Metabolomic analysis reveals paraquat-induced metabolic alternation in BV2 microglia: Focus on glutamate metabolism

IF 3.9 3区环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Comparative Biochemistry and Physiology C-toxicology & Pharmacology Pub Date : 2025-05-26 DOI:10.1016/j.cbpc.2025.110234

Xutong Qin , Yaxin Han , Jiming Zhang, Zheng Wang, Qiuyun Gu, Jiayi Li, Zhijun Zhou, Xiuli Chang

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Abstract

Paraquat (PQ), a commonly used contact herbicide, is known to induce oxidative stress and energy depletion, leading to cell death. Chronic low-dose exposure to PQ has been associated with an increased risk of Parkinson's disease, with microglia playing a significant role in its pathogenesis. However, little research has been conducted on the specific effects of PQ on microglial metabolism. This study employs ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) to investigate the metabolic changes in BV2 microglial cells exposed to varying concentrations of 0, 2.5, 5, 10, and 20 μM of PQ. A dose-response fitting model was constructed to determine the effective concentrations and identify sensitive differential metabolites (DMs). Furthermore, reverse transcription-PCR (RT-PCR) was used to assess the expression levels of key genes involved in glutamate metabolism, namely SLC7A11, GLS and SLC38A1. The study identified 40 intracellular inter-group DMs, mainly enriched in amino acid metabolic pathways. d-Glucosamine 6-phosphate and pantothenic acid were identified as the most sensitive DMs. Glutamate emerged as a pivotal metabolite, with its upregulation being accompanied by a significant increase in SLC7A11 expression increasing with PQ concentration, indicating an enhanced cellular response to oxidative stress via glutathione synthesis. Moreover, increased expression of GLS and SLC38A1 was observed exclusively at the 2.5 concentration group, suggesting a shift in glutamate synthesis mechanisms depending on PQ exposure levels. These findings contribute to the understanding of PQ's impact on microglial metabolism and its potential role in neurodegenerative diseases.

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代谢组学分析揭示百草枯诱导BV2小胶质细胞的代谢改变：重点是谷氨酸代谢。

百草枯（Paraquat， PQ）是一种常用的接触性除草剂，已知会引起氧化应激和能量消耗，导致细胞死亡。慢性低剂量暴露于PQ与帕金森病风险增加有关，小胶质细胞在其发病机制中起重要作用。然而，关于PQ对小胶质细胞代谢的具体影响的研究很少。本研究采用超高效液相色谱-质谱法（UPLC-MS）研究了不同浓度的PQ（0、2.5、5、10和20 μM）对BV2小胶质细胞代谢的影响。建立剂量-反应拟合模型，确定有效浓度，鉴别敏感差异代谢物（DMs）。利用逆转录- pcr （RT-PCR）技术检测谷氨酸代谢关键基因SLC7A11、GLS和SLC38A1的表达水平。该研究鉴定了40种细胞内组间dm，主要富集于氨基酸代谢途径。6-磷酸葡萄糖胺和泛酸是最敏感的dm。谷氨酸作为关键代谢物出现，其上调伴随着SLC7A11表达的显著增加，随着PQ浓度的增加，表明通过谷胱甘肽合成增强了细胞对氧化应激的反应。此外，仅在2.5浓度组观察到GLS和SLC38A1的表达增加，这表明谷氨酸合成机制取决于PQ暴露水平的变化。这些发现有助于理解PQ对小胶质细胞代谢的影响及其在神经退行性疾病中的潜在作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Comparative Biochemistry and Physiology C-toxicology & Pharmacology 医学-动物学

CiteScore

7.50

自引率

5.10%

发文量

206

审稿时长

30 days

期刊介绍： Part C: Toxicology and Pharmacology. This journal is concerned with chemical and drug action at different levels of organization, biotransformation of xenobiotics, mechanisms of toxicity, including reactive oxygen species and carcinogenesis, endocrine disruptors, natural products chemistry, and signal transduction with a molecular approach to these fields.