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Study on the metabolism toxicity, susceptibility and mechanism of di-(2-ethylhexyl) phthalate on rat liver BRL cells with insulin resistance in vitro
- Ding, Yangyang, Liu, Yongchao, Fei, Fan, Yang, Liuqing, Mao, Guanghua, Zhao, Ting, Zhang, Zhehan, Yan, Mengjiao, Feng, Weiwei, Wu, Xiangyang
- Toxicology 2019 v.422 pp. 102-120
- alanine transaminase, apoptosis, aspartate transaminase, caspase-3, genes, glucose, glucose transporters, hepatocytes, humans, insulin, insulin resistance, liver, metabolism, phosphatidylinositol 3-kinase, phosphorylation, phthalates, plasticizers, rats, risk, serine, toxicity
- Di-(2-ethylhexyl) phthalate (DEHP) is the most commonly used plasticizer which could be easily absorbed by humans and animals through various channels. It has been found that exposure to DEHP could increase the incidence of insulin resistance. In this study, therefore, the metabolism toxicity, susceptibility and mechanism of DEHP (5500 and 50,000 nM exposure for 24 h) on normal BRL cells (Buffalo Rat Liver cells) and BRL cells with insulin resistance induced by insulin were investigated. The results showed that DEHP could cause cell damage with ALT and AST activities and MDA levels increased, cell apoptosis with Caspase-3 levels increased and insulin resistance with IR-β levels decreased in BRL cells with resistance and normal BRL cells. Western-blot analysis and Q-PCR showed that the levels and gene expressions of insulin signaling proteins (IRS-1, GLUT4, GSK-3α, GSK-3β, PI3K, AKT, mTOR), cell signaling proteins (RAS, ERK1/2, MEK1/2, BAD, BAX, BCL-2) and immediate early genes in insulin resistance cells and normal cells were significantly altered by DEHP. DEHP significantly promoted serine phosphorylation of IRS-1. The insulin resistance cells in metabolism toxicity were more sensitive to DEHP than normal cells. Intervention with insulin could improve the metabolism toxicity and insulin resistance. The results indicated that DEHP exerted metabolic toxic effects and increased insulin resistance through interfering with glucose metabolism and insulin signaling transduction pathway. Moreover, the risks of DEHP-induced metabolic toxicity and insulin resistance in BRL cells with insulin resistance were higher than that of normal BRL cells.