She Yan, Jiang Liping, Zheng Liangliang, Zuo Heming, Chen Min, Sun Xiance, Li Qiujuan, Geng Chengyan, Yang Guang, Jiang Lijie, Liu Xiaofang
Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, No.9, West Segment of South Lvshun Road, Dalian 116044, Liaoning, PR China; Natural Products Engineering Technology Center, Dalian Medical University, No.9, West Segment of South Lvshun Road, Dalian 116044, Liaoning, PR China.
Preventive Medicine Laboratory, College of Public Health, Dalian Medical University, No.9, West Segment of South Lvshun Road, Dalian 116044, Liaoning, PR China; Natural Products Engineering Technology Center, Dalian Medical University, No.9, West Segment of South Lvshun Road, Dalian 116044, Liaoning, PR China.
Chem Biol Interact. 2017 Mar 1;265:8-15. doi: 10.1016/j.cbi.2017.01.015. Epub 2017 Jan 20.
Di(2-ethyhexyl) phthalate (DEHP) is commonly used as a plasticizer, which loosely binds to plastic materials and easily leaches out of these products and enters into the environment. Exposure to DEHP can impair pancreatic beta cells (INS-1 cells)function, which is associated with Insulin Resistance (IR) and type 2 diabetes. However, the mechanism of how DEHP leads to Insulin Resistance is unknown. Our results showed that the cell viability of INS-1 cells exposed to DEHP (0-1600 μM) were decreased in a concentration-dependent manner. DEHP caused significant increases of DNA migration and oxidative damage in INS-1 cells. Lysosomal membrane permeability was increased and mitochondrial membrane potential was reduced after INS-1 cells treated with DEHP. DEHP was also shown to induce ROS production and cause GSH depletion in INS-1 cells. DEHP brought a significant decrease in super oxide dismutase (SOD) and led to accumulation of malondialdehyde (MDA) in the INS-1 cells. DEHP increased significantly the expression of P53 and ATM gene of INS-1 cell at high dose levels. Simultaneously, Pyrroloquinoline Quinone (PQQ), an antioxidant, and alcohol were used in the study to determine their effects on DEHP-induced INS-1 cells damage. PQQ could protect the INS-1 cells from the damage induced by DEHP to some extent, while alcohol aggravated the toxic effects of DEHP. These results indicate that DEHP-mediated INS-1 cell dysfunction through a lysosomal-mitochondrial pathway, involving oxidative stress and p53 and ATM activation.
邻苯二甲酸二（2-乙基己基）酯（DEHP）常用作增塑剂，它与塑料材料结合不紧密，容易从这些产品中渗出并进入环境。接触DEHP会损害胰腺β细胞（INS-1细胞）功能，这与胰岛素抵抗（IR）和2型糖尿病有关。然而，DEHP导致胰岛素抵抗的机制尚不清楚。我们的结果表明，暴露于DEHP（0-1600μM）的INS-1细胞的细胞活力呈浓度依赖性降低。DEHP导致INS-1细胞的DNA迁移和氧化损伤显著增加。用DEHP处理INS-1细胞后，溶酶体膜通透性增加，线粒体膜电位降低。DEHP还被证明可诱导INS-1细胞产生ROS并导致谷胱甘肽（GSH）消耗。DEHP使超氧化物歧化酶（SOD）显著降低，并导致INS-1细胞中丙二醛（MDA）积累。在高剂量水平下，DEHP显著增加INS-1细胞的P53和ATM基因表达。同时，本研究使用抗氧化剂吡咯喹啉醌（PQQ）和酒精来确定它们对DEHP诱导的INS-1细胞损伤的影响。PQQ可以在一定程度上保护INS-1细胞免受DEHP诱导的损伤，而酒精则加剧了DEHP的毒性作用。这些结果表明，DEHP通过溶酶体-线粒体途径介导INS-1细胞功能障碍，涉及氧化应激以及p53和ATM激活。
