Soman-induced toxicity, cholinesterase inhibition and neuropathology in adult male Göttingen minipigs.
Soman-induced toxicity, cholinesterase inhibition and neuropathology in adult male Göttingen minipigs.
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DOI：
10.1016/j.toxrep.2021.04.005
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发表时间：
2021
影响因子：
--
通讯作者：
Shih TM
中科院分区：
文献类型：
--
作者：
Lumley L;Du F;Marrero-Rosado B;Stone M;Keith ZM;Schultz C;Whitten K;Walker K;Acon-Chen C;Wright L;Shih TM
在成年雄性哥廷根小型猪中估计梭曼的半数致死剂量（GD）。GD暴露诱导小型猪胆碱酯酶抑制和行为性癫痫发作。GD引起视皮层和外侧膝状体神经元变性。长期癫痫发作与广泛的小胶质细胞活化和细胞死亡有关。小型猪可能是非人灵长类动物的一种有用的替代大型动物模型。动物模型对于评估化学战神经毒剂（CWNAs）的毒性以推断人类风险是必不可少的，并且对于评估医学对策的功效是必要的。哥廷根小型猪越来越多地用于毒理学研究，因为它具有与人类相似的解剖学和生理学特征。我们的目的是确定小型猪是否是一个有用的大型动物模型，以评估梭曼（GD）的毒性作用。我们使用升降给药方法测定了成年雄性哥廷根小型猪的GD肌内（IM）半数致死量（LD 50）。除了致死率估计，我们的特点是可观察到的迹象，毒性，血液和组织胆碱酯酶（胆碱酯酶）的活性和脑病理学GD暴露后。GD的24 h LD 50估计为4.7 μg/kg，95%置信限为3.6和6.3 μg/kg。正如预期的那样，GD抑制血液和几种组织中的胆碱酯酶活性。神经组织病理学分析显示，暴露于4.7 μg/kg GD的幸存者出现神经变性和神经炎症，包括初级视觉皮层和各种丘脑核团。这些发现表明，小型猪将是一个有用的大型动物模型，用于评估药物，以减轻暴露于CWNAs的神经病理学影响。
The median lethal dose of soman (GD) was estimated in adult male Göttingen minipigs. GD exposure induces cholinesterase inhibition and behavioral seizure in minipigs. GD induces neurodegeneration in visual cortex and lateral geniculate nucleus. Prolonged seizure is associated with widespread microglial activation and cell death. The minipig may be a useful alternative large animal model to the non-human primate. Animal models are essential for evaluating the toxicity of chemical warfare nerve agents (CWNAs) to extrapolate to human risk and are necessary to evaluate the efficacy of medical countermeasures. The Göttingen minipig is increasingly used for toxicological studies because it has anatomical and physiological characteristics that are similar to those of humans. Our objective was to determine whether the minipig would be a useful large animal model to evaluate the toxic effects of soman (GD). We determined the intramuscular (IM) median lethal dose (LD50) of GD in adult male Göttingen minipigs using an up-and-down dosing method. In addition to lethality estimates, we characterized the observable signs of toxicity, blood and tissue cholinesterase (ChE) activity and brain pathology following GD exposure. The 24 h LD50 of GD was estimated to be 4.7 μg/kg, with 95 % confidence limits of 3.6 and 6.3 μg/kg. As anticipated, GD inhibited ChE activity in blood and several tissues. Neurohistopathological analysis showed neurodegeneration and neuroinflammation in survivors exposed to 4.7 μg/kg of GD, including in the primary visual cortex and various thalamic nuclei. These findings suggest that the minipig will be a useful large animal model for assessing drugs to mitigate neuropathological effects of exposure to CWNAs.
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影响因子：
1.9
作者：
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通讯作者：
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影响因子：
3.8
作者：
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4.5
作者：
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3.2
作者：
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通讯作者：
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