Toxic Action Reevaluation of Okadaic Acid, Dinophysistoxin-1 and Dinophysistoxin-2: Toxicity Equivalency Factors Based on the Oral Toxicity Study
Toxic Action Reevaluation of Okadaic Acid, Dinophysistoxin-1 and Dinophysistoxin-2: Toxicity Equivalency Factors Based on the Oral Toxicity Study
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DOI：
10.1159/000493039
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Botana, Luis M.
中科院分区：
文献类型：
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作者：
Abal, Paula;Carmen Louzao, M.;Botana, Luis M.
背景/目标：冈田酸（Okadaic acid，OA）和结构上相关的甲藻毒素-1（dinophysistoxin-1，DTX 1）、甲藻毒素-2（dinophysistoxin-2，DTX 2）是一类海洋藻毒素，可引起人类摄食受污染的贝类引起的贝类中毒。为保障消费者权益，监管机构已将DSP毒素的最高水平界定为160微克OA当量kg（-1）贝类肉。对于风险评估和总体毒性测定，需要了解每种类似物的相对毒性。在缺乏足够的人类中毒信息的情况下，小鼠经口毒性是建立毒性等效因子（TEF）的最可靠数据。方法：小鼠灌胃染毒，观察染毒后24 h内小鼠的病理变化和死亡率。在尸检时收集器官损伤数据，并使用透射电子显微镜（TEM）进行超微结构研究。通过HPLC-MS/MS分析尿液、粪便和血液中的毒素。通过蛋白磷酸酶2A（PP 2A）抑制试验评价OA、DTX 1和DTX 2的体外效力。结果：DSP毒素灌胃小鼠以腹泻为主要症状。这些毒素引起类似的胃肠道改变以及肠道超微结构的变化。然而，DSP毒素没有改变紧密连接，引发腹泻。它们具有不同的毒代动力学和毒性。DTX 1的半数致死剂量（LD 50）为487 μ g kg（-1）bw，OA为760 μ g kg（-1）bw，DTX 2为2262 μ g kg（-1）bw。因此，口服TEF值为：OA = 1，DTX 1 = 1.5和DTX 2 = 0.3。结论：这是第一个DSP毒素的比较研究进行了准确的充分表征的标准和急性毒性数据的基础上。结果证实，DTX 1经口途径的毒性大于OA，而DTX 2的毒性较低。因此，应修改目前基于腹腔内毒性的TEF。此外，需要重新评估这类毒素普遍接受的毒性作用模式。(C)2018作者（S）由S发布。Karger AG，巴塞尔。
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 mu g 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 mu g kg(-1) bw for DTX1, 760 mu g kg(-1) bw for OA and 2262 mu g 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. (C) 2018 The Author(s) Published by S. Karger AG, Basel.