Study of possible combined toxic effects of azaspiracid-1 and okadaic acid in mice via the oral route

Aune, Tore; Espenes, Arild; Aasen, John A.B.; Quilliam, Michael A.; Heß, Philipp; Larsen, Stig

doi:10.1016/j.toxicon.2012.06.007

Cited by 62 publications

(73 citation statements)

References 13 publications

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“…Therefore, to evaluate the toxicity of a shellfish sample regardless of the DSP toxins present, oral TEFs proposed in the present study are more appropriate to protect human health than TEF based on i.p toxicity [18]. Symptoms reported after OA or DTX1 administration were similar to those previously described [24,29]. It should be noted the fast appearance of diarrhea less than one hour and a half for both toxins and that this symptom in most cases disappeared 3-4 h postdosification.…”

Section: Discussionsupporting

confidence: 75%

“…Results indicated that OA is less toxic than DTX1 with oral LD 50 values of 760 and 487 µg kg -1 bw respectively, while DTX2 is the less potent with an oral LD 50 of 2262 µg kg -1 bw [29]. Those LD 50 values were lower than previously reported and differences could be related to the quality of the marine toxins utilized [19,[24][25][26][27][28]. Based in these results the order of oral toxic potency is DTX1 > OA > DTX2 in agreement with the PP2A inhibitory potency.…”

Section: Discussionmentioning

confidence: 72%

“…Only a few studies reported values of oral toxicity of DSP toxins. The previously described lethal oral doses of OA were 400 [21] 600 [22] and between 1000 -2000 μg kg -1 bw [23], with a described LD 50 of 880 μg kg -1 bw [24,25]. Some studies have reported values of DTX1 lethal dose below 300 μg kg -1 bw while others reported no deaths in mice at the oral dose 750 μg kg -1 bw [19,[26][27][28].…”

Section: Introductionmentioning

confidence: 99%

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Toxic Action Reevaluation of Okadaic Acid, Dinophysistoxin-1 and Dinophysistoxin-2: Toxicity Equivalency Factors Based on the Oral Toxicity Study

Abal

Louzao

Suzuki

et al. 2018

Cell Physiol Biochem

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Background/Aims: Okadaic acid (OA) and the structurally related compounds dinophysistoxin-1 (DTX1) and dinophysistoxin-2 (DTX2) are marine phycotoxins that cause diarrheic shellfish poisoning (DSP) in humans due to ingestion of contaminated shellfish. In order to guarantee consumer protection, the regulatory authorities have defined the maximum level of DSP toxins as 160 µg OA equivalent kg^-1 shellfish meat. For risk assessment and overall toxicity determination, knowledge of the relative toxicities of each analogue is required. In absence of enough information from human intoxications, oral toxicity in mice is the most reliable data for establishing Toxicity Equivalence Factors (TEFs). Methods: Toxins were administered to mice by gavage, after that the symptomatology and mice mortality was registered over a period of 24 h. Organ damage data were collected at necropsy and transmission electron microscopy (TEM) was used for ultrastructural studies. Toxins in urine, feces and blood were analyzed by HPLC-MS/MS. The evaluation of in vitro potencies of OA, DTX1 and DTX2 was performed by the protein phosphatase 2A (PP2A) inhibition assay. Results: Mice that received DSP toxins by gavage showed diarrhea as the main symptom. Those toxins caused similar gastrointestinal alterations as well as intestine ultrastructural changes. However, DSP toxins did not modify tight junctions to trigger diarrhea. They had different toxicokinetics and toxic potency. The lethal dose 50 (LD₅₀) was 487 µg kg^-1 bw for DTX1, 760 µg kg^-1 bw for OA and 2262 µg kg^-1 bw for DTX2. Therefore, the oral TEF values are: OA = 1, DTX1 = 1.5 and DTX2 = 0.3. Conclusion: This is the first comparative study of DSP toxins performed with accurate well-characterized standards and based on acute toxicity data. Results confirmed that DTX1 is more toxic than OA by oral route while DTX2 is less toxic. Hence, the current TEFs based on intraperitoneal toxicity should be modified. Also, the generally accepted toxic mode of action of this group of toxins needs to be reevaluated.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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Toxic Action Reevaluation of Okadaic Acid, Dinophysistoxin-1 and Dinophysistoxin-2: Toxicity Equivalency Factors Based on the Oral Toxicity Study

Abal

Louzao

Suzuki

et al. 2018

Cell Physiol Biochem

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“…The ingestion of contaminated shellfish leads to the syndrome known as Azaspiracid poisoning (AZP) [4], manifested through gastrointestinal symptoms such as diarrhea, nausea, vomiting and stomach cramps in humans. Due to the similarity of these acute symptoms AZP was initially considered as a diarrhetic shellfish poisoning (DSP), but later AZAs were demonstrated not to share DSPs mechanism of toxicity [5]. …”

Section: Introductionmentioning

confidence: 99%

“…Toxicological studies have indicated that oral administration of AZAs to mice induces dose and time-dependent gastrointestinal symptoms, in addition to widespread organ damage [5, 6]. Those studies revealed fluid accumulation in the small intestine and necrosis of lamina propia leading to erosion, also fatty acid droplets in liver, reduction of lymphocytes in the spleen and thymus and increased prevalence of lung tumor [6].…”

Section: Introductionmentioning

confidence: 99%

Absorption and Effect of Azaspiracid-1 Over the Human Intestinal Barrier

Abal¹,

Louzao²,

Fraga-Corral³

et al. 2017

Cell Physiol Biochem

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Background: Azaspiracids (AZAs) are marine biotoxins produced by the dinoflagellates genera Azadinium and Amphidoma. These toxins cause azaspiracid poisoning (AZP), characterized by severe gastrointestinal illness in humans after the consumption of bivalve molluscs contaminated with AZAs. The main aim of the present study was to examine the consequences of human exposure to AZA1 by the study of absorption and effects of the toxin on Caco-2 cells, a reliable model of the human intestine. Methods: The ability of AZA1 to cross the human intestinal epithelium has been evaluated by the Caco-2 transepithelial permeability assay. The toxin has been detected and quantified using a microsphere-based immunoassay. Cell alterations and ultrastructural effects has been observed with confocal and transmission electron microscopy Results: AZA1 was absorbed by Caco-2 cells in a dose-dependent way without affecting cell viability. However, modifications on occludin distribution detected by confocal microscopy imaging indicated a possible monolayer integrity disruption. Nevertheless, transmission electron microscopy imaging revealed ultrastructural damages at the nucleus and mitochondria with autophagosomes in the cytoplasm, however, tight junctions and microvilli remained unaffected. Conclusion: After the ingestion of molluscs with the AZA1, the toxin will be transported through the human intestinal barrier to blood causing damage on epithelial cells.

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