Effect of di(2-ethylhexyl) phthalate on Nrf2-regulated glutathione homeostasis in mouse kidney
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ORIGINAL PAPER
Effect of di(2-ethylhexyl) phthalate on Nrf2-regulated glutathione homeostasis in mouse kidney Ines Amara 1,2 & Amal Salah 1 & Rim Timoumi 1 & Emna Annabi 1 & Maria Scuto 2 & Angela Trovato 2 & Fadwa Neffati 3 & Vittorio Calabrese 2 & Salwa Abid-Essefi 1 Received: 5 March 2020 / Revised: 21 May 2020 / Accepted: 25 May 2020 # Cell Stress Society International 2020
Abstract Environmental toxicants such as phthalate have been involved in multiple health disorders including renal diseases. Oxidative damage is implicated in many alterations caused by phthalate especially the di(2-ethylhexyl) phthalate (DEHP), which is the most useful phthalate. However, information regarding its mechanism of renal damage is lacking. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates gene expression implicated in free radical scavenging and cytoprotection including the antioxidant glutathione (GSH) pathway. The aim of this study was to assess whether DEHP affects the Nrf2 pathway and the GSH concentration. Mice were divided into four groups: a control group and three groups treated with DEHP at different concentrations (5, 50, and 200 mg/kg body weight) for 30 days. Our results showed that DEHP altered the normal levels of serum biochemical parameters creatinine (CREA), urea, and lactate dehydrogenase (LDH). This phthalate caused oxidative damage through the induction of lipid peroxidation and protein oxidation as marked by increase of protein carbonyl (PC) and loss of protein-bound sulfhydryls (PSH). Simultaneously, DEHP treatment decreased the protein level of Nrf-2, HO-1, and GCLC (responsible of GSH synthesis) and decreased the GSH level. Inhibition of the Nrf2 pathway is related to the activation of the mitochondrial pathway of apoptosis. This apoptotic process is evidenced by an upregulation of p53 and Bax protein levels in addition to a downregulation of Bcl-2. Collectively, our data demonstrated that depletion of Nrf2 and GSH was associated with the elevation of oxidative stress and the activation of intrinsic apoptosis in mouse kidney treated with DEHP. Keywords Di(2-ethylhexyl) phthalate . Oxidative stress . Nrf2 antioxidant pathway . Glutathione homeostasis . Apoptosis
Introduction Highlights • DEHP induces oxidative stress in mouse kidney. • DEHP inhibits Nrf2 antioxidant pathway in mouse kidney. • DEHP decreases GSH content in mouse kidney. • DEHP induces apoptosis through the mitochondrial pathway in mouse kidney. * Salwa Abid-Essefi [email protected] 1
Faculty of Dental Medicine, Laboratory for Research on Biologically Compatible Compounds, University of Monastir, LR01SE1, Rue Avicenne, 5000 Monastir, Tunisia
2
Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
3
Monastir University Hospital, Laboratory of Biochemistry-Toxicology, University of Monastir, Monastir, Tunisia
Exposure to persistent environmental pollutants such as phthalate has been linked to the induction of multiple human pathologies inc
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