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Journal: Toxicon : official journal of the International Society on Toxinology


The use of ecotoxicological techniques for the evaluation of the quality of limnetic waters allows the early detection of toxic agents that pose risks to human health. In this study Moina micrura (two clones), Daphnia laevis (two clones) and Daphnia similis, a temperate species, were used to evaluate the toxicity of six Microcystis extracts from two Colombian reservoirs. Toxin was detected and quantified by HPLC. Microcystin-LR was found in all extracts with the highest concentrations in one sample from each reservoir (434 μg g(-1) and 538 μg g(-1)). The extracts that had the highest toxin concentration also had the highest toxicities to cladocerans. Measurement of 48-h LC50 showed consistent differences between cladoceran species but not clones, Also, reproduction data in two species were consistent with the MC-LR content of one sample tested, with decreased reproduction and disruption of egg production. However, only some growth results of neonates exposed to extracts were consistent with the acute response. In conclusion, Daphnia species are a good model for monitoring cyanotoxins as they respond in a sensitive way to natural phytoplankton samples containing microcystin-LR.

Concepts: Human, Egg, Crustacean, Toxicology, Toxicity, Branchiopoda, Cladocera, Daphnia


Animal venoms are complex chemical mixtures that typically contain hundreds of proteins and non-proteinaceous compounds, resulting in a potent weapon for prey immobilization and predator deterrence. However, because venoms are protein-rich, they come with a high metabolic price tag. The metabolic cost of venom is sufficiently high to result in secondary loss of venom whenever its use becomes non-essential to survival of the animal. The high metabolic cost of venom leads to the prediction that venomous animals may have evolved strategies for minimizing venom expenditure. Indeed, various behaviors have been identified that appear consistent with frugality of venom use. This has led to formulation of the “venom optimization hypothesis” (Wigger et al. (2002) Toxicon 40, 749-752), also known as “venom metering”, which postulates that venom is metabolically expensive and therefore used frugally through behavioral control. Here, we review the available data concerning economy of venom use by animals with either ancient or more recently evolved venom systems. We conclude that the convergent nature of the evidence in multiple taxa strongly suggests the existence of evolutionary pressures favoring frugal use of venom. However, there remains an unresolved dichotomy between this economy of venom use and the lavish biochemical complexity of venom, which includes a high degree of functional redundancy. We discuss the evidence for biochemical optimization of venom as a means of resolving this conundrum.

Concepts: Metabolism, Fish, Economics, Cost, Toxin, Venom, Scorpion, Spider bite


Phospholipases A(2) (PLA(2)s) are abundant components of snake venoms, where they play toxic and digestive roles. Despite having a similar three-dimensional structure, venom PLA(2)s exert an amazing variety of toxic and pharmacological effects, which include neurotoxic, myotoxic, hemolytic, edematogenic, hyperalgesic, pro-inflammatory, hypotensive, platelet-aggregation inhibitory, anticoagulant, cytotoxic, and bactericidal activities. Toxinologists have made significant contributions to deciphering the structure, molecular evolution, mechanisms of action, receptors, role of enzymatic activity for toxicity, structural determinants of toxicity and selectivity, and the impact of these enzymes in the overall pathophysiology of snakebite envenoming. The present work highlights some of the most relevant contributions in the study of venom PLA(2)s, including the personal accounts of the authors of these studies.

Concepts: Signal transduction, Toxicology, Toxicity, Poison, Toxin, Venom, Toxins, Snake venom


We have synthesized cis- and trans-dihydroanatoxin-a and cis- and trans-dihydrohomoanatoxin-a using a short synthetic route. The relative configuration of N-tert-butoxycarbonyl-cis-dihydroanatoxin-a was determined by X-ray crystallography, while that of N-tert-butoxycarbonyl-trans-dihydroanatoxin-a was confirmed by epimerization leading to the cis-diastereoisomer. The relative configuration of N-tert-butoxycarbonyl-trans- and cis-dihydrohomoanatoxin-a was inferred from their NMR spectra. Using an optimized LC-MS/MS analytical method and pure standards we have simultaneously determined anatoxin-a, homoanatoxin-a and their dihydroderivatives in axenic strains of cyanobacteria and in environmental samples from the Tarn River, France. However, in these analytical conditions, the cis- and trans-dihydroanatoxin-a and cis- and trans-dihydrohomoanatoxin-a could not be separated. In axenic strains, the dihydroderivatives represented less than 3% of the total toxin content, while in field samples dihydroanatoxin-a represented from 17% to 90% of the total toxin content. Thus, the reduction of anatoxin-a to dihydroanatoxin-a is predominant in the environment. The ratio of anatoxin-a concentration over that of homoanatoxin-a in axenic strains was variable, and among the eight strains studied we found three exclusive anatoxin-a producers and five producers of homoanatoxin-a and anatoxin-a, the latter representing from 0.5% to 2.0% of the total. In the strains studied, we have amplified by PCR, and sequenced the region of anaG coding for the methylation domain proposed to be responsible for the formation of homoanatoxin-a. The sequences showed at least 88% identity and we could not relate the toxin profile of the strains to the sequence of the methylation domain.

