農藥的使用對提高作物產量和品質有益，但不當使用可能導致人體過度暴露，引起急性或慢性疾病，膳食攝入是主要的農藥暴露途徑，而蔬果類是主要的農藥殘留食物，有機磷(Organophosphates, OP)和氨基甲酸鹽(Carbamate, CM)農藥在神經系統中作為乙醯膽鹼酯酶抑制劑，導致神經傳導物質累積，並對神經系統、肝臟和腎臟產生毒性，農藥殘留存在農作物或環境中，更可能對敏感族群帶來健康風險。
本研究聚焦於暴露農藥對腎功能的影響，因腎臟中的血液循環及電解質平衡受到膽鹼性神經元控制，有機磷和氨基甲酸鹽類農藥的暴露可能對腎功能造成損害，尤其在短時間內大量暴露下，可能引發急性腎損傷，而長期暴露則可能影響慢性腎臟病(Chronic Kidney Disease , CKD)的發展。本研究之目標為探討CKD第三至五期患者中，多項農藥的暴露，對代謝路徑及疾病進程的影響。透過世代研究追蹤方式，共收集了89位CKD第三至五期患者的尿液樣本，利用高效液相層析串聯質譜儀(UPLC-MS/MS)分析氧化壓力指標8-hydroxydeoxyguanosine(8-OHdG)的濃度，接著利用高解析四極桿串聯傅立葉轉換電場軌道質譜儀(High-Resolution Quadrupole-Orbitrap Mass Spectrometry, Q-Exactive Orbitrap HRMS)進行尿液中的非標靶代謝體學分析，並透過主成分分析(Principal components analysis, PCA)和正交偏最小二乘判別分析(Orthogonal Projections to Latent Structures Discriminant Analysis, OPLS-DA)，篩選出追蹤後改變且與農藥暴露相關的差異代謝物，並分析其相關代謝路徑，以探討患者暴露於農藥暴露對8-OHdG濃度、疾病進程及特定代謝路徑的影響。
本研究中於受試者之尿液共檢測到71種農藥及農藥代謝物，其中9種為氨基甲酸鹽類農藥，且治滅蝨(Metolcarb)兩次追蹤檢出率均大於95%，此結果顯示氨基甲酸鹽農藥的廣泛應用性，同時，由代謝體分析出8個與農藥暴露相關代謝路徑，包含胺醯tRNA生物合成(Aminoacyl-tRNA biosynthesis)、丙胺酸、天門冬胺酸與麩胺酸代謝(Alanine, aspartate and glutamate metabolism)、色胺酸代謝(Tryptophan metabolism)、檸檬酸循環(Citrate cycle ; TCA cycle)、乙醛酸及二羧酸酯代謝(Glyoxylate and dicarboxylate metabolism)、精胺酸生物合成(Arginine biosynthesis)、β-丙胺酸代謝(beta-Alanine metabolism)、甘胺酸、絲胺酸與蘇胺酸代謝(Glycine, serine and threonine metabolism)及麩胱甘肽代謝(Glutathione metabolism)，此結果指出，受試者在飲食或生活中，暴露較高之CM之半定量濃度後，體內受到影響的代謝路徑多與氧化壓力、胺基酸代謝及粒線體能量代謝有關，不同的農藥在代謝體反應上可能具有相似的生物化學特徵。本研究利用L-麩醯胺酸(L-glutamine, L-Gln)、3-氯酪胺酸(3-chlorotyrosine, ClY)以及N2, N2二甲基鳥苷(N2, N2-Dimethylguanosine, M22G)之預測結果可能可做為農藥暴露與腎功能關聯性之生物標記模型，此模型之AUC(Area Under Curve)值為0.903，這些因為暴露農藥而造成改變的代謝物，可能可作為評估農藥暴露對CKD患者造成影響，甚至長期下來可能影響腎功能的生物標記，並有助於反應農藥暴露對於敏感性族群所造成的傷害。
此外，半胱胺酸(L-Cysteine, L-Cys)、乙醯輔酶A(Acetyl-CoA)、L-麩胺酸(L-Glutamate, L-Glu)及L-組胺酸(L-Histidine, L-His)，這些代謝物為造成本研究中與第三期至第五期的CKD受試者eGFR變化且與農藥暴露量相關的代謝物，在eGFR下降組別中，觀察到L-Cys的上調較其他組別明顯；在eGFR上升≥3 mL/min/1.73 m2的組別中發現，L-Glu相較其他組別，有上調的趨勢；在eGFR下降≥5 mL/min/1.73 m2的組別中發現，相較於其他組別，受試者體內Acetyl-CoA下調，這些同時與CKD進程與農藥暴露相關的代謝物，與氧化壓力、神經傳導及組織修復相關。本研究透過代謝體學研究尋找暴露於農藥後改變的代謝物，以及評估這些代謝物與CKD之間的相關性，本研究透過早期鑑定出因農藥暴露所造成之代謝物濃度異常以及預測其可能於潛在疾病過程中之生理途徑，將有助於腎臟疾病的預防與治療。

Pesticide application is crucial for crop enhancement, but improper use can lead to health risks, especially for sensitive populations. This study aims to investigate the exposure of organophosphates (OP)and carbamate (CM)pesticides among patients with CKD from stage 3-5, examining their effects on metabolic pathways and disease progression. A longitudinal study was conducted and 89 CKD patients was recruited in ths study. 71 pesticides in urine samples were identified, including 9 carbamates. Concentrations of the oxidative stress marker 8-hydroxydeoxyguanosine were measured using UPLC-MS/MS, and non-targeted metabolomic analysis was conducted with High-Resolution Q-Exactive Plus. PCA and OPLS-DA identified the altered metabolites associated with pesticide exposure. The current result revealed that 8 metabolic pathways influenced by carbamates exposure. The higher carbamate concentrations in diet or lifestyle may significantly influenced oxidative stress, amino acid metabolism, and mitochondrial energy metabolism. Pesticides displayed similar metabolic fingerprints, with altered metabolites serving as potential biomarkers for oxidative stress impact on CKD patients. The study identified L-glutamine (L-Gln), 3-chlorotyrosine (ClY) and N2, N2-Dimethylguanosine (M22G) as potential indicators of pesticide exposure. Through a biomarker model, the study further analyzed the exploratory value and significance of its clinical application. CKD and pesticide exposure induced abnormalities in amino acid and energy metabolism, with key metabolites such as L-Cysteine (L-Cys), Acetyl-CoA, L-Glutamate (L-Glu), and L-Histidine (L-His). Detecting exposure-altered metabolites through metabolomics aids in early identification, contributing to understanding and preventing deterioration of kidney diseases.

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