Maternal exposure to di-(2-ethylhexyl) phthalate disrupts placental growth and development in pregnant mice

Zong, Teng; Lai, Lidan; Hu, Jia; Guo, Meijun; Li, Mo; Zhang, Lu; Zhong, Chengxue; Yang, Bei; Wu, Lei; Zhang, Dalei; Tang, Min; Kuang, Haibin

doi:10.1016/j.jhazmat.2015.04.065

Cited by 95 publications

(59 citation statements)

References 31 publications

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“…Our study demonstrated that DEHP induced apoptosis by decreasing in the ΔΨm and increasing in the caspase‐3 expression. These findings supported that DEHP induced an apoptotic activity as described by Zong et al who demonstrated that this phthalate‐induced apoptosis in pregnant mice placenta as revealed by significant downregulation of Bcl‐2 and upregulation of Bax and caspase‐3 mRNA expression and protein.…”

Section: Discussionsupporting

confidence: 86%

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: 86%

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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“…Dosages were adjusted daily for body weight changes. The dosage levels of DEHP were based on previous studies, which included the teratogenic range of DEHP on mice (Li et al, ; Niermann, Rattan, Brehm, & Flaws, ; Zong et al, ). However, the intervention doses used might be much higher than that in human daily life.…”

Section: Methodsmentioning

confidence: 99%

The effect of maternal exposure to di‐(2‐ethylhexyl)‐phthalate on fetal cardiac development in mice

Tang

Deng²,

Duan

et al. 2018

J of Applied Toxicology

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Accumulating evidence has suggested a link between maternal di-(2-ethylhexyl)-phthalate (DEHP) exposure and various developmental abnormalities. However, the evidence regarding the effect of maternal DEHP exposure on fetal cardiac development is scarce. The present study aimed to determine the effect of maternal DEHP exposure on fetal cardiac development in mice and explore the possible involved mechanism preliminarily. The C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 250 mg kg DEHP group (n = 15), 500 mg kg DEHP group (n = 20) and 1 g kg DEHP group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from embryonic day (E)6.5 to E14.5. Maternal weights were monitored every day and samples were collected at E15.5. Hematoxylin and eosin staining was used to examine fetal cardiac malformations. Real-time quantitative polymerase chain reaction and western blot were applied to detect peroxisome proliferator-activated receptor (PPAR)α/PPARγ/Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. Maternal DEHP exposure significantly decreased maternal body weight, fetal weight and placental weight, and remarkably elevated fetal cardiac malformations rate. The phenotypes of cardiac anomalies mainly include septal defects, ventricular myocardium noncompaction and cardiac hypoplasia. Higher doses DEHP (500 mg kg and 1 g kg ) could significantly decreased fetal cardiac Gata4/Mef2c/Chf1 expression, while PPARγ expression was upregulated. Maternal exposure to higher doses of DEHP could result in fetal cardiac development malformations in mice and it might have resulted from the inhibition of cardiac GATA4/Mef2c/Chf1 expression via PPARγ activation.

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“…30 In di-(2-ethylhexyl) phthalate-treated placenta, the area of spongiotrophoblast and expression levels of Ascl2 mRNA dramatically decreased in mice on GD 13. 20 However, the area of placental spongiotrophoblast significantly increased in the 10 mg/kg/day TiO 2 NP group compared to control group. This suggested that the development of spongiotrophoblast with exposure to TiO 2 NPs was not closely related to the downregulation of Ascl2.…”

mentioning

confidence: 84%

Gestational exposure to titanium dioxide nanoparticles impairs the placentation through dysregulation of vascularization, proliferation and apoptosis in mice

Zhang

Xie

Zhou

et al. 2018

IJN

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Background Titanium dioxide nanoparticles (TiO 2 NPs) have recently found applications in a wide variety of consumer goods. TiO 2 NPs exposure significantly increases fetal deformities and mortality. However, the potential toxicity of TiO 2 NPs on the growth and development of placenta has been rarely studied during mice pregnancy. Purpose The objective of this study was to investigate the effects of maternal exposure of TiO 2 NPs on the placentation. Methods Mice were administered TiO 2 NPs by gavage at 0, 1 and 10 mg/kg/day from gestational day (GD) 1 to GD 13. Uteri and placentas from these mice were collected and counted the numbers of implanted and resorbed embryo and measured the placental weight on GD 13. Placental morphometry was observed by hematoxylin and eosin staining. The levels of Hand1, Esx1 , Eomes , Hand2 , Ascl2 and Fra1 mRNA were assessed by qRT-PCR. Uterine NK (uNK) cells were detected by using DBA lectin. Laminin immunohistochemical staining was to identify fetal vessels. Western blotting and transmission electron micrograph (TEM) were used to assess the apoptosis of placenta. Results No treatment-related difference was observed in the numbers of implanted and resorbed embryos and weight of placenta between the groups. However, 1 mg/kg/day TiO 2 NPs treatment significantly reduced the ratio of placenta/body weight on GD 13. The proportion of spongiotrophoblast in the 10 mg/kg/day dose group became higher than that in the control group, yet that of labyrinth was significantly lower in 10 mg/kg/day mice. The expression levels of Hand1 , Esx1 , Eomes , Hand2 , Ascl2 and Fra1 mRNA markedly decreased in TiO 2 NP treated placentas. Furthermore, TiO 2 NPs treatment impaired the formation of intricate networks of fetal vessels and reduced the number of uNK cells, and inhibited proliferation and induced apoptosis of placenta by nuclear pyknosis, the activation of caspase-3 and upregulation of Bax protein and downregulation of Bcl-2 protein on GD 13. Conclusion Gestational exposure to TiO 2 NPs significantly impairs the growth and development of placenta in mice, with a mechanism that seems to be involved in the dysregulation of vascularization, proliferation and apoptosis. Therefore, our results suggested the need for great caution while handling of the nanomaterials by workers and specially pregnant consumers.

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Maternal exposure to di-(2-ethylhexyl) phthalate disrupts placental growth and development in pregnant mice

Cited by 95 publications

References 31 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

The effect of maternal exposure to di‐(2‐ethylhexyl)‐phthalate on fetal cardiac development in mice

Gestational exposure to titanium dioxide nanoparticles impairs the placentation through dysregulation of vascularization, proliferation and apoptosis in mice

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