97)00102-5. 9690788. 1998.
  7. Bradshaw D, Groenewald P, Laubscher R, Nannan N, Nojilana B, Norman B, Pieterse D, Schneider M . 3. 2003 . Initial Burden of Disease Estimates for South Africa, 2000 . South African Medical Journal . 93 . 9 . 682–688 . Cape Town . South African Medical Research Council . 14635557 . 978-1-919809-64-9 . 2014-08-04 . https://web.archive.org/web/20160303234628/http://www.mrc.co.za/bod/initialbodestimates.pdf . 2016-03-03 . dead .
  8. Fatoki, O.S., Muyima, N.Y.O. & Lujiza, N. 2001. Situation analysis of water quality in the Umtata River Catchment. Water SA, (27) pp. 467–474.
  9. Oberholster PJ, Botha AM, Cloete TE . 2005 . An overview of toxic freshwater cyanobacteria in South Africa with special reference to risk, impact, and detection by molecular marker tools . Biokemistri . 17 . 2 . 57–71 . 10.4314/biokem.v17i2.32590.
  10. Oberholster PJ, Botha AM . 2007 . Use of PCR based technologies for risk assessment of a winter cyanobacterial bloom in Lake Midmar, South Africa . African Journal of Biotechnology . 6 . 15 . 14–21 .
  11. Oberholster, P. 2008. Parliamentary Briefing Paper on Cyanobacteria in Water Resources of South Africa. Annexure "A" of CSIR Report No. CSIR/NRE/WR/IR/2008/0079/C. Pretoria. Council for Scientific and Industrial Research (CSIR).
  12. Web site: Oberholster . P.J. . Cloete . T.E. . van Ginkel . C. . Botha . A-M. . Ashton . P.J. . 3. 2008 . The use of remote sensing and molecular markers as early warning indicators of the development of cyanobacterial hyperscum crust and microcystin-producing genotypes in the hypertrophic Lake Hartebeespoort, South Africa . Pretoria . Council for Scientific and Industrial Research . dead . https://web.archive.org/web/20140811072713/http://www.anthonyturton.com/admin/my_documents/my_files/1.Hartbeespoort_Dam_Paper_-_Distribution_Copy.pdf . 2014-08-11 .
  13. Web site: Oberholster . P.J. . Ashton . P.J. . 2008 . State of the Nation Report: An Overview of the Current Status of Water Quality and Eutrophication in South African Rivers and Reservoirs . Pretoria . Council for Scientific and Industrial Research . dead . https://web.archive.org/web/20140808044721/http://npc.gov.za/MediaLib/Downloads/Home/Tabs/Diagnostic/MaterialConditions2/An%20overview%20of%20the%20current%20status%20of%20water%20quality%20in%20South%20Africa.pdf . 2014-08-08 .
  14. Turton, A.R. 2015. Water Pollution and South Africa's Poor. Johannesburg: South African Institute of Race Relations. http://irr.org.za/reports-and-publications/occasional-reports/files/water-pollution-and-south-africas-poor
  15. Web site: Harmful Algal Blooms and Bird Die-offs in Chesapeake Bay: A Potential Link? . Barnett A. Rattner, Glenn H. Olsen, Peter C. McGowan, Betty K. Ackerson, and Moira A. McKernan . Patuxent Wildlife Research Center .
  16. Kangur . K . Meriluoto . J . Spoof . L . Tanner . R . Hepatotoxic cyanobacterial peptides in Estonian freshwater bodies and inshore marine water . Proceedings of the Estonian Academy of Sciences. Biology. Ecology . 2005 . 54 . 1 . 40 . 10.3176/biol.ecol.2005.1.03 . 240466873 . free .
  17. Gulledge . Brian M . Aggen . James B . Eng . Hugo . Sweimeh . Khuloud . Chamberlin . A.Richard . 3. Microcystin analogues only of adda and a single additional amino acid retain moderate activity as PP1/PP2A inhibitors . Bioorganic & Medicinal Chemistry Letters . September 2003 . 13 . 17 . 2907–2911 . 10.1016/S0960-894X(03)00588-2 . 14611855.
  18. Web site: Impacts of Climate Change on the Occurrence of Harmful Algal Blooms. EPA. 2013. 2014-08-03. 2020-08-07. https://web.archive.org/web/20200807214330/https://www.epa.gov/sites/production/files/documents/climatehabs.pdf. dead.
