Laboratory of Toxicant Analysis, Institute of Toxicology and Pharmacology, Academy of Military Medical Sciences, Beijing 100850, China.
School of Investigation, People's Public Security University of China, Beijing 102206, China.
Chem Res Toxicol. 2024 Feb 19;37(2):385-394. doi: 10.1021/acs.chemrestox.3c00338. Epub 2024 Jan 11.
Paraquat is a highly toxic quaternary ammonium herbicide. It can damage the functions of multiple organs and cause irreversible pulmonary fibrosis in the human body. However, the toxicological mechanism of paraquat is not yet fully understood, and due to the lack of specific antidotes, the clinical treatment of paraquat intoxication is still a great medical challenge. In-depth research on its toxicity mechanism, toxicokinetics, and effective antidotes is urgently demanded. A new molecular imaging technique, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), can simultaneously achieve quantitative and spatial analysis and offer an alternative, distinct, and useful technique for paraquat intoxication and consequent detoxication. Here, we visualized the spatial-temporal distribution and conducted toxicokinetic research on paraquat in zebrafish by using stable isotope-labeled internal-standard-aided MALDI-MSI for the first time. The results indicated that paraquat had a fast absorption rate and was widely distributed in different organs, such as the brain, gills, kidneys, and liver in zebrafish. Its half-life was long, and the elimination rate was slow. Paraquat reached its peak at 30 min and was mainly distributed in kidneys and intestines and then showed a tendency of declining first but mildly rising later at 6 h, accompanied by a wide distribution in kidneys and intestines again. It suggested that entero-systemic recirculation might lead to the observed secondary peaks, and perhaps it extended the residence time of paraquat in the body. In addition, we validated the potential detoxification effect of sodium salicylate as a potential antidote for paraquat from both the dimensions of distribution and quantification. In conclusion, MALDI-MSI conveniently provided the distinct and quantitative spatial-temporal distribution information on paraquat in the whole body of zebrafish; it will promote the understanding of its toxicokinetic characteristics and provide more valuable information for clinical treatment.
百草枯是一种剧毒的季铵类除草剂。它可以损害多个器官的功能，并导致人体肺部不可逆转的纤维化。然而，百草枯的毒理学机制尚未完全阐明，由于缺乏特异性解毒剂，百草枯中毒的临床治疗仍然是一个巨大的医学挑战。深入研究其毒性机制、毒代动力学和有效的解毒剂迫在眉睫。一种新的分子成像技术，基质辅助激光解吸电离质谱成像（MALDI-MSI），可以同时实现定量和空间分析，为百草枯中毒及其解毒提供了一种替代的、独特的、有用的技术。在这里，我们首次使用稳定同位素标记内标辅助 MALDI-MSI 对斑马鱼中的百草枯进行了时空分布可视化和毒代动力学研究。结果表明，百草枯吸收速度快，分布广泛，存在于鱼的大脑、鳃、肾脏和肝脏等不同器官中。其半衰期长，消除率慢。百草枯在 30 分钟时达到峰值，主要分布在肾脏和肠道中，然后在 6 小时时呈先降后升的趋势，再次广泛分布于肾脏和肠道中。这表明肠-全身再循环可能导致观察到的二次峰值，也许它延长了百草枯在体内的停留时间。此外，我们从分布和定量两个维度验证了水杨酸钠作为潜在解毒剂对百草枯的潜在解毒效果。总之，MALDI-MSI 方便地提供了百草枯在斑马鱼全身的独特和定量的时空分布信息；它将促进对其毒代动力学特征的理解，并为临床治疗提供更有价值的信息。
Methods Mol Biol. 2025
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