微塑料联合MEHP抑制SIRT3/SOD2诱导肝细胞线粒体损伤和氧化应激
Microplastics Combined with MEHP Induced Mitochondrial Damage and Oxidative Stress via Inhibiting SIRT3/SOD2 in Hepatocytes
-
摘要: 微塑料(microplastics, MPs)常与多种塑料相关产品共同暴露损害人体健康。邻苯二甲酸二(2-乙基己基)酯(di-2-ethylhexyl phthalate, DEHP)是常见的塑化剂，其主要代谢物为邻苯二甲酸单(2-乙基己基)酯(mono-2-ethylhexyl phthalate, MEHP)。MPs与MEHP进入机体后均在肝脏蓄积，因此研究MPs与MEHP的联合暴露对肝脏的毒性效应及潜在机制具有重要意义。本研究采用聚苯乙烯微塑料(polystyrene microplastics, PS-MPs)和MEHP单独及二者联合处理HepG2细胞，检测细胞活力、活性氧水平、线粒体膜电位、COXⅠ、COXⅢ、SIRT3和SOD2的蛋白表达水平。结果表明，PS-MPs和MEHP单独暴露均引起活性氧生成增加、线粒体膜电位降低。PS-MPs单独暴露也导致COXⅠ与COXⅢ蛋白表达水平降低。两者联合暴露时上述有害作用更为显著，为协同效应。进一步的分子机制研究表明，PS-MPs下调了SIRT3和SOD2蛋白表达，MEHP下调了SIRT3蛋白表达，而PS-MPs和MEHP联合暴露对SIRT3和SOD2的蛋白表达的影响表现为协同效应。综上所述，PS-MPs和MEHP联合暴露导致HepG2细胞氧化应激和线粒体损伤，其分子机制与抑制SIRT3/SOD2信号通路有关。Abstract: Microplastics (MPs) are usually co-exposed with a variety of plastic-related products. This co-exposed is harmful to human health. Mono-2-ethylhexyl phthalate (MEHP) is a primary metabolite of di-2-ethylhexyl phthalate (DEHP), a common plasticizer. Once entering into the body, MPs and MEHP accumulate in the liver. Therefore, it is important to study the toxic effects of the co-exposed of MPs and MEHP on the liver and explore the potential mechanisms. In this study, HepG2 cells were treated with polystyrene microplastics (PS-MPs), MEHP, or PS-MPs combined with MEHP. The cell viability, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and protein expression of COXⅠ, COXⅢ, SIRT3 and SOD2 were measured. The results showed that PS-MPs or MEHP exposure increased ROS generation and decreased MMP. PS-MPs exposure alone reduced protein expression of COXⅠ and COXⅢ. These harmful effects were more pronounced when combined exposure，indicated a synergistic effect. Further molecular mechanism study exhibited that PS-MPs treatment down-regulated the protein expression of SIRT3 and SOD2. MEHP treatment down-regulated the protein expression of SIRT3. The combined exposure of PS-MPs and MEHP synergistically down-regulated the protein expression of SIRT3 and SOD2. In summary, the combined exposure of PS-MPs and MEHP resulted in oxidative stress and mitochondrial damage in HepG2 cells, and the underlying molecular mechanism is related to the inhibition of the SIRT3/SOD2 signaling pathway.
-
Key words:
- microplastics /
- MEHP /
- HepG2 cells /
- combined exposure /
- oxidative stress /
- mitochondrial damage /
- SIRT3
-
-
Kumar R, Manna C, Padha S, et al. Micro(nano)plastics pollution and human health: How plastics can induce carcinogenesis to humans? [J]. Chemosphere, 2022, 298: 134267 Yang X N, Jiang J, Wang Q, et al. Gender difference in hepatic AMPK pathway activated lipid metabolism induced by aged polystyrene microplastics exposure [J]. Ecotoxicology and Environmental Safety, 2022, 245: 114105 Browne M A, Galloway T, Thompson R. Microplastic: An emerging contaminant of potential concern? [J]. Integrated Environmental Assessment and Management, 2007, 3(4): 559-561 Thompson R C, Olsen Y, Mitchell R P, et al. Lost at sea: Where is all the plastic? [J]. Science, 2004, 304(5672): 838 Rist S, Carney Almroth B, Hartmann N B, et al. A critical perspective on early communications concerning human health aspects of microplastics [J]. The Science of the Total Environment, 2018, 626: 720-726 Liu Z Q, Zhuan Q R, Zhang L Y, et al. Polystyrene microplastics induced female reproductive toxicity in mice [J]. Journal of Hazardous Materials, 2022, 424(Pt C): 127629 Capó X, Company J J, Alomar C, et al. Long-term exposure to virgin and seawater exposed microplastic enriched-diet causes liver oxidative stress and inflammation in gilthead seabream Sparus aurata, Linnaeus 1758[J]. The Science of the Total Environment, 2021, 767: 144976 Yin K, Wang D X, Zhang Y, et al. Polystyrene microplastics promote liver inflammation by inducing the formation of macrophages extracellular traps [J]. Journal of Hazardous Materials, 2023, 452: 131236 Félix L, Carreira P, Peixoto F. Effects of chronic exposure of naturally weathered microplastics on oxidative stress level, behaviour, and mitochondrial function of adult zebrafish (Danio rerio) [J]. Chemosphere, 2023, 310: 136895 Choi K, Joo H, Campbell J L Jr, et al. In vitro intestinal and hepatic metabolism of di(2-ethylhexyl) phthalate (DEHP) in human