  19. News: Farming practices and climate change at root of Toledo water pollution. Suzanne Goldenberg. The Guardian. August 3, 2014.
  20. Ceballos-Laita . Laura . Marcuello . Carlos . Lostao . Anabel . Calvo-Begueria . Laura . Velazquez-Campoy . Adrián . Bes . María Teresa . Fillat . María F. . Peleato . María-Luisa . 3. Microcystin-LR Binds Iron, and Iron Promotes Self-Assembly . Environmental Science & Technology . 2 May 2017 . 51 . 9 . 4841–4850 . 10.1021/acs.est.6b05939. 28368104 . 2017EnST...51.4841C .
  21. Sevilla . E . Martin-Luna . B . Vela . L . Bes . MT . Fillat . MF . Peleato . ML . 3 . Iron availability affects mcyD expression and microcystin-LR synthesis in Microcystis aeruginosa PCC7806. . Environmental Microbiology . October 2008 . 10 . 10 . 2476–83 . 10.1111/j.1462-2920.2008.01663.x . 18647335. 2008EnvMi..10.2476S .
  22. Wang . X . Wang . P . Wang . C . Qian . J . Feng . T . Yang . Y . 3. Relationship between Photosynthetic Capacity and Microcystin Production in Toxic Microcystis Aeruginosa under Different Iron Regimes. . International Journal of Environmental Research and Public Health . 7 September 2018 . 15 . 9 . 1954 . 10.3390/ijerph15091954 . 30205471 . 6163392 . free.
  23. Davis . Timothy W. . Berry . Dianna L. . Boyer . Gregory L. . Gobler . Christopher J. . The effects of temperature and nutrients on the growth and dynamics of toxic and non-toxic strains of Microcystis during cyanobacteria blooms . Harmful Algae . June 2009 . 8 . 5 . 715–725 . 10.1016/j.hal.2009.02.004 . 2009HAlga...8..715D . 10.1.1.467.411 .
  24. Kaebernick . M . Dittmann . E . Börner . T . Neilan . BA . Multiple alternate transcripts direct the biosynthesis of microcystin, a cyanobacterial nonribosomal peptide. . Applied and Environmental Microbiology . February 2002 . 68 . 2 . 449–55 . 10.1128/AEM.68.2.449-455.2002 . 11823177 . 126702.
  25. Pearson . L . Mihali . T . Moffitt . M . Kellmann . R . Neilan . B . On the chemistry, toxicology and genetics of the cyanobacterial toxins, microcystin, nodularin, saxitoxin and cylindrospermopsin. . Marine Drugs . 10 May 2010 . 8 . 5 . 1650–80 . 10.3390/md8051650 . 20559491 . 2885083 . free.
  26. Funari E, Testai E. 2008. Human health risk assessment related to cyanotoxins exposure. Critical Reviews in Toxicology. 38(2). 97–125
  27. Azevedo, Sandra M.F.O, Wayne W Carmichael, Elise M Jochimsen, Kenneth L Rinehart, Sharon Lau, Glen R Shaw, and Geoff K Eaglesham. 2002. “Human Intoxication by Microcystins During Renal Dialysis Treatment in Caruaru—Brazil.” Toxicology (Amsterdam) 181. 441–446.
  28. 10.1155/2013/596429. 23936728. Degradation of [Dha7]MC-LR by a Microcystin Degrading Bacterium Isolated from Lake Rotoiti, New Zealand. ISRN Microbiology. 2013. 1–8. 2013. Somdee. Theerasak. Thunders. Michelle. Ruck. John. Lys. Isabelle. Allison. Margaret. Page. Rachel. 3. 3712209. free.
  29. Microwave oven and boiling waterbath extraction of hepatotoxins from cyanobacterial cells . 10.1111/j.1574-6968.2000.tb09021.x. 2000 . Metcalf . James S. . Codd . Geoffrey A. . FEMS Microbiology Letters . 184 . 2 . 241–246 . 10713428 . free .
  30. Codd GA, Metcalf JS, Beattie KA . Retention of Microcystis aeruginosa and microcystin by salad lettuce (Lactuca sativa) after spray irrigation with water containing cyanobacteria . Toxicon . 37 . 8 . 1181–5 . August 1999 . 10400301 . 10.1016/S0041-0101(98)00244-X.
