Abstract：
Development of stereoisomeric neonicotinoid pesticides with lower toxicity is key to preventing global population declines of honeybees, whereas little is known about the in situ metabolic regulation of honeybees in response to stereoisomeric pesticides. Herein, we demonstrate an integrated mass spectrometry imaging (MSI) and untargeted metabolomics method to disclose disturbed metabolic expression levels and spatial differentiation in honeybees (Apis cerana) associated with stereoisomeric dinotefuran. This method affords a metabolic network mapping capability regarding a wide range of metabolites involved in multiple metabolic pathways in honeybees. Metabolomics results indicate more metabolic pathways of honeybees can be significantly affected by S-(+)-dinotefuran than R-(-)-dinotefuran, such as tricarboxylic acid (TCA) cycle, glyoxylate and dicarboxylate metabolism, and various amino acid metabolisms. MSI results demonstrate the cross-regulation and spatial differentiation of crucial metabolites involved in the TCA cycle, purine, glycolysis, and amino acid metabolisms within honeybees. Taken together, the integrated MSI and metabolomics results indicated the higher toxicity of S-(+)-dinotefuran arises from metabolic pathway disturbance and its inhibitory role in the energy metabolism, resulting in significantly reduced degradation rates of detoxification mechanisms. From the view of spatial metabolomics, our findings provide novel perspectives for the development and applications of pure chiral agrochemicals.
摘要：
开发具有低毒性的立体异构新烟碱类农药是防止全球蜜蜂数量减少的关键。而对蜜蜂响应立体异构农药的原位代谢调节知之甚少。在这里，我们展示了一种整合质谱成像（MSI）和非靶向代谢组学方法，以揭示与立体异构dinotfuran相关的蜜蜂（Apiscerana）的代谢表达水平和空间分化受到干扰。该方法提供了有关蜜蜂中多种代谢途径中涉及的广泛代谢物的代谢网络映射能力。代谢组学结果表明,S-(+)-dinotfuran对蜜蜂代谢途径的影响比R-(-)-dinotfuran显著,例如三羧酸（TCA）循环，乙醛酸和二羧酸代谢，和各种氨基酸代谢。MSI结果表明参与TCA循环的关键代谢物的交叉调节和空间分化，嘌呤,糖酵解,和蜜蜂体内的氨基酸代谢。一起来看,综合MSI和代谢组学结果表明,S-(+)-呋喃胺的毒性较高是由于代谢途径紊乱及其对能量代谢的抑制作用,导致解毒机制的降解率显着降低。从空间代谢组学的角度来看，我们的发现为纯手性农用化学品的开发和应用提供了新的视角。
