Activation of Trim17 by PPARγ is involved in Di(2-ethylhexyl) phthalate (DEHP)-induced apoptosis on Neuro-2a cells

Lin, Chuang-Hao; Chen, Tsan-Ju; Chen, Shun-Sheng; Hsiao, Pei-Chun; Yang, Rei-Cheng

doi:10.1016/j.toxlet.2011.08.002

Cited by 54 publications

(34 citation statements)

References 35 publications

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“…However, these phthalates have different structures, which may explain their distinct actions in neuronal cells. Similar to the effects of DBP observed in our study, DEHP and MEHP activated caspase-3 in neuro-2a cells and in neurons derived from mouse embryonic stem cells (Lim et al 2009; Lin et al 2011). More recently, Peng showed that exposure of adult mice to diisononyl phthalate increased ROS levels and caspase-3 activity and expression in brain tissues (Peng 2015).…”

Section: Discussionsupporting

confidence: 89%

Dibutyl Phthalate (DBP)-Induced Apoptosis and Neurotoxicity are Mediated via the Aryl Hydrocarbon Receptor (AhR) but not by Estrogen Receptor Alpha (ERα), Estrogen Receptor Beta (ERβ), or Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Mouse Cortical Neurons

Wójtowicz¹,

et al. 2016

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Dibutyl phthalate (di-n-butyl phthalate, DBP) is one of the most commonly used phthalate esters. DBP is widely used as a plasticizer in a variety of household industries and consumer products. Because phthalates are not chemically bound to products, they can easily leak out to enter the environment. DBP can pass through the placental and blood–brain barriers due to its chemical structure, but little is known about its mechanism of action in neuronal cells. This study demonstrated the toxic and apoptotic effects of DBP in mouse neocortical neurons in primary cultures. DBP stimulated caspase-3 and LDH activities as well as ROS formation in a concentration (10 nM–100 µM) and time-dependent (3–48 h) manner. DBP induced ROS formation at nanomolar concentrations, while it activated caspase-3 and LDH activities at micromolar concentrations. The biochemical effects of DBP were accompanied by decreased cell viability and induction of apoptotic bodies. Exposure to DBP reduced Erα and Pparγ mRNA expression levels, which were inversely correlated with protein expression of the receptors. Treatment with DBP enhanced Ahr mRNA expression, which was reflected by the increased AhR protein level observed at 3 h after exposure. ERα, ERβ, and PPARγ antagonists stimulated DBP-induced caspase-3 and LDH activities. AhR silencing demonstrated that DBP-induced apoptosis and neurotoxicity are mediated by AhR, which is consistent with the results from DBP-induced enhancement of AhR mRNA and protein expression. Our study showed that AhR is involved in DBP-induced apoptosis and neurotoxicity, while the ERs and PPARγ signaling pathways are impaired by the phthalate.

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Section: Discussionsupporting

confidence: 89%

Dibutyl Phthalate (DBP)-Induced Apoptosis and Neurotoxicity are Mediated via the Aryl Hydrocarbon Receptor (AhR) but not by Estrogen Receptor Alpha (ERα), Estrogen Receptor Beta (ERβ), or Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Mouse Cortical Neurons

Wójtowicz¹,

et al. 2016

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“…An in vitro study with a neural cell line showed that DEHP activated the Trim17 protein and led to apoptosis via PPARγ. This activation was enhanced by a PPARγ agonist (troglitazone) and was reversed by a PPARγ antagonist (GW9662) (Lin et al, ). An in vivo study also showed that there was a significantly change in PPARγ expression in the livers of mice exposed to DEHP (Schmidt et al, ).…”

Section: Discussionmentioning

confidence: 99%

The combined effects of DEHP and PCBs on phospholipase in the livers of mice

Lin

Huang

Chen

et al. 2013

Environmental Toxicology

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Di(2-ethylhexyl) phthalate (DEHP) and polychlorinated biphenyls (PCBs) are two widely distributed pollutants that are of great concern due to their adverse health effects. However, few studies have investigated the combined effects of DEHP and PCBs. In this study, adult mice were continuously exposed to mixtures of DEHP (15 mg/kg bodyweight/day) and Aroclor 1254 (7.5 mg/kg bodyweight/day) for 12 days to investigate the combined effects of these compounds. The results showed that the ratio of the liver weight to the body weight was higher in the treated group than that in the control group. The effects of combined exposure on three important receptors, the proliferator-activated receptor (PPAR), estrogen receptor (ER), and aryl hydrocarbon receptor (AHR), were investigated. The mRNA level of PPARγ was significantly up-regulated after exposure. The expression level of ERα was decreased in the male treated group. In contrast, the expression levels of AHR and related genes (cyp1a1 and cyp1b1) were not markedly affected. The expression level of phospholipase A (PLA) was significantly down-regulated at both the mRNA and protein levels in male mice after combined treatment. In all, our study demonstrated the combined effects of DEHP and PCBs on the expression levels of key receptors in mice. The combined exposure led to a decrease in phospholipase in male mice.