Concepts: DNA, Cyanobacteria, Bacteria, Mass spectrometry, Ratio, Sequence, Tandem mass spectrometry, Cyanotoxin


The assessment of the capacity of antivenoms to neutralize the lethal activity of snake venoms is the gold standard in the preclinical analysis of antivenom efficacy, and is routinely performed by manufacturers and quality control laboratories. However, the complexity of snake venom composition and toxicological profile demands that, for many venoms, such as those of viperid snakes and some elapids, the neutralization of lethality be complemented with the analysis of the neutralization of other relevant toxic activities, such as hemorrhagic, myotoxic, necrotizing, procoagulant and defibrinogenating effects. This expanded protocol for preclinical testing of antivenoms should be used when a new antivenom is developed or when an existing antivenom is introduced in a new geographical setting for the neutralization of either homologous or heterologous venoms. In recent years, the assessment of the immunological reactivity of antivenoms has been enriched by the use of proteomic tools, with a methodology named ‘antivenomics’. This allows the identification of venom components to which antivenoms have, or lack, antibodies, and thus complements the data gathered in neutralization tests, paving the way for a knowledge-based improvement of antivenom design and efficacy. International projects involving participants of manufacturing, quality control and academic research groups should be promoted in order to gain a deeper understanding on the preclinical neutralizing spectrum of antivenoms.

Concepts: Quality control, Viperidae, Venom, Snake, Snakes, Neutralization, Neutral, Antivenom


OBJECTIVE: We investigated clinical patterns of crotaline envenomation presenting to a tertiary-care academic hospital in Central California over a 10-year period. METHODS: An IRB-approved, retrospective chart review was conducted on all patients diagnosed with snakebite from December 2000 to December 2010. Data abstracted: demographics, anatomic location of bite, comorbid conditions and intoxicants, length of stay, antivenom dose, laboratory results, and complications or procedures. RESULTS: There were 46 snakebite cases admitted over the study period. Five were “dry bites;” the remaining cases (41/46) received antivenom. There was a male predominance (83% male victims). Upper extremity bites were more common (32/41 upper vs 10/42 lower extremity). One victim sustained bilateral bites to the hands. Thirty-five patients (85%) were admitted, with an average length of stay 2.12 days. The longest hospitalization was 15 days. There were no fatalities. The average time from bite to ED presentation was 2 hours 44 minutes. Bites occurred during every month except November, with the majority occurring during spring and summer months and peaking in June (12/42 cases). Most bites occurred in the hours between noon and 8 pm. The amount of antivenom given ranged from 2 to 35 vials (average, 9 vials). Interfacility transfers were common in our study population: thirteen (32%) patients were transferred into our emergency department for a higher level of care, and 3 (7%) were transferred out (two because of insurance requirements, and one for higher level of Pediatric ICU care). There were no surgical interventions in our study group. Intoxication did not appear to play a major role in this population as only 3 patients (7%) were found to be acutely intoxicated: one with cannabis and amphetamines, 1 with alcohol, and 1 with opioids. CONCLUSIONS: In Central California, crotaline envenomations occurred mainly in adult males. Dry bites, or bites not requiring antivenom administration, were uncommon, comprising only 10% of bites in this study population. Contrary to popular and clinical beliefs, substance abuse and/or alcohol intoxication did not appear to play a role in the majority of patients in this study. Care providers and snakebite specialists should be aware that snakebite patients are often transferred between facilities, a finding that may be useful in designing future first aid protocols and research. We hope these findings add concrete data and help correct some common misconceptions about snakebites in Central California.

Concepts: Hospital, Snakebite, Intoxication, Rattlesnake, Skinny Puppy, Alcohol intoxication, Crotalinae, Remission


Documented envenomations by the pygmy rattlesnake (Sistrurus miliarius barbouri) are rare. While there have been no documented fatalities, several older case reports describe significant morbidity. We describe the first known case of pygmy rattlesnake envenomation that was treated with Crotalidae Polyvalent Immune Fab Antivenom (CroFab(®)). CASE: A 28-year-old man with no significant past medical history presented after being envenomated on the right hand by his friend’s pet pygmy rattlesnake. He developed swelling and pain in his hand and forearm. He responded well to a ten vial loading dose and a 18 h maintenance protocol of CroFab and was discharged the following day without developing any hematological or electrolyte derangements. CONCLUSION: This is the first documented use of CroFab for S. m. barbouri envenomation. The outcome of this case suggests that CroFab is a safe treatment modality in this setting.

