Evaluating the protective effects of melatonin on di(2-ethylhexyl) phthalate-induced testicular injury in adult mice

Bahrami, Nosrat; Goudarzi, Mehdi; Hosseinzadeh, Azam; Sabbagh, Susan; Reíter, Russel J.; Mehrzadi, Saeed

doi:10.1016/j.biopha.2018.09.044

Cited by 76 publications

(39 citation statements)

References 81 publications

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“…In addition, our results showed that treatment of cells with DEHP induced over generation of intracellular ROS that leads to a disturbance of redox status balance in cells. In agreement with our studies, a significant increase in ROS generation was observed in vivo and in vitro studies following DEHP treatment . ROS overproduction observed in this work is an index of oxidative stress installation that could be the result of the antioxidant system incapacity to neutralize the ROS overproduction.…”

Section: Discussionsupporting

confidence: 92%

“…As expected, in the present study, the MTT assay indicated that Abbreviations: GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HO-1, heme oxygenase-1; Nrf2, NF-E2 related factor 2. significant increase in ROS generation was observed in vivo and in vitro studies following DEHP treatment. [44][45][46] ROS overproduction observed in this work is an index of oxidative stress installation that could be the result of the antioxidant system incapacity to neutralize the ROS overproduction. In our study, compared with those of the control group, the activities of SOD and CAT increased significantly in DEHP treated cells.…”

Section: Discussionmentioning

confidence: 89%

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

Amara

Timoumi

Graiet

et al. 2019

Environmental Toxicology

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 89%

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

Amara

Timoumi

Graiet

et al. 2019

Environmental Toxicology

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“…Nevertheless, these increases were insufficient to protect the liver from free radicals. In agreement with our studies, a significant increase in oxidative stress generation was observed in vivo and in vitro studies following DEHP treatment …”

Section: Discussionsupporting

confidence: 93%

Di (2‐ethylhexyl) phthalate targets the thioredoxin system and the oxidative branch of the pentose phosphate pathway in liver of Balb/c mice

Amara

Timoumi

Annabi

et al. 2019

Environmental Toxicology

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Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that gives flexibility to various polyvinyl chloride products. It is a pollutant easily released into the environment and can cause many adverse effects to living organisms including hepatotoxicity. The thioredoxin system is a determining factor in the redox balance maintaining in the liver, which is a vulnerable tissue of reactive oxygen species overproduction because of its high energy needs. In order to determine if the thioredoxin system is a target in the development of DEHP hepatotoxicity, Balb/c mice were administered with DEHP intraperitoneally daily for 30 days. Results demonstrated that after DEHP exposure, biochemical profile changes were observed. This phthalate causes oxidative damage through the induction of lipid peroxydation as well as the increase of superoxide dismutase and catalase activities. As new evidence provided in this study, we demonstrated that the DEHP affected the thioredoxin system by altering the expression and the activity of thioredoxin (Trx) and thioredoxin Reductase (TrxR1). The two enzyme activities of the oxidative phase of the pentose phosphate pathway:Glucose-6-phosphate dehydrogenase and 6-Phosphogluconate dehydrogenase were also affected by this phthalate. This leads to a decrease in the level of nicotinamide adenine dinucleotide phosphate used by the TrxR1 to maintain the regeneration of the reduced Trx. We also demonstrated that such effects can be responsible of DEHP-induced DNA damage. K E Y W O R D S di (2-ethylhexyl) phthalate, DNA damage, oxidative stress, pentose phosphate pathway, thioredoxin system 1 | INTRODUCTION Di (2-ethylhexyl) phthalate (DEHP) is an organic compound abundantly used as a plasticizer to soften and increase the flexibility ofplastic. It has aroused public concern since the large mass of DEHPbased product frequently used like food packaging, cosmetics, perfumes, and medical devices. 1 Due to its low covalent binding to plastic polymers, DEHP can migrate from plastic matrix to foods, beverages, and even in a direct way in body fluids. 2 Therefore, exposure to this phthalate appears to be inevitable and humans may be exposed to it through digestive system and skin absorption or via inhalation. Nakamiya et al 3 reported that human body introduces around 25 mg of DEHP every day only from food. It was found that DEHP concentrations are approximately 25 mg/kg in cheese, 158 mg/kg in oily

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“…The finding that melatonin counteracted the actions of DEHP on the ovaries caused by the pollutant is in line with several other studies indicating that melatonin protects a variety of organs and cell types including adult testes and ovaries and sperm and oocytes against phthalate toxicity. 49,50 Melatonin exerts its effect through its receptors and in this regard. We report here that oocytes express significant level of MT1 receptor and the addition of DEHP promoted the expression of MT1.…”

Section: Discussionmentioning

confidence: 99%

Identification of oxidative stress–related Xdh gene as a di(2‐ethylhexyl)phthalate (DEHP) target and the use of melatonin to alleviate the DEHP‐induced impairments in newborn mouse ovaries

Liu

Yan

et al. 2019

Journal of Pineal Research

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This study, using an in vitro ovary culture model, investigates the mechanisms through which di(2‐ethylhexyl)phthalate (DEHP) impairs germ cell cyst breakdown and primordial follicle assembly. The results indicate the latter effects exerted by 10 or 100 µmol/L DEHP in cultured newborn ovaries were associated with increased levels of reactive oxygen species (ROS) and apoptosis. Based on a transcriptome analysis, we found the expression of the oxidative stress–related gene Xdh (xanthine dehydrogenase) was significantly upregulated in DEHP‐cultured ovaries. Two treatments, namely Xdh RNAi or the addition of melatonin to the ovary culture, inhibited the increase in Xdh expression and ROS levels caused by DEHP and, at the same time, reduced apoptosis and the impairment of primordial follicle assembly in the treated ovaries. Together, the results identify Xdh gene as one of the major targets of DEHP in newborn ovaries and that the consequent increased level of ROS is possibly responsible for the increment of apoptosis and primordial follicle assembly impairment. At the same time, they highlight that melatonin alleviates the effects of DEHP as with other endocrine‐disrupting compounds on the ovary.

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Evaluating the protective effects of melatonin on di(2-ethylhexyl) phthalate-induced testicular injury in adult mice

Cited by 76 publications

References 81 publications

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

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

Di (2‐ethylhexyl) phthalate targets the thioredoxin system and the oxidative branch of the pentose phosphate pathway in liver of Balb/c mice

Identification of oxidative stress–related Xdh gene as a di(2‐ethylhexyl)phthalate (DEHP) target and the use of melatonin to alleviate the DEHP‐induced impairments in newborn mouse ovaries

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