and rat [J]. Toxicology in Vitro: An International Journal Published in Association with BIBRA, 2013, 27(5): 1451-1457 Chen L, Qi M, Zhang L L, et al. Di(2-ethylhexyl) phthalate and microplastics cause necroptosis and apoptosis in hepatocytes of mice by inducing oxidative stress [J]. Environmental Toxicology, 2023, 38(6): 1226-1238 Cheng W, Li X L, Zhou Y, et al. Polystyrene microplastics induce hepatotoxicity and disrupt lipid metabolism in the liver organoids [J]. The Science of the Total Environment, 2022, 806(Pt 1): 150328 Zhao Y, Bao R K, Zhu S Y, et al. Lycopene prevents DEHP-induced hepatic oxidative stress damage by crosstalk between AHR-Nrf2 pathway [J]. Environmental Pollution, 2021, 285: 117080 Panizzi S, Suciu N A, Trevisan M. Combined ecotoxicological risk assessment in the frame of European authorization of pesticides [J]. The Science of the Total Environment, 2017, 580: 136-146 王菲迪, 张海军, 耿柠波, 等. 短链氯化石蜡(SCCPs)和多环芳烃(PAHs)联合暴露对HepG2细胞抗氧化系统的影响[J]. 生态毒理学报, 2018, 13(5): 218-225 Wang F D, Zhang H J, Geng N B, et al. Combined effects of SCCPs and PAHs on the antioxidant system in HepG2 cells [J]. Asian Journal of Ecotoxicology, 2018, 13(5): 218-225(in Chinese)
Sheng Y F, Ye X Y, Zhou Y, et al. Microplastics (MPs) act as sources and vector of pollutants-impact hazards and preventive measures [J]. Bulletin of Environmental Contamination and Toxicology, 2021, 107(4): 722-729 Prata J C, da Costa J P, Lopes I, et al. Environmental exposure to microplastics: An overview on possible human health effects [J]. The Science of the Total Environment, 2020, 702: 134455 Vethaak A D, Legler J. Microplastics and human health [J]. Science, 2021, 371(6530): 672-674 Xu J, Wang L M, Zhang L H, et al. Mono-2-ethylhexyl phthalate drives progression of PINK1-parkin-mediated mitophagy via increasing mitochondrial ROS to exacerbate cytotoxicity [J]. Redox Biology, 2021, 38: 101776 Das A. The emerging role of microplastics in systemic toxicity: Involvement of reactive oxygen species (ROS) [J]. The Science of the Total Environment, 2023, 895: 165076 Wang S C, Liu J, Yao Y J, et al. Polystyrene microplastics-induced ROS overproduction disrupts the skeletal muscle regeneration by converting myoblasts into adipocytes [J]. Journal of Hazardous Materials, 2021, 417: 125962 Zhang Y Z, Hui J, Xu Y, et al. MEHP promotes liver fibrosis by down-regulating STAT5A in BRL-3A hepatocytes [J]. Chemosphere, 2022, 295: 133925 Wu H, Liu Q H, Yang N X, et al. Polystyrene-microplastics and DEHP co-exposure induced DNA damage, cell cycle arrest and necroptosis of ovarian granulosa cells in mice by promoting ROS production [J]. The Science of the Total Environment, 2023, 871: 161962 Liu T, Hou B L, Wang Z P, et al. Polystyrene microplastics induce mitochondrial damage in mouse GC-2 cells [J]. Ecotoxicology and Environmental Safety, 2022, 237: 113520 Chen X, Wang J S, Qin Q Z, et al. Mono-2-ethylhexyl phthalate induced loss of mitochondrial membrane potential and activation of Caspase3 in HepG2 cells [J]. Environmental Toxicology and Pharmacology, 2012, 33(3): 421-430 Brischigliaro M, Zeviani M. Cytochrome c oxidase deficiency [J]. Biochimica et Biophysica Acta Bioenergetics, 2021, 1862(1): 148335 García-Villegas R, Camacho-Villasana Y, Shingú-Vázquez M Á, et al. The Cox1 C-terminal domain is a central regulator of cytochrome c oxidase biogenesis in yeast mitochondria [J]. The Journal of Biological Chemistry, 2017, 292(26): 10912-10925 Pi H F, Xu S C, Reiter R J, et al. SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin [J]. Autophagy, 2015, 11(7): 1037-1051 Li D P, Chen Y L, Jiang H Y, et al. Phosphocreatine attenuates Gynura segetum-induced hepatocyte apoptosis via a SIRT3-SOD2-mitochondrial reactive oxygen species pathway [J]. Drug Design, Development and Therapy, 2019, 13: 2081-2096 Zou H, Qu H Y, Bian Y S, et al. Polystyrene microplastics induce oxidative stress in mouse hepatocytes in relation to their size [J]. International Journal of Molecular Sciences, 2023, 24(8): 7382 Dai X Y, Zhao Y, Ge J, et al. Lycopene attenuates di(2-ethylhexyl) phthalate-induced mitophagy in spleen by regulating the sirtuin 3-mediated pathway [J]. Food & Function, 2021, 12(10): 4582-4590 -
点击查看大图
计量
- 文章访问数: 1359
- HTML全文浏览数: 1359
- PDF下载数: 175
- 施引文献: 0
下载:
