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Algae dietary supplements are marketed worldwide as natural health products. Although their proprieties have been claimed as beneficial to improve overall health, there have been several previous reports of contamination by cyanotoxins. These products generally contain non-toxic cyanobacteria, but the methods of cultivation in natural waters without appropriate quality controls allow contamination by toxin producer species present in the natural environment. In this study, we investigated the presence of total microcystins, seven individual microcystins (RR, YR, LR, LA, LY, LW, LF), anatoxin-a, dihydroanatoxin-a, epoxyanatoxin-a, cylindrospermopsin, saxitoxin, and β-methylamino-l-alanine in 18 different commercially available products containing Spirulina or Aphanizomenon flos-aquae. Total microcystins analysis was accomplished using a Lemieux oxidation and a chemical derivatization using dansyl chloride was needed for the simultaneous analysis of cylindrospermopsin, saxitoxin, and β-methylamino-l-alanine. Moreover, the use of laser diode thermal desorption (LDTD) and ultra-high performance liquid chromatography (UHPLC) both coupled to high resolution mass spectrometry (HRMS) enabled high performance detection and quantitation. Out of the 18 products analyzed, 8 contained some cyanotoxins at levels exceeding the tolerable daily intake values. The presence of cyanotoxins in these algal dietary supplements reinforces the need for a better quality control as well as consumer’s awareness on the potential risks associated with the consumption of these supplements.

Hepatotoxic microcystins (MCs) are the most widespread class of cyanotoxins and the one that has most often been implicated in cyanobacterial toxicosis. One of the main challenges in studying and monitoring MCs is the great structural diversity within the class. The full chemical structure of the first MC was elucidated in the early 1980s and since then, the number of reported structural analogues has grown steadily and continues to do so, thanks largely to advances in analytical methodology. The structures of some of these analogues have been definitively elucidated after chemical isolation using a combination of techniques including nuclear magnetic resonance, amino acid analysis, and tandem mass spectrometry (MS/MS). Others have only been tentatively identified using liquid chromatography-MS/MS without chemical isolation. An understanding of the structural diversity of MCs, the genetic and environmental controls for this diversity and the impact of structure on toxicity are all essential to the ongoing study of MCs across several scientific disciplines. However, because of the diversity of MCs and the range of approaches that have been taken for characterizing them, comprehensive information on the state of knowledge in each of these areas can be challenging to gather. We have conducted an in-depth review of the literature surrounding the identification and toxicity of known MCs and present here a concise review of these topics. At present, at least 279 MCs have been reported and are tabulated here. Among these, about 20% (55 of 279) appear to be the result of chemical or biochemical transformations of MCs that can occur in the environment or during sample handling and extraction of cyanobacteria, including oxidation products, methyl esters, or post-biosynthetic metabolites. The toxicity of many MCs has also been studied using a range of different approaches and a great deal of variability can be observed between reported toxicities, even for the same congener. This review will help clarify the current state of knowledge on the structural diversity of MCs as a class and the impacts of structure on toxicity, as well as to identify gaps in knowledge that should be addressed in future research.

Microcystins (MCs) are common cyanobacterial toxins that occur in freshwaters worldwide. Only two of the >200 MC variants have been tested for potential toxicity after oral exposure. This paper reports on the toxicity of 10 different MC congeners identified in algal blooms, microcystin-LR (MCLR), MCLA, MCLF, MCLW, MCLY, MCRR, [Asp3]MCRR, [Asp3,Dhb7]MCRR, MCWR, and MCYR after single administrations to BALB/c mice. In a preliminary MCLR dose–response study of 3 to 9 mg/kg doses, ≥5 mg/kg induced clinical changes, increased serum levels of ALT, AST, and GLDH, liver congestion, increased liver/body weight ratios, and reduced serum glucose and total protein. Based on the extent of these effects, the 10 congeners were administered as single 7 mg/kg oral doses and toxicity evaluated. The greatest toxicity was observed with MCLA and MCLR including a high percentage of moribundity. In addition to eliciting effects similar to those listed above for MCLR, MCLA also induced serum alterations indicative of jaundice. MCLY, and MCYR induced changes like those noted with MCLR, but to lesser extents. MCLW and MCLF exhibited some serum and morphological changes associated with hepatic toxicity, while there were few indications of toxicity after exposures to MCRR, [Asp3]MCRR, [Asp3,Dhb7]MCRR, or MCWR. These data illustrate a wide spectrum of hepatic effects and different potencies of these MC congeners.

Blooms of cyanobacteria have been documented throughout history, all over the world. Mass populations of these organisms typically present hazards to human health and are known for the production of a wide range of highly toxic metabolites—cyanotoxins, of which among the most common and most investigated are the microcystins. The toxicity of the family of microcystin congeners to animal and cell models has received much attention; however, less is known about their negative effects on human health, whether via acute or chronic exposure. Useful information may be acquired through epidemiological studies since they can contribute to knowledge of the relationships between cyanotoxins and human health in environmental settings. The aim of this review is to compile and evaluate the available published reports and epidemiological investigations of human health incidents associated with exposure to mass populations of cyanobacteria from throughout the world and to identify the occurrence and likely role of microcystins in these events. After an initial screening of 134 publications, 42 publications (25 on the chronic and 17 on the acute effects of cyanotoxins) describing 33 cases of poisonings by cyanobacterial toxins in 11 countries were reviewed. The countries were Australia, China, Sri Lanka, Namibia, Serbia, Sweden, UK, Portugal, Brazil, USA, and Canada. At least 36 publications link cyanobacteria/cyanotoxins including microcystins to adverse human health effects. The studies were published between 1960 and 2016. Although the scattered epidemiological evidence does not provide a definitive conclusion, it can serve as additional information for the medical assessment of the role of microcystins in cancer development and other human health problems. This paper discusses the major cases of cyanotoxin poisonings as well as the strengths, weaknesses, and importance of the performed epidemiological research. This study also proposes some recommendations for future epidemiological work.

Microcystins are ubiquitous toxins produced by photoautotrophic cyanobacteria. Human exposures to microcystins occur through the consumption of contaminated drinking water, fish and shellfish, vegetables, and algal dietary supplements and through recreational activities. Microcystin-leucine-arginine (MCLR) is the prototypical microcystin because it is reported to be the most common and toxic variant and is the only microcystin with an established tolerable daily intake of 0.04 µg/kg. Microcystin toxicokinetics is characterized by low intestinal absorption, rapid and specific distribution to the liver, moderate metabolism to glutathione and cysteinyl conjugates, and low urinary and fecal excretion. Molecular toxicology involves covalent binding to and inhibition of protein phosphatases, oxidative stress, cell death (autophagy, apoptosis, necrosis), and cytoskeleton disruption. These molecular and cellular effects are interconnected and are commonly observed together. The main target organs for microcystin toxicity are the intestine, liver, and kidney. Preclinical data indicate microcystins may also have nervous, pulmonary, cardiac, and reproductive system toxicities. Recent evidence suggests that exposure to other hepatotoxic insults could potentiate microcystin toxicity and increase the risk for chronic diseases. This review summarizes the current knowledge for microcystin toxicokinetics, molecular toxicology, and pathophysiology in preclinical rodent models and humans. More research is needed to better understand human toxicokinetics and how multifactorial exposures contribute to disease pathogenesis and progression.

Microcystin can be present in variable concentrations, phases (dissolved and particulate), and structural forms (congeners), all which impact the toxicity and persistence of the algal metabolite. Conducting incubation experiments with six bloom assemblages collected from the Chowan River, North Carolina, we assessed microcystin dynamics during active growth and biomass degradation. Upon collection, average particulate and dissolved microcystin ranged between 0.2 and 993 µg L−1 and 0.5 and 3.6 µg L−1, respectively. The presence of congeners MC-LA, -LR, -RR, and -YR was confirmed with MC-RR and MC-LR being the most prevalent. Congener composition shifted over time and varied between dissolved and particulate phases. Particulate microcystin exponentially declined in five of six incubations with an average half-life of 10.2 ± 3.7 days, while dissolved microcystin remained detectable until the end of the incubation trials (up to 100 days). Our findings suggest that concerns about food-web transfer via intracellular toxins seem most warranted within the first few weeks of the bloom peak, while dissolved toxins linger for several months in the aftermath of the event. Also, it was indicated there were differences in congener profiles linked to the sampling method. We believe this study can inform monitoring strategies and aid microcystin-exposure risk assessments for cyanobacterial blooms.

Lake Okeechobee, FL, USA, has been subjected to intensifying cyanobacterial blooms that can spread to the adjacent St. Lucie River and Estuary via natural and anthropogenically-induced flooding events. In July 2016, a large, toxic cyanobacterial bloom occurred in Lake Okeechobee and throughout the St. Lucie River and Estuary, leading Florida to declare a state of emergency. This study reports on measurements and nutrient amendment experiments performed in this freshwater-estuarine ecosystem (salinity 0-25 PSU) during and after the bloom. In July, all sites along the bloom exhibited dissolved inorganic nitrogen-to-phosphorus ratios < 6, while Microcystis dominated (> 95%) phytoplankton inventories from the lake to the central part of the estuary. Chlorophyll a and microcystin concentrations peaked (100 and 34 μg L-1, respectively) within Lake Okeechobee and decreased eastwards. Metagenomic analyses indicated that genes associated with the production of microcystin (mcyE) and the algal neurotoxin saxitoxin (sxtA) originated from Microcystis and multiple diazotrophic genera, respectively. There were highly significant correlations between levels of total nitrogen, microcystin, and microcystin synthesis gene abundance across all surveyed sites (p < 0.001), suggesting high levels of nitrogen supported the production of microcystin during this event. Consistent with this, experiments performed with low salinity water from the St. Lucie River during the event indicated that algal biomass was nitrogen-limited. In the fall, densities of Microcystis and concentrations of microcystin were significantly lower, green algae co-dominated with cyanobacteria, and multiple algal groups displayed nitrogen-limitation. These results indicate that monitoring and regulatory strategies in Lake Okeechobee and the St. Lucie River and Estuary should consider managing loads of nitrogen to control future algal and microcystin-producing cyanobacterial blooms.

