{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T17:40:04Z","timestamp":1793036404429,"version":"4.5.0"},"reference-count":59,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:00:00Z","timestamp":1788048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Microcystins (MCs) are cyanobacterial hepatotoxins that contaminate bloom-affected freshwater, drinking-water sources, aquatic food webs, and recreational environments. Human evidence for chronic or repeated exposure remains fragmented across study designs and organ systems. We systematically reviewed epidemiological evidence for hepatic, renal, and metabolic outcomes and integrated supporting mechanistic toxicology. PubMed, Scopus, and Web of Science searches identified 9021 records published from 1990 to 2025; an update search was conducted in April 2026. Risk of bias was assessed using a domain-based framework adapted from the Newcastle\u2013Ottawa Scale and OHAT. The review was not prospectively registered. The qualitative evidence architecture retained 192 studies: 34 human epidemiological studies and 158 supporting mechanistic or contextual studies. Only seven independent adjusted estimates met the one-study\u2013one-main-estimate rule for the primary quantitative synthesis. The hepatic meta-analysis included two estimates (OR 2.13; 95% CI, 1.29\u20133.53), the renal finding was a descriptive single-study estimate (OR 4.81; 95% CI, 1.96\u201311.81), and the metabolic meta-analysis included four estimates (OR 1.73; 95% CI, 1.00\u20132.98) with substantial heterogeneity (I2 = 91%; prediction interval, 0.56\u20135.36). Mechanistic evidence supported biological plausibility but was not treated as causal human evidence. Human evidence was relatively more consistent for hepatic outcomes, although it remained limited to two independent studies with different endpoints; renal and metabolic findings remain sparse or heterogeneous.<\/jats:p>","DOI":"10.3390\/toxins18090373","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:55:56Z","timestamp":1788155756000},"page":"373","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human Health Effects of Chronic Microcystin Exposure: A Systematic Review and Meta-Analysis of Hepatic, Renal, and Metabolic Outcomes"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9564-4444","authenticated-orcid":false,"given":"Seong-Dae","family":"Moon","sequence":"first","affiliation":[{"name":"NEB Co., Seoul 08504, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae-Sik","family":"Hwang","sequence":"additional","affiliation":[{"name":"NEB Co., Seoul 08504, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung-Suk","family":"Lee","sequence":"additional","affiliation":[{"name":"NEB Co., Seoul 08504, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9225-028X","authenticated-orcid":false,"given":"Su-Ok","family":"Hwang","sequence":"additional","affiliation":[{"name":"Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2211-1011","authenticated-orcid":false,"given":"Hans W.","family":"Paerl","sequence":"additional","affiliation":[{"name":"Institute of Marine Sciences, Department of Earth, Marine and Environmental Sciences, University of North Carolina at Chapel Hill, Morehead City, NC 28557, USA"},{"name":"Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Morehead City, NC 28557, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7144-0770","authenticated-orcid":false,"given":"Baik-Ho","family":"Kim","sequence":"additional","affiliation":[{"name":"Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea"},{"name":"Department of Environmental Science, Hanyang University, Seoul 04763, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/S0140-6736(17)32345-0","article-title":"The Lancet Commission on pollution and health","volume":"391","author":"Landrigan","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.hal.2011.10.027","article-title":"The rise of harmful cyanobacteria blooms: The potential roles of eutrophication and climate change","volume":"14","author":"Davis","year":"2012","journal-title":"Harmful Algae"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1016\/j.watres.2011.12.016","article-title":"Eco-physiological adaptations that favour freshwater cyanobacteria in a changing climate","volume":"46","author":"Carey","year":"2012","journal-title":"Water Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.hal.2015.12.006","article-title":"How rising CO2 and global warming may stimulate harmful cyanobacterial blooms","volume":"54","author":"Visser","year":"2016","journal-title":"Harmful Algae"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Verspagen, J.M.H., Van de Waal, D.B., Finke, J.F., Visser, P.M., Van Donk, E., and Huisman, J. (2014). Rising CO2 levels will intensify phytoplankton blooms in eutrophic and hypertrophic lakes. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104325"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/s41586-019-1648-7","article-title":"Widespread global increase in intense lake phytoplankton blooms since the 1980s","volume":"574","author":"Ho","year":"2019","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/s41579-018-0040-1","article-title":"Cyanobacterial blooms","volume":"16","author":"Huisman","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6448","DOI":"10.1073\/pnas.1216006110","article-title":"Record-setting algal bloom in Lake Erie caused by agricultural and meteorological trends consistent with expected future conditions","volume":"110","author":"Michalak","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4359","DOI":"10.1007\/s10750-019-04087-y","article-title":"Mitigating eutrophication and toxic cyanobacterial blooms in large lakes: The evolution of a dual nutrient (N and P) reduction paradigm","volume":"847","author":"Paerl","year":"2020","journal-title":"Hydrobiologia"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chorus, I., and Welker, M. (2021). Toxic Cyanobacteria in Water: A Guide to Their Public Health Consequences, Monitoring and Management, CRC Press. [2nd ed.].","DOI":"10.1201\/9781003081449"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/s43017-024-00578-2","article-title":"Harmful algal blooms in inland waters","volume":"5","author":"Feng","year":"2024","journal-title":"Nat. Rev. Earth Environ."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.hal.2015.12.007","article-title":"A review of the global ecology, genomics, and biogeography of the toxic cyanobacterium, Microcystis spp.","volume":"54","author":"Harke","year":"2016","journal-title":"Harmful Algae"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1007\/s00204-016-1913-6","article-title":"Cyanotoxins: Producing organisms, occurrence, toxicity, mechanism of action and human health toxicological risk evaluation","volume":"91","author":"Buratti","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1021\/acs.est.0c06653","article-title":"Toxic cyanobacteria: A growing threat to water and air quality","volume":"55","author":"Plaas","year":"2021","journal-title":"Environ. Sci. Technol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0140-6736(97)12285-1","article-title":"Fatal microcystin intoxication in haemodialysis unit in Caruaru, Brazil","volume":"352","author":"Pouria","year":"1998","journal-title":"Lancet"},{"key":"ref_16","unstructured":"World Health Organization (2020). Cyanobacterial Toxins: Microcystins, World Health Organization. Available online: https:\/\/iris.who.int\/handle\/10665\/338066."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"639","DOI":"10.3109\/1354750X.2013.841756","article-title":"Microcystins: Measuring human exposure and the impact on human health","volume":"18","author":"Meneely","year":"2013","journal-title":"Biomarkers"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.toxicon.2018.07.010","article-title":"Exposure routes and health effects of microcystins on animals and humans: A mini-review","volume":"151","author":"Massey","year":"2018","journal-title":"Toxicon"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"104604","DOI":"10.1016\/j.ebiom.2023.104604","article-title":"Harmful algal bloom aerosols and human health","volume":"93","author":"Lim","year":"2023","journal-title":"EBioMedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/toxsci\/kfp009","article-title":"First identification of the hepatotoxic microcystins in the serum of a chronically exposed human population together with indication of hepatocellular damage","volume":"108","author":"Chen","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1289\/ehp.1002412","article-title":"A cross-sectional investigation of chronic exposure to microcystin in relationship to childhood liver damage in the Three Gorges Reservoir Region, China","volume":"119","author":"Li","year":"2011","journal-title":"Environ. Health Perspect."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1002\/hep.29310","article-title":"Serum microcystin levels positively linked with risk of hepatocellular carcinoma: A case-control study in southwest China","volume":"66","author":"Zheng","year":"2017","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15818","DOI":"10.1021\/acs.est.2c02287","article-title":"Microcystin-LR combined with cadmium exposures and the risk of chronic kidney disease: A case-control study in central China","volume":"56","author":"Feng","year":"2022","journal-title":"Environ. Sci. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gao, H., Zhu, N., Deng, S., Du, C., Tang, Y., Tang, P., Xu, S., Liu, W., Shen, M., and Xiao, X. (2023). Combination effect of microcystins and arsenic exposures on CKD: A case-control study in China. Toxins, 15.","DOI":"10.3390\/toxins15020144"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Feng, S., Cao, M., Tang, P., Deng, S., Chen, L., Tang, Y., Zhu, L., Chen, X., Huang, Z., and Shen, M. (2023). Microcystins exposure associated with blood lipid profiles and dyslipidemia: A cross-sectional study in Hunan Province, China. Toxins, 15.","DOI":"10.3390\/toxins15040293"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lin, Y., An, R., Wu, C., Liu, H., Deng, J., Tan, H., Chen, L., Chen, M., and Ma, S. (2023). Serum microcystin-LR levels and risk of gestational diabetes mellitus: A Chinese nested case-control study. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1047866"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Feng, S., Zeng, Y., Song, F., Shen, M., and Yang, F. (2024). Microcystins exposure and the risk of metabolic syndrome: A cross-sectional study in central China. Toxins, 16.","DOI":"10.3390\/toxins16120542"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/0014-5793(90)80245-E","article-title":"Cyanobacterial microcystin-LR is a potent and specific inhibitor of protein phosphatases 1 and 2A from both mammals and higher plants","volume":"264","author":"MacKintosh","year":"1990","journal-title":"FEBS Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.taap.2004.08.012","article-title":"Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin","volume":"203","author":"Fischer","year":"2005","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Arman, T., and Clarke, J.D. (2021). Microcystin toxicokinetics, molecular toxicology, and pathophysiology in preclinical rodent models and humans. Toxins, 13.","DOI":"10.3390\/toxins13080537"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.mrrev.2011.01.002","article-title":"Genotoxicity and potential carcinogenicity of cyanobacterial toxins\u2014A review","volume":"727","year":"2011","journal-title":"Mutat. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Roy, S., Saha, P., Bose, D., Trivedi, A., More, M., Xiao, S., Diehl, A.M., and Chatterjee, S. (2023). Hepatic NLRP3-derived Hsp70 binding to TLR4 mediates MASLD to MASH progression upon inhibition of PP2A by harmful algal bloom toxin microcystin, a second hit. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216354"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yao, X., Liu, Y., Yang, Y., Li, Y., Hu, N., Song, F., and Yang, F. (2023). Microcystin-LR-exposure-induced kidney damage by inhibiting MKK6-mediated mitophagy in mice. Toxins, 15.","DOI":"10.3390\/toxins15060404"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e14349","DOI":"10.1002\/advs.202514349","article-title":"Microcystin-LR triggers renal tubular ferroptosis through epigenetic repression of GPX4: Implications for environmental nephrotoxicity","volume":"13","author":"Zhang","year":"2026","journal-title":"Adv. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"102429","DOI":"10.1016\/j.hal.2023.102429","article-title":"Cyanobacterial bloom monitoring and assessment in Latin America","volume":"125","author":"Aguilera","year":"2023","journal-title":"Harmful Algae"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5518","DOI":"10.1038\/s41598-017-05791-2","article-title":"Prevalence of metabolic syndrome among adults with liver function injury in rural area of Southwest China: A cross-sectional study","volume":"7","author":"Zeng","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1126\/science.aay3164","article-title":"The exposome and health: Where chemistry meets biology","volume":"367","author":"Vermeulen","year":"2020","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Xu, S., Yi, X., Liu, W., Zhang, C., Massey, I.Y., Yang, F., and Tian, L. (2020). A review of nephrotoxicity of microcystins. Toxins, 12.","DOI":"10.3390\/toxins12110693"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/s43247-021-00178-8","article-title":"Perceived global increase in algal blooms is attributable to intensified monitoring and emerging bloom impacts","volume":"2","author":"Hallegraeff","year":"2021","journal-title":"Commun. Earth Environ."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1289\/ehp.1307175","article-title":"The Navigation Guide systematic review methodology: A rigorous and transparent method for translating environmental health science into better health outcomes","volume":"122","author":"Woodruff","year":"2014","journal-title":"Environ. Health Perspect."