Ingestion of Bis(2-ethylhexyl) phthalate (DEHP) during adolescence causes depressive-like behaviors through hypoactive glutamatergic signaling in the medial prefrontal cortex

Kang, Jae Soon; Baek, Ji Hyeong; Jung, Soonwoong; Chung, Hanshik; Lee, Dong Kun; Kim, Hyun Joon

doi:10.1016/j.envpol.2021.117978

Cited by 16 publications

(15 citation statements)

References 51 publications

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“…We also investigated the effects of insulin treatment on Glu and Gln levels and found no significant differences between the STZ and SI groups ( Figure 8 a). Previously, we demonstrated that hypoactive glutamatergic signaling causes depressive behaviors [ 10 , 11 , 14 ]. Therefore, we hypothesized that the depressive-like behaviors of the SI group were due to hypoactive glutamatergic signaling in the mPFC, even when Glu and Gln levels were sufficient.…”

Section: Resultsmentioning

confidence: 99%

“…In the present study, we also confirmed that STZ-induced hyperglycemia caused depressive-like behaviors with social interactive, anhedonic, and despair behavioral changes ( Figure 1 and Figure 2 ). It is known that decreased activity of glutamatergic neurotransmission can lead to depressive and anhedonic behaviors [ 10 , 11 ]. However, despite the decrease in glutamatergic neurotransmission in the STZ mice, there was no change in GS activity, and the Gln level was increased in the PFC.…”

Section: Discussionmentioning

confidence: 99%

“…Animals were given free access to laboratory chow and water under a 12 h light/dark cycle (lights on at 06:00 a.m.) at a constant temperature (25 ± 2 °C). For electrophysiologic experiments, we used VGLUT2-CRE::tdTomato or VGLUT2-CRE::EGFP mice developed in our previous study [ 10 , 11 ]. These animals express fluorescent proteins in cells expressing the VGLUT2 protein, which are predominantly glutamatergic neurons.…”

Section: Methodsmentioning

confidence: 99%

“…The Y-maze test was performed to evaluate exploratory behavior and memory, as described in a previous study [ 13 ]. Social interaction tests were also performed as described previously [ 11 ]. The sucrose preference test (SPT), tail suspension test (TST), and female urine sniffing test (FUST) were performed to identify symptoms of anhedonia and despair, as previously described [ 13 , 14 ].…”

Section: Methodsmentioning

confidence: 99%

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Long-Term Hyperglycemia Causes Depressive Behaviors in Mice with Hypoactive Glutamatergic Activity in the Medial Prefrontal Cortex, Which Is Not Reversed by Insulin Treatment

Baek

Son

Kang

et al. 2022

Cells

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The etiology of hyperglycemic-induced depressive behaviors is unclear. We hypothesized that long-term hyperglycemia may induce long-lasting disturbances in glutamatergic signaling and neural damages, causing depressive behaviors. To prove our hypothesis, a C57BL/6N mouse model of hyperglycemia was maintained for 4 weeks (equivalent to approximately 3 years in humans), after which insulin treatment was administered for an additional 4 weeks to normalize hyperglycemia-induced changes. Hyperglycemic mice showed depressive-like behaviors. Glutamatergic neurons and glial cells in the medial prefrontal cortex (mPFC) were affected by hyperglycemia. Insulin treatment improved blood glucose, water intake, and food intake to normoglycemic levels, but did not improve depressive-like behaviors. Glutamatergic signaling decreased with long-term hyperglycemia and did not normalize with insulin-induced normoglycemia. Importantly, hyperglycemia-induced changes in the mPFC were almost not reversed by the 4-week insulin treatment. In particular, levels of insulin receptor beta subunit (IRβ), IRS-1, vesicular glutamate transporter 1, glutamine transporter SNAT2, phosphate-activated glutaminase, and GLUT-3 were not changed by insulin. Nitration and the dephosphorylation of IRβ in the PFC also did not improve with insulin treatment. Therefore, our results suggest that hypoactive glutamatergic activity in the mPFC is involved in diabetic-associated depressive behaviors, and it is difficult to cure with glycemic regulation alone.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Long-Term Hyperglycemia Causes Depressive Behaviors in Mice with Hypoactive Glutamatergic Activity in the Medial Prefrontal Cortex, Which Is Not Reversed by Insulin Treatment

Baek

Son

Kang

et al. 2022

Cells

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“…In brief, 6-week-old mice were randomly divided into four groups (15 mice per group), namely, a control group (C group, fed normal diet freely), di-(2-ethylhexyl) phthalate group (DEHP group, mice were fed food containing 200 mg/kg DEHP and normal water), polystyrