School of Chemistry, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, and GDMPA Key Laboratory for Process Control and Quality Evaluation of Chiral Pharmaceuticals, South China Normal University, Guangzhou 510006, China.
School of Chemistry, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, and GDMPA Key Laboratory for Process Control and Quality Evaluation of Chiral Pharmaceuticals, South China Normal University, Guangzhou 510006, China; MOE Key laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
Pestic Biochem Physiol. 2023 Aug;194:105499. doi: 10.1016/j.pestbp.2023.105499. Epub 2023 Jun 14.
Paclobutrazol is a plant growth inhibitor widely used in agricultural production. However, toxicology studies of paclobutrazol enantiomers towards aquatic organisms are limited. Herein, effects of paclobutrazol and its two enantiomers (2R, 3R; 2S, 3S) on glycolipid metabolism of zebrafish have been systemically explored at the concentration of 10 mg/L through biochemical analyses, LC-MS/MS, molecular dynamics simulation, and gene expression. In all treatments, the contents of glucose, citric acid and lactate significantly were increased while the glycogen and pyruvate contents were decreased, in which (2R, 3R)-paclobutrazol exhibited a greater effect than the (2S, 3S)-enantiomer (P < 0.05). Then, activities of hexokinase and lactate dehydrogenase in (2R, 3R)-paclobutrazol treatment were 0.74- and 1.18-fold higher than (2S, 3S)-enantiomer treatment, respectively (P < 0.001), and the results of molecular dynamics simulation revealed that the binding free energy of hexokinase 1 to (2R, 3R)-paclobutrazol was higher than that to the antipode. Moreover, lipids including triglycerides, total cholesterol, fatty acids, bile acids and glycerophospholipids in zebrafish were strikingly affected after paclobutrazol exposure. The (2R, 3R)-paclobutrazol-treated group showed the most obvious changes, indicating that it possessed much stronger disruption ability on the lipid metabolism of zebrafish. Furthermore, qRT-PCR analysis results revealed that (2R, 3R)-enantiomer significantly impacted expressions of glycolipid metabolism-related genes (hk1, g6pc, pck1, pk, aco, cebpa, cyp51, fasn and ppara) in zebrafish than (2S, 3S)-enantiomer (P < 0.05). Briefly, this study provides new evidences for the toxicity of paclobutrazol to aquatic organisms and the potential risk to human health at the chiral level.
多效唑是一种广泛应用于农业生产的植物生长抑制剂。然而，关于多效唑对水生生物对映体的毒理学研究还很有限。本研究在 10mg/L 浓度下，通过生化分析、LC-MS/MS、分子动力学模拟和基因表达，系统地研究了多效唑及其两种对映体（2R,3R;2S,3S）对斑马鱼糖脂代谢的影响。在所有处理中，葡萄糖、柠檬酸和乳酸的含量显著增加，而糖原和丙酮酸的含量减少，其中（2R,3R）-多效唑的作用大于（2S,3S）-对映体（P<0.05）。然后，（2R,3R）-多效唑处理组的己糖激酶和乳酸脱氢酶活性分别比（2S,3S）-对映体处理组高 0.74 倍和 1.18 倍（P<0.001），分子动力学模拟结果表明，己糖激酶 1 与（2R,3R）-多效唑的结合自由能高于与对映体的结合自由能。此外，暴露于多效唑后，斑马鱼中的脂类，包括甘油三酯、总胆固醇、脂肪酸、胆汁酸和甘油磷脂，受到显著影响。（2R,3R）-多效唑处理组表现出最明显的变化，表明其对斑马鱼脂质代谢具有更强的破坏能力。此外，qRT-PCR 分析结果表明，（2R,3R）-对映体显著影响了糖脂代谢相关基因（hk1、g6pc、pck1、pk、aco、cebpa、cyp51、fasn 和 ppara）在斑马鱼中的表达，而（2S,3S）-对映体的影响较小（P<0.05）。综上所述，本研究为多效唑对水生生物的毒性及其在手性水平上对人类健康的潜在风险提供了新的证据。
