Di(2-ethylhexyl) phthalate inhibits glutathione regeneration and dehydrogenases of the pentose phosphate pathway on human colon carcinoma cells

Abstract

Phthalates, particularly di(2-ethylhexyl) phthalate (DEHP), are compounds widely used as plasticizers and have become serious global contaminants. Because of the bioaccumulation of such substances, the food chain is at risk. The food contamination by some phthalates has been linked to different side effects in experimental animals. That is why we have chosen the intestinal system's cells which represent the primary targets of these compounds to test their toxic effects. Human colon carcinoma cells (HCT 116) were chosen to elucidate whether DEHP triggers oxidative stress and apoptosis. Our results indicated that DEHP is cytotoxic; it induces the overexpression of Hsp70 protein and causes oxidative damage through the generation of free radicals leading to lipid peroxidation induction and the increase of superoxide dismutase (SOD) and catalase (CAT) activities. In addition, cell treatment with DEHP resulted in a glutathione (GSH) content decrease and a decrease in the glutathione reductase (GR) activity. As new evidence provided in this study, we demonstrated that the DEHP affected the two enzymes' activities of the oxidative phase of the pentose phosphate pathway: Glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD). This leads to a decrease in the level of NADPH used by the GR to maintain the regeneration of the reduced GSH. We also demonstrated that such effects can be responsible for DEHP-induced apoptosis.

Therapeutic efficacy ofN‐acetylcysteine and zinc sulphate against di‐(2‐ethylhexyl) phthalate‐induced testicular oxido‐nitrergic stress in male Wistar rat

“…Although, much has not been reported on effect of phthalates on sulphydryl, the result of the present study is an indication that DEHP may have caused the observed effect. This supports our hypothesis that oxido‐nitrergic stress may serve as a common mediator of DEHP‐cytotoxicity also purported by Huang et al (2010) and Amara et al (2020) in their respective studies. In relation to the testicular NO level in this study, one could infer that DEHP might have altered protein content of the testes by increasing NO level and reducing SH level via oxidative stress pathway.…”

“…Although, much has not been reported on effect of phthalates on sulphydryl, the result of the present study is an indication that DEHP may have caused the observed effect. This supports our hypothesis that oxido-nitrergic stress may serve as a common mediator of DEHP-cytotoxicity also purported by Huang et al (2010) and Amara et al (2020) NAC is a known precursor for GSH synthesis and scavenges ROS (Wang et al, 2014), an anti-inflammatory and antioxidant agent with the ability to inhibit NO production in several types of cells (Xiong et al, 2019). Similarly, it is known that zinc is one of the essential components of the body's most important natural antioxidant (Chian et al, 2000) and its sulphate is a potent anti-inflammatory and antioxidant agent.…”

Lycopene regulates the mitochondrial unfolded protein response to prevent DEHP-induced cardiac mitochondrial damage in mice

“…14 It will disrupt the health of humans and animals through the food chain. 10,15,16 Numerous studies have shown that the exposure of DEHP could cause harm to the liver, 17 spleen 18 and testis 19 in mice. A previous study showed that it would disrupt the heart rate variability and cardiovascular reactivity after DEHP exposure.…”

Lineage-Selective Disturbance of Early Human Hematopoietic Progenitor Cell Differentiation by the Commonly Used Plasticizer Di-2-ethylhexyl Phthalate via Reactive Oxygen Species: Fatty Acid Oxidation Makes the Difference

“…The extent of DEHP-mediated toxicity, as well as general effects associated with exposure, differs depending on the target cell type under study [5,7,[17][18][19][20][21][22]. With respect to the mechanism, most of these effects appear to be mediated via DEHP-dependent activation of the peroxisome proliferator-activated receptor-gamma (PPARγ) or the aryl hydrocarbon receptor (AhR) followed by the generation of reactive oxygen species (ROS) [5,7,[21][22][23][24][25][26].…”