Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 49, Issue 11, Pages 1779-1791Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2010.09.011
Keywords
Di (2 ethylhexyl)phthalate; Hepatic oxidative stress; NF kappa B; MAPK; Apoptosis; Free radicals
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Di-(2-ethylhexyl)phthalate (DEHP) is a widely used plasticizer found in a variety of polyvinyl chloride medical products Although DEHP-induced cytotoxicity and apoptosis are well studied in various cell types the precise mechanisms are not well understood so far This study aimed at going beyond the toxicology approach focuses on the molecular mechanisms through which DEHP causes hepatotoxicity We show that DEHP induces apoptotic cell death in a dose-dependent manner as proven by an Increase in annexin V positively stained cells DAPI/PI staining and immunofluorescence studies The DEHP-induced decrease in cell viability was significantly inhibited by adding catalase (CAT) but CAT treatment did not suppress the DEHP stimulated calcium flux in the hepatocytes whereas BAPTA-AM significantly reduced the DEHP-stimulated DCF intensity These results demonstrate that DEHP increases the intracellular calcium level which mediates the generation of H2O2 in hepatocytes Investigating cell signaling mechanisms we found that DEHP induced apoptotic cell death by mitochondrial-dependent caspase-3 activation and PARP cleavage These changes due to DEHP exposure were associated with increased IKK and NF kappa B phosphorylation Preexposure of hepatocytes to an IKK inhibitor (PS-1145) prevented DEHP-induced caspase 3 and PARP cleavage DEHP also markedly increased the activity of ERK1/2 MAPK Pretreatment with the ERK inhibitor PD98059 attenuated NF kappa B and IKK phosphorylation indicating that ERK MAPK is mainly involved in DEHP induced NF-kappa B activation These results for the first time reveal that DEHP induces apoptosis in hepatocytes via the activation of the ERK/NF-kappa B signaling pathway in which calcium ions and hydrogen peroxide act as the pivotal mediators of the apoptone signaling (C) 2010 Elsevier Inc All rights reserved
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