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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.
- Source :
- Journal of Cellular & Molecular Medicine; Mar2015, Vol. 19 Issue 3, p581-594, 14p
- Publication Year :
- 2015
-
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 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 μM DEHP for 24 hrs. Cell viability, glucose-stimulated insulin secretion, reactive oxygen species ( ROS) generation, cellular antioxidant response, Ca<superscript>2+</superscript> 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<superscript>2+</superscript> 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 2α (e IF2α), 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15821838
- Volume :
- 19
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Journal of Cellular & Molecular Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 101140281
- Full Text :
- https://doi.org/10.1111/jcmm.12409