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“…In addition, it was reported that di(2-ethylhexyl) phthalate (DEHP) induced apoptosis of Neuro-2a cells because of activation of Trim17 [30]. Apoptosis induced by DEHP was also reported to depend on an increase in Bax content [31].…”

Section: Discussionmentioning

confidence: 99%

Diethyl Phthalate Enhances Apoptosis Induced by Serum Deprivation in PC12 Cells

Sun

Takahashi

Hosokawa

et al. 2012

Basic Clin Pharma Tox

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In this study, to examine the mechanism of diethyl phthalate toxicity to cells, the effects of diethyl phthalate on apoptosis in a PC12 cell system were investigated by assaying apoptotic factors such as caspase-3, Bax, cytochrome c and DNA damage. Diethyl phthalate was shown to enhance the apoptosis induced by serum deprivation according to the results of DNA electrophoresis and TUNEL signal assays, although it could not induce apoptosis itself in the cells. This enhancement was thought to be because of an increase in caspase-3-like activity. In addition, the expression of bax and contents of cytochrome c in the cytosol showed a tendency to increase the cells exposed to diethyl phthalate. These results indicated that diethyl phthalate, a potential endocrine disrupter, affects the apoptotic system in PC12 cells. Diethyl phthalate may enhance oxidative stress such as that induced by reactive oxygen species in PC12 cells.Phthalates (PAEs), phthalic acid esters, are used widely in industrial production of plastics and daily consumable products as plasticizers to produce polymeric materials. Recently, many studies have reported that some of them are endocrinedisrupting chemicals [1][2][3], and they exhibit toxicity and bioaccumulation [4][5][6]. Phthalates are of interest because of their potential toxicity to human beings since animal toxicity studies suggest that some PAEs affect male reproductive development, apparently via inhibition of androgen biosynthesis [7]. Phthalates, diesters of phthalic acid, are manufactured by reacting phthalic anhydride with alcohols of desired carbonchain lengths. One of the PAEs, diethyl phthalate (DEP), is widely used in personal care products, plastics and medical devices at various concentrations. However, it is toxic at high exposure levels as well as at low doses for a prolonged period. Treatment with higher concentrations of DEP results in mitochondrial proliferation as well as accumulation of glycogen, cholesterol and triglycerides within the liver, but exposure to lower concentrations for a longer period results in an increase in the number of peroxisomes leading to severe hepatocellular changes [8].The potential for exposure is, to a certain extent, a consequence of the physical and chemical properties of each phthalate. As molecular weight increases, vapour pressure, water solubility and dermal uptake are reduced [9,10]. The major route of human exposure to most PAEs is ingestion. Exposure by inhalation, through drinking water and via dermal contact tends to be limited [11]. After ingestion, PAEs are metabolized to their corresponding hydrolytic monoesters and may further metabolize to more hydrophilic oxidative products. These metabolites can be excreted unchanged or can undergo phase II biotransformation to glucuronide conjugates [12].Bioanalysis for toxicity of DEP is considered important for clarification of its effects on future generations. Continuous exposure to DEP through food, gestation and lactation over three generations, in spite of dose reduction, ...

show abstract

Activation of Trim17 by PPARγ is involved in Di(2-ethylhexyl) phthalate (DEHP)-induced apoptosis on Neuro-2a cells

Cited by 54 publications

References 35 publications

Dibutyl Phthalate (DBP)-Induced Apoptosis and Neurotoxicity are Mediated via the Aryl Hydrocarbon Receptor (AhR) but not by Estrogen Receptor Alpha (ERα), Estrogen Receptor Beta (ERβ), or Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Mouse Cortical Neurons

Dibutyl Phthalate (DBP)-Induced Apoptosis and Neurotoxicity are Mediated via the Aryl Hydrocarbon Receptor (AhR) but not by Estrogen Receptor Alpha (ERα), Estrogen Receptor Beta (ERβ), or Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Mouse Cortical Neurons

The combined effects of DEHP and PCBs on phospholipase in the livers of mice

Diethyl Phthalate Enhances Apoptosis Induced by Serum Deprivation in PC12 Cells

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