Multiple metabolic pathways are predictive of ricin intoxication in a rat model
Multiple metabolic pathways are predictive of ricin intoxication in a rat model
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DOI：
10.1007/s11306-019-1547-9
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发表时间：
2019-07-01
期刊：
影响因子：
3.6
通讯作者：
Dunn, Warwick B.
中科院分区：
文献类型：
--
作者：
D'Elia, Riccardo, V;Goodchild, Sarah A.;Dunn, Warwick B.
接触蓖麻毒素可能是致命的，目前正在开发的治疗方法在接触蓖麻毒素后施用的机会窗口很短。因此，必须实现蓖麻毒素暴露的早期检测，为暴露个体提供最佳预后。可以通过几种基于抗体的技术在临床样品中检测蓖麻毒素，但由于毒素在体内的快速处理和细胞摄取以及随后的低血蓖麻毒素浓度，这些技术的功效可能受到限制。因此，需要其他以正交方式执行的诊断工具。目的探讨静脉注射蓖麻毒素后Sprague-Dawley大鼠体内代谢变化的时间依赖性。方法在两项独立研究中，对sprague - dawley大鼠静脉注射蓖麻毒素，并在暴露后48小时内收集每只动物的多次血液样本。血浆样品采用HILIC和C-18反相UHPLC-MS分析，然后进行单因素和多因素分析。结果在Sprague-Dawley大鼠中，我们已经证明了血液中代谢变化的测量可以区分静脉注射蓖麻毒素的大鼠和对照组在24小时后出现中毒行为体征之前。与对照组相比，暴露于蓖麻毒素后，总共有37种代谢物发生了显著改变。精氨酸/脯氨酸、胆汁酸和甘油三酯代谢途径被强调为重要的，暴露后8h有两种甘油三酯，AUROC评分为0.94。在16h和24h， AUROC评分分别增加到0.98和1.0，代谢产物数量分别增加到5个和7个。结论这些数据表明，代谢产物可能是诊断和检测蓖麻毒素暴露的有用工具，从而提高支持治疗和未来蓖麻毒素特异性药物治疗的有效性。
IntroductionExposure to ricin can be lethal and treatments that are under development have short windows of opportunity for administration after exposure. It is therefore essential to achieve early detection of ricin exposure to provide the best prognosis for exposed individuals. Ricin toxin can be detected in clinical samples via several antibody-based techniques, but the efficacy of these can be limited due to the rapid processing and cellular uptake of toxin in the body and subsequent low blood ricin concentrations. Other diagnostic tools that perform, in an orthogonal manner, are therefore desirable.ObjectivesTo determine time-dependent metabolic changes in Sprague-Dawley rats following intravenous exposure to ricin.MethodsSprague-Dawley rats were intravenously exposed to ricin and multiple blood samples were collected from each animal for up to 48h following exposure in two independent studies. Plasma samples were analysed applying HILIC and C-18 reversed phase UHPLC-MS assays followed by univariate and multivariate analysis.ResultsIn Sprague-Dawley rats we have demonstrated that metabolic changes measured in blood can distinguish between rats exposed intravenously to ricin and controls prior to the onset of behavioral signs of intoxication after 24h. A total of 37 metabolites were significantly altered following exposure to ricin when compared to controls. The arginine/proline, bile acid and triacylglyceride metabolic pathways were highlighted as being important with two triacylglycerides at 8h post exposure giving an AUROC score of 0.94. At 16h and 24h the AUROC score increased to 0.98 and 1.0 with the number of metabolites in the panel increasing to 5 and 7, respectively.ConclusionsThese data demonstrate that metabolites may be a useful tool to diagnose and detect ricin exposure, thus increasing the effectiveness of supportive therapy and future ricin-specific medical treatments.