Concepts: Rattlesnake, Crotalinae, Antivenom, Medical history, Reptiles of the United States, Sistrurus miliarius, Sistrurus, Sistrurus miliarius barbouri


Blue-ringed octopuses (genus Hapalochlaena) possess the potent neurotoxin tetrodotoxin (TTX). We examined the microdistribution of TTX in ten tissues of Hapalochlaena lunulata and Hapalochlaena fasciata by immunolabeling for fluorescent light microscopy (FLM). We visualized TTX throughout the posterior salivary gland, but the toxin was concentrated in cells lining the secretory tubules within the gland. Tetrodotoxin was present just beneath the epidermis of the integument (mantle and arms) and also concentrated in channels running through the dermis. This was suggestive of a TTX transport mechanism in the blood of the octopus, which would also explain the presence of the toxin in the blood-rich brachial hearts, gills, nephridia, and highly vascularized Needham’s sac (testes contents). We also present the first report of TTX in any cephalopod outside of the genus Hapalochlaena. A specimen of Octopus bocki from French Polynesia contained a small amount of TTX in the digestive gland.

Concepts: Glands, Tetrodotoxin, Neurotoxin, Cephalopod, Blue-ringed octopus, Octopus, Octopodidae, Greater Blue-ringed Octopus


Paralytic shellfish poisoning (PSP) toxins are a group of naturally occurring neurotoxic alkaloids produced among several genera of primarily freshwater cyanobacteria and marine dinoflagellates. Although saxitoxin (STX) and analogs are all potent Na(+) channel blockers in vertebrate cells, the functional role of these compounds for the toxigenic microorganisms is unknown. Based upon the known importance of monovalent cations (such as sodium) in the maintenance of cellular homeostasis and ion channel function, we examined the effect of high extracellular concentrations of these ions on growth, cellular integrity, toxin production and release to the external medium in the filamentous freshwater cyanobacterium, Raphidiopsis brookii D9; a gonyautoxins (GTX2/3) and STX producing toxigenic strain. We observed a toxin export in response to high (17 mM) NaCl and KCl concentrations in the growth medium that was not primarily related to osmotic stress effects, compared to the osmolyte mannitol. Addition of exogenous PSP toxins with the same compositional profile as the one produced by R. brookii D9 was able to partially mitigate this effect of high Na(+) (17 mM). The PSP toxin biosynthetic gene cluster (sxt) in D9 has two genes (sxtF and sxtM) that encode for a MATE (multidrug and toxic compound extrusion) transporter. This protein family, represented by NorM in the bacterium Vibrio parahaemolyticus, confers resistance to multiple cationic toxic agents through Na(+)/drug antiporters. Conserved domains for Na(+) and drug recognition have been described in NorM. For the D9 sxt cluster, the Na(+) recognition domain is conserved in both SxtF and SxtM, but the drug recognition domain differs between them. These results suggest that PSP toxins are exported directly in response to the presence of monovalent cations (Na(+), K(+)) at least at elevated concentrations. Thus, the presence of both genes in the sxt cluster from strain D9 can be explained as a selective recognition mechanism by the SxtF/M transporters for GTX2/3 and STX. We propose that these toxins in cyanobacteria could act extracellularly as a protective mechanism to ensure homeostasis against extreme salt variation in the environment.

Concepts: Protein, Bacteria, Sodium chloride, Ion, Potassium, Poison, Toxin, Paralytic shellfish poisoning


In the present study, we report for the first time, the molecular, biochemical and electrophysiological characterization of the components present in the soluble venom from Mesobuthus gibbosus (Brullé, 1832). According to the epidemiological and clinical situation of scorpion envenomation cases M. gibbosus scorpion is one of the most important health-threatening species of Turkey. Despite the medical importance reported for M. gibbosus, there is no additional information on toxin peptides and venom components to clarify the toxic effect of the M. gibbosus sting. Biochemical characterization of the venom was performed using different protocols and techniques following a bioassay-guided strategy (HPLC, mass spectrometry and Edman degradation sequencing). Venom fractions were tested in electrophysiological assays on a panel of six K(+) channels (K(v)1.1-1.6) by using the two-electrode voltage clamp technique. Three new α-KTx peptides were found and called MegKTx1, MegKTx2 and MegKTx3 (M. gibbosus, K(+) channel toxin number 1-3). A cDNA library from the telson was constructed and specific screening of transcripts was performed. Biochemical and molecular characterization of MegKTx peptides and transcripts shows a relation with toxins of three different α-KTx subfamilies (α-KTx3.x, α-KTx9.x and α-KTx16.x).

Concepts: DNA, Protein, Molecular biology, Action potential, Electrophysiology, Venom, Scorpion, Voltage clamp