  31. Toshihiko . Abe . Tracy . Lawson . Jonathan D. B. . Weyers . Geoffrey A. . Codd . August 1996 . Microcystin-LR Inhibits Photosynthesis of Phaseolus vulgaris Primary Leaves: Implications for Current Spray Irrigation Practice . New Phytologist . 133 . 4 . 651–8 . 2558683 . 10.1111/j.1469-8137.1996.tb01934.x. free .
  32. Web site: Algal bloom leaves 500,000 without drinking water in northeast Ohio. Reuters. August 2, 2014.
  33. Web site: Toxins contaminate drinking water in northwest Ohio. August 2, 2014. Rick Jervis, USA TODAY. USA Today.
  34. John Raphael BEWARE: High Levels of Freshwater Toxin Found in Shellfish from San Francisco Bay Oct 28, 2016. Nature World News
  35. Kate Payne Toxic Bacteria Blooms Impacting Water Systems Across Iowa, DNR Survey Shows. November 1, 2018. National Public Radio
  36. Web site: Oregon Health Authority : Current Cyanobacteria Advisories : Cyanobacteria Blooms : State of Oregon . 2023-08-26 . www.oregon.gov.
  37. Web site: 2023-08-13 . Swimmers, boaters should avoid toxic algae in Willamette River and Sauvie Island . 2023-08-26 . Multnomah County . en.
  38. Book: Ian R. . Falconer . 1998 . Algal Toxins and Human Health . Jiři . Hrubec . Quality and Treatment of Drinking Water II . 5 / 5C . The Handbook of Environmental Chemistry . 53–82 . 10.1007/978-3-540-68089-5_4. 978-3-662-14774-0 .
  39. Falconer, I.R. 2005. Cyanobacterial Toxins of Drinking Water Supplies: Cylindrospermopsins and Microcystins. Florida: CRC Press. 279 pages.
  40. https://www.epa.gov/nutrient-policy-data/health-and-ecological-effects#what1 What health risks do humans face as a result of exposure to cyanotoxins?
  41. Carmichael, W.W. 1992. Cyanobacteria secondary metabolites: The cyanotoxins. J. Appl. Bacteriol. 72, 445–459
  42. Humpage AR, Hardy SJ, Moore EJ, Froscio SM, Falconer IR . 3. Microcystins (cyanobacterial toxins) in drinking water enhance the growth of aberrant crypt foci in the mouse colon . Journal of Toxicology and Environmental Health, Part A . 61 . 3 . 155–65 . October 2000 . 11036504 . 10.1080/00984100050131305. 2000JTEHA..61..155A. 220439112 .
  43. Ito E, Kondo F, Terao K, Harada K . Neoplastic nodular formation in mouse liver induced by repeated intraperitoneal injections of microcystin-LR . Toxicon . 35 . 9 . 1453–7 . September 1997 . 9403968 . 10.1016/S0041-0101(97)00026-3.
  44. Nishiwaki-Matsushima R, Nishiwaki S, Ohta T, etal . Structure-function relationships of microcystins, liver tumor promoters, in interaction with protein phosphatase . Japanese Journal of Cancer Research . 82 . 9 . 993–6 . September 1991 . 1657848 . 5918597 . 10.1111/j.1349-7006.1991.tb01933.x.
  45. Ueno Y, Nagata S, Tsutsumi T, etal . 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 . 1317–21 . June 1996 . 8681449 . 10.1093/carcin/17.6.1317. free .
  46. Book: Yu S-Z . 1989 . Drinking water and primary liver cancer . Primary Liver Cancer . Z.Y. Tang . M.C. Wu . S.S. Xia . China Academic Publishers . New York . 30–7 . 978-0-387-50228-1.
  47. Zhou L, Yu H, Chen K . Relationship between microcystin in drinking water and colorectal cancer . Biomedical and Environmental Sciences . 15 . 2 . 166–71 . June 2002 . 12244757.
  48. https://www.epa.gov/sites/production/files/2017-06/documents/microcystins-report-2015.pdf Drinking Water Health Advisory for the Cyanobacterial Microcystin Toxins

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