Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Co-innovation Center of Henan Province for New drug R & D and preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, PR China.
Department of Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
Sci Total Environ. 2021 Jan 1;750:141685. doi: 10.1016/j.scitotenv.2020.141685. Epub 2020 Aug 12.
Human exposure to bisphenol A (BPA) is unavoidable in daily life. Recently, research has showen that BPA could induce oxidative imbalance, thereby causing reproductive toxicity and liver dysfunction. Accumulated evidence has demonstrated that metformin possesses strong anti-oxidative properties. This study aimed to study the mechanism underlying the hepatic-protective effect of metformin on liver injury induced by BPA in rats via the UPLC-MS/MS metabolomics approach. Forty-two male rats were randomly divided into six groups (n = 7), namely the saline group (control), the corn oil group (vehicle), the metformin group (Met), the bisphenol A group (BPA), the bisphenol A and metformin group (BPA + Met), and the bisphenol A and diammonium glycyrrhizinate (positive control) group (BPA + DG). Serum was collected for biochemical analysis and metabolomics, and liver tissue was collected for histopathology and metabolomics in each group. We found that metformin could significantly reduce the levels of liver function enzymes (ALT, AST and GGT) and ameliorate inflammatory cell infiltration and hepatocyte necrosis induced by BPA. On the other hand, metformin could significantly enhance the total antioxidant capacity in BPA rats. Notably, metabolomics data indicated that the principal altered metabolic pathways based on the 26 differential metabolites in liver tissue, and 21 in serum among vehicle, BPA and BPA + Met groups, respectively, including cysteine and methionine metabolism, glutathione metabolism, and arginine biosynthesis and purine metabolism. Additionally, metformin significantly increased cystathionine β synthase (CBS) and cystathionine γ lyase (CSE), thus reducing serum levels of homocysteine and increasing hepatic levels of cysteine and glutathione in BPA-treated rats. Overall, this study's results provided new insights into the role and mechanism of metformin in BPA-induced liver injury in rats.
人在日常生活中不可避免地会接触到双酚 A（BPA）。最近的研究表明，BPA 可诱导氧化失衡，从而导致生殖毒性和肝功能障碍。大量证据表明，二甲双胍具有很强的抗氧化特性。本研究旨在通过 UPLC-MS/MS 代谢组学方法研究二甲双胍对 BPA 诱导大鼠肝损伤的肝保护作用机制。42 只雄性大鼠随机分为 6 组（n=7），即生理盐水组（对照）、玉米油组（溶剂）、二甲双胍组（Met）、双酚 A 组（BPA）、双酚 A 和二甲双胍组（BPA+Met）和双酚 A 和甘草酸二铵（阳性对照）组（BPA+DG）。每组采集血清进行生化分析和代谢组学分析，采集肝组织进行组织病理学和代谢组学分析。结果发现，二甲双胍可显著降低肝功能酶（ALT、AST 和 GGT）水平，并改善 BPA 引起的炎症细胞浸润和肝细胞坏死。另一方面，二甲双胍可显著增强 BPA 大鼠的总抗氧化能力。值得注意的是，代谢组学数据表明，基于组织中 26 个差异代谢物和血清中 21 个差异代谢物的主要改变代谢途径，分别在溶剂、BPA 和 BPA+Met 组中，包括半胱氨酸和蛋氨酸代谢、谷胱甘肽代谢、精氨酸生物合成和嘌呤代谢。此外，二甲双胍可显著增加胱硫醚-β合酶（CBS）和胱硫醚-γ裂解酶（CSE），从而降低 BPA 处理大鼠血清同型半胱氨酸水平，增加肝内半胱氨酸和谷胱甘肽水平。总之，本研究结果为二甲双胍在 BPA 诱导大鼠肝损伤中的作用和机制提供了新的见解。
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