Microcystins (MCs) classified as hepatotoxic and carcinogenic are the most commonly reported cyanobacterial toxins found in the environment. Microcystis sp. possessing a series of MC synthesis genes (mcyA-mcyJ) are well documented for their excessive abundance, numerous bloom occurrences and MC producing capacity. About 246 variants of MC which exert severe animal and human health hazards through the inhibition of protein phosphatases (PP1 and PP2A) have been characterized. To minimize and prevent MC health consequences, the World Health Organization proposed 1 µg/L MC guidelines for safe drinking water quality. Further the utilization of bacteria that represent a promising biological treatment approach to degrade and remove MC from water bodies without harming the environment has gained global attention. Thus the present review described toxic effects and bacterial degradation of MCs.

Microcystins (MCs) are cyclic peptides produced by cyanobacteria, which can be harmful to humans and animals when ingested. Differences in the coding of the non‑ribosomal peptide synthetase/polyketide synthase enzyme complex responsible for microcystin production have resulted in more than 100 microcystin variants being reported to date. The microcystin diversity of Microcystis CAWBG11 was investigated using matrix-assisted laser desorption/ionization-time of flight mass spectrometry and liquid chromatography-mass spectrometry. This revealed that CAWBG11 simultaneously produced 21 known microcystins and six new congeners: [Asp3] MC-RA, [Asp3] MC-RAba, [Asp3] MC-FA, [Asp3] MC-WA, MC-FAba and MC-FL. The new congeners were putatively characterized by tandem mass spectrometry and chemical derivatization. A survey of the microcystin congeners produced by 49 cyanobacterial strains documented in scientific literature showed that cyanobacteria generally produce four microcystin congeners, but strains which produce up to 47 microcystin congeners have been reported. Microcystis CAWBG11 (which produces at least 27 congeners) was positioned in the top ten percentile of the strains surveyed, and showed fluidity of the amino acids incorporated into both position two and position four.

Cyanobacterial harmful algal blooms (CyanoHABs) originate from the excessive growth or bloom of cyanobacteria often referred to as blue-green algae. They have been on the rise globally in both marine and freshwaters in recently years with increasing frequency and severity owing to the rising temperature associated with climate change and increasing anthropogenic eutrophication from agricultural runoff and urbanization. Humans are at a great risk of exposure to toxins released from CyanoHABs through drinking water, food, and recreational activities, making CyanoHAB toxins a new class of contaminants of emerging concern. We investigated the toxic effects and mechanisms of microcystin-LR (MC-LR), the most prevalent CyanoHAB toxin, on the ovary and associated reproductive functions. Mouse models with either chronic daily oral or acute intraperitoneal exposure, an engineered three-dimensional ovarian follicle culture system, and human primary ovarian granulosa cells were tested with MC-LR of various dose levels. Single-follicle RNA sequencing, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, immunohistochemistry (IHC), and benchmark dose modeling were used to examine the effects of MC-LR on follicle maturation, hormone secretion, ovulation, and luteinization. Mice exposed long term to low-dose MC-LR did not exhibit any differences in the kinetics of folliculogenesis, but they had significantly fewer corpora lutea compared with control mice. Superovulation models further showed that mice exposed to MC-LR during the follicle maturation window had significantly fewer ovulated oocytes. IHC results revealed ovarian distribution of MC-LR, and mice exposed to MC-LR had significantly lower expression of key follicle maturation mediators. Mechanistically, in both murine and human granulosa cells exposed to MC-LR, there was reduced protein phosphatase 1 (PP1) activity, disrupted PP1-mediated PI3K/AKT/FOXO1 signaling, and less expression of follicle maturation-related genes. Using both and murine and human model systems, we provide data suggesting that environmentally relevant exposure to the CyanoHAB toxin MC-LR interfered with gonadotropin-dependent follicle maturation and ovulation. We conclude that MC-LR may pose a nonnegligible risk to women's reproductive health by heightening the probability of irregular menstrual cycles and infertility related to ovulatory disorders. https://doi.org/10.1289/EHP12034.