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1289\/ehp.1307972","article-title":"Systematic review and evidence integration for literature-based environmental health science assessments","volume":"122","author":"Rooney","year":"2014","journal-title":"Environ. Health Perspect."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"105926","DOI":"10.1016\/j.envint.2020.105926","article-title":"Recommendations for the conduct of systematic reviews in toxicology and environmental health research (COSTER)","volume":"143","author":"Whaley","year":"2020","journal-title":"Environ. Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/j.envint.2018.07.015","article-title":"Identifying the PECO: A framework for formulating good questions to explore the association of environmental and other exposures with health outcomes","volume":"121","author":"Morgan","year":"2018","journal-title":"Environ. Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1002\/etc.34","article-title":"Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment","volume":"29","author":"Ankley","year":"2009","journal-title":"Environ. Toxicol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.tox.2013.08.011","article-title":"The adverse outcome pathway concept: A pragmatic tool in toxicology","volume":"312","author":"Vinken","year":"2013","journal-title":"Toxicology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jclinepi.2016.01.021","article-title":"PRESS Peer Review of Electronic Search Strategies: 2015 guideline statement","volume":"75","author":"McGowan","year":"2016","journal-title":"J. Clin. Epidemiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13643-020-01542-z","article-title":"PRISMA-S: An extension to the PRISMA statement for reporting literature searches in systematic reviews","volume":"10","author":"Rethlefsen","year":"2021","journal-title":"Syst. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan\u2014A web and mobile app for systematic reviews","volume":"5","author":"Ouzzani","year":"2016","journal-title":"Syst. Rev."},{"key":"ref_50","unstructured":"Wells, G.A., Shea, B., O\u2019Connell, D., Peterson, J., Welch, V., Losos, M., and Tugwell, P. (2025). The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses, Ottawa Hospital Research Institute. Available online: http:\/\/www.ohri.ca\/programs\/clinical_epidemiology\/oxford.asp."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13750-022-00264-0","article-title":"Principles and framework for assessing the risk of bias for studies included in comparative quantitative environmental systematic reviews","volume":"11","author":"Frampton","year":"2022","journal-title":"Environ. Evid."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"GRADE: An emerging consensus on rating quality of evidence and strength of recommendations","volume":"336","author":"Guyatt","year":"2008","journal-title":"BMJ"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.envint.2016.01.004","article-title":"GRADE: Assessing the quality of evidence in environmental and occupational health","volume":"92\u201393","author":"Morgan","year":"2016","journal-title":"Environ. Int."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1136\/ebmed-2017-110668","article-title":"Rating the certainty in evidence in the absence of a single estimate of effect","volume":"22","author":"Murad","year":"2017","journal-title":"Evid. Based Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting meta-analyses in R with the metafor package","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/sim.1186","article-title":"Quantifying heterogeneity in a meta-analysis","volume":"21","author":"Higgins","year":"2002","journal-title":"Stat. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in meta-analysis detected by a simple, graphical test","volume":"315","author":"Egger","year":"1997","journal-title":"BMJ"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1002\/sim.1221","article-title":"A graphical method for exploring heterogeneity in meta-analyses: Application to a meta-analysis of 65 trials","volume":"21","author":"Baujat","year":"2002","journal-title":"Stat. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/jrsm.11","article-title":"Outlier and influence diagnostics for meta-analysis","volume":"1","author":"Viechtbauer","year":"2010","journal-title":"Res. Synth. Methods"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/18\/9\/373\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T06:07:33Z","timestamp":1788156453000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/18\/9\/373"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,30]]},"references-count":59,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["toxins18090373"],"URL":"https:\/\/doi.org\/10.3390\/toxins18090373","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,30]]}}}