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Di(2-ethylhexyl) phthalate-induced apoptosis in rat INS-1 cells is dependent on activation of endoplasmic reticulum stress and suppression of antioxidant protection.

ABSTRACT: Di(2-ethylhexyl) phthalate (DEHP) is used as plasticizer and is ubiquitously found in the environment. Exposure to DEHP has been linked to an increased incidence of type 2 diabetes. Pancreatic ?-cell dysfunction is a hallmark of type 2 diabetes; however, it is unknown whether DEHP exposure contributes to this risk. Here, we aimed to investigate the cytotoxic effects of DEHP on INS-1 cells and to further explore the related underlying mechanisms. INS-1 cells were exposed to 0, 5, 25, 125 or 625 ?M DEHP for 24 hrs. Cell viability, glucose-stimulated insulin secretion, reactive oxygen species (ROS) generation, cellular antioxidant response, Ca(2+) homoeostasis and the levels of genes and proteins involved in endoplasmic reticulum (ER) stress were measured. The results showed that DEHP decreased insulin secretion and content and induced apoptosis in INS-1 cells in a dose-dependent manner. Furthermore, ROS generation was increased and Nrf2-dependent antioxidant defence protection was dysregulated in INS-1 cells after DEHP exposure. Most importantly, DEHP effectively depleted ER Ca(2+) and triggered the ER stress response as demonstrated by the elevated transcription and translation of the ER chaperone GRP78 and GRP94, the increased phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and its downstream substrate eukaryotic translation initiation factor 2? (eIF2?), as well as the increased levels of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). Taken together, DEHP exerted toxic effects on INS-1 cells by inducing apoptosis, which is dependent on the activation of the PERK-ATF4-CHOP ER stress signalling pathway and the suppression of Nrf2-dependent antioxidant protection.

SUBMITTER: Sun X

PROVIDER: S-EPMC4369815 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Di(2-ethylhexyl) phthalate-induced apoptosis in rat INS-1 cells is dependent on activation of endoplasmic reticulum stress and suppression of antioxidant protection.

Sun Xia X Lin Yi Y Huang Qiansheng Q Shi Junpeng J Qiu Ling L Kang Mei M Chen Yajie Y Fang Chao C Ye Ting T Dong Sijun S

Journal of cellular and molecular medicine 20141123 3

Di(2-ethylhexyl) phthalate (DEHP) is used as plasticizer and is ubiquitously found in the environment. Exposure to DEHP has been linked to an increased incidence of type 2 diabetes. Pancreatic β-cell dysfunction is a hallmark of type 2 diabetes; however, it is unknown whether DEHP exposure contributes to this risk. Here, we aimed to investigate the cytotoxic effects of DEHP on INS-1 cells and to further explore the related underlying mechanisms. INS-1 cells were exposed to 0, 5, 25, 125 or 625 μ ...[more]

PMID: 25418486

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Project description:Maintaining essential fatty acid (EFA) homeostasis during pregnancy is critical for fetal development. As the organ that controls the maternal-to-fetal supply of nutrients, the placenta plays a significant role in guiding EFA transfer to the fetus. Many EFA homeostasis proteins are regulated by peroxisome proliferator-activated receptors (PPARs). The metabolites of di-(2-ethylhexyl)-phthalate (DEHP), a ubiquitous environmental contaminant, might influence EFA homeostasis via trans-activation of PPARs with subsequent downstream effects on EFA transporters and enzymes. To investigate DEHP's effect on placental/fetal EFA homeostasis, female Sprague-Dawley rats were orally gavaged with either vehicle or DEHP at 750 or 1500 mg/kg/day from gestational day (GD) 0 to GD 19. Changes in the expression of several EFA homeostasis regulating proteins were determined in the junctional (JXN) and labyrinthine (LAB) zones of the placenta, including PPAR isoforms (alpha, beta and gamma), fatty acid translocase (FAT/CD36), fatty acid transport protein 1 (FATP1), plasma membrane fatty acid binding protein (FABPpm), heart cytoplasmic fatty acid binding protein (HFABP), cytochrome P450 (CYP) 4A1, and cyclooxygenase (COX)-1 and -2. Additionally, effects of DEHP maternal exposure on the placental transfer and fetal distribution of representative EFAs, arachidonic acid (AA) and docosahexaenoic acid (DHA), and the placental production of prostaglandins (PGs) were investigated. Expression of PPARalpha, PPARgamma, FAT/CD36, FATP1, HFABP and CYP4A1 was up-regulated in JXN and/or LAB while COX-2 was down-regulated in JXN. PPARbeta, FABPpm, and COX-1 demonstrated variable expression. Reduced directional maternal-to-fetal placental transfer and altered fetal distribution of AA and DHA were observed in concordance with a decreased total placental PG production. These results correlate with previous in vitro data, suggesting that DEHP could influence placental EFA homeostasis with potential downstream effects in the developing fetus.

Project description:Allergic rhinitis (AR) is a common chronic inflammatory disease of the upper respiratory tract. Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer and belongs to environmental endocrine disruptors (EDCs). It can be entered the human body which is harmful to health. The relationship between DEHP and AR is still inconclusive. This study aims to investigate the effect of environmental pollutants DEHP on AR. By examining DEHP metabolites in the urine of AR patients and building an AR model. 24 BALB/c mice were used as the study subjects, and ovalbumin (OVA) and DEHP (3 mg/kg/body) were used for intragastric administration. They were divided into control group, DEHP group, OVA group and OVA?+?DEHP group. Examination, behavioral scoring, inflammatory factor testing, oxidative stress testing, detection of aryl hydrocarbon receptor (AhR) and signaling pathways CYP1A1 and CYP1B1 related proteins and mRNA. The concentrations of 3 metabolites of DEHP (MEHHP, MEOHP, and MEHP) in urine of AR patients were higher. And HE-staining showed that for the control group, many chronic inflammatory cell infiltration and nasal mucosal destruction were observed in the OVA?+?DEHP group and were more severe than the OVA group. Allergic symptom scores were obtained from sneezing, scratching, number of scratching, and nose flow. The scores of the OVA group and the OVA?+?DEHP group were higher than 7 points. Serum ELISA and nasal mucosal oxidative stress tests are more serious in the OVA?+?DEHP group. The expression of AhR protein and its mRNA was increased in the DEHP group, OVA group and OVA?+?DEHP group. The OVA?+?DEHP group was more significant in the OVA group and DEHP group. And the mRNAs of the AhR-related signaling pathways CYP1A1 and CYP1B1 were also more prominent in the OVA?+?DEHP group. DEHP may aggravate its inflammatory response through the AhR pathway closely related to the environment. When combined with OVA, DEHP can further aggravate the OVA-induced nasal inflammatory response and make the nasal cavity have undergone severe changes, and many inflammatory cells have infiltrated. DEHP has shown an adjuvant effect, and the AhR-related signaling pathways CYP1A1 and CYP1B1 may be critical.

Dataset Information

Di(2-ethylhexyl) phthalate-induced apoptosis in rat INS-1 cells is dependent on activation of endoplasmic reticulum stress and suppression of antioxidant protection.

Publications

Di(2-ethylhexyl) phthalate-induced apoptosis in rat INS-1 cells is dependent on activation of endoplasmic reticulum stress and suppression of antioxidant protection.

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