Di (2‐ethylhexyl) phthalate induces cytotoxicity in HEK‐293 cell line, implication of the Nrf‐2/HO‐1 antioxidant pathway

Abstract

The di (2‐ethylhexyl) phthalate (DEHP) is a plasticizer used in the polyvinyl chloride industry. Human exposure to this plasticizer is inevitable and contributes to several side effects. In this study, we examined whether DEHP induces apoptosis and oxidative stress in embryonic kidney cells (HEK‐293) and whether the nuclear factor E2‐related factor 2 (Nrf‐2)/heme oxygenase‐1 (HO‐1) antioxidant pathway is involved in the pathogenesis of this process. We demonstrated that DEHP is cytotoxic to HEK‐293 cells. It causes oxidative damage through the generation of free radicals, induces lipid peroxidation, and alters superoxide dismutase and catalase activities. Simultaneously, DEHP treatment decreases the expression and the protein level of Nrf‐2 and HO‐1. Inhibition of the Nrf‐2/HO‐1 pathway is related to the mitochondrial pathway of apoptosis. This apoptotic process is characterized by a loss of mitochondrial transmembrane potential (ΔΨm) and upregulation of the expression of caspase‐3 mRNA as well as its protein level.

Effects of Lycium barbarum glycopeptide on renal and testicular injury induced by di(2-ethylhexyl) phthalate

“…In this research, we detected that DEHP caused apoptosis in HEK-293 and HK-2 cells at 24 h, 48 h, and 72 h. A previous study found that management of HEK-293 cells with DEHP for 24 h can induce apoptosis by oxidative stress (Amara et al 2019 ), which is consistent with this study. In addition, different concentrations of LbGp improved DEHP-induced apoptosis.…”

“…ConA, which can promote cell proliferation, served as a positive control for LbGp. The concentrations of DEHP (Amara et al 2019 ), LbGp, and ConA (Du et al 2004 ) were determined based on previous studies and pre-experiments. Cells in each group were treated with dimethyl sulfoxide (DMSO), DMSO + 200 µg/ml DEHP, DMSO + 200 µg/ml DEHP + 300 µg/ml LbGp, DMSO + 200 µg/ml DEHP + 750 µg/ml LbGp, DMSO + 200 µg/ml DEHP + 1500 µg/ml LbGp, or DMSO + 10 µg/ml ConA.…”

“…A low dose of DEHP can properly activate autophagy to protect the testis, while a high dose of DEHP can mediate apoptosis to damage the testis (Fu et al 2020 ). DEHP can induce apoptosis of mouse renal cells and human embryonic kidney-293 (HEK-293) cells (Amara et al 2019 , 2020 ). Autophagy and apoptosis are the regulatory mechanisms for cells to adapt to external stress and jointly maintain cell homeostasis (Elmore 2007 ; Maiuri et al 2007 ; Mizushima et al 2008 ; Song et al 2017 ).…”

Di-2-ethylhexyl phthalate (DEHP) induces apoptosis of mouse HT22 hippocampal neuronal cells via oxidative stress

“…However, oxidative stress occurs when excessive ROS are produced, which has been implicated in the progression of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease (Gilgun-Sherki et al, 2001). DEHP was shown to induce oxidative stress in many kinds of cells such as mouse NE-4C neural stem cells (Wu et al, 2019), mouse Leydig cells (Sun et al, 2018), and human embryonic kidney cells (Amara et al, 2019). In the present study, we found that there was a significant increase in the MDA level as well as a dramatic decrease in the enzyme activities of SOD and GSH-PX and the content of GSH.…”

Potential Role of Lycopene in the Inhibition of Di(2-ethylhexyl) Phthalate-Induced Ferroptosis in Spleen Via Modulation of Iron Ion Homeostasis

“…There were investigations that have revealed that DEHP induced lipid accumulation and peroxidation in the tissues or cells. 19,20 Chronic DEHP exposure could significantly lead to mitochondrial dysfunction and morphological damage. 17,21 These findings together imply that DEHP may be a potential way to induce cell death via induction of ferroptosis.…”