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Effect of di(2-ethylhexyl) phthalate on Nrf2-regulated glutathione homeostasis in mouse kidney

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Cell Stress and Chaperones Aims and scope

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.

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Funding

This research was supported by the Ministère Tunisien de l’Enseignement Superieur et de la Recherche Scientifique et de la Technologie (Laboratoire de Recherche sur les Substances Biologiquement Compatibles, LRSBC).

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Correspondence to Salwa Abid-Essefi.

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The experimental procedures were performed in accordance with the National Institute of Health Guidelines for Animal Care (Council of European Communities, 1986) and approved by the local Ethics Committee of Faculty of Pharmacy of Monastir (ethical number: FPHM/Pro, 201563).

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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.

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Amara, I., Salah, A., Timoumi, R. et al. Effect of di(2-ethylhexyl) phthalate on Nrf2-regulated glutathione homeostasis in mouse kidney. Cell Stress and Chaperones 25, 919–928 (2020). https://doi.org/10.1007/s12192-020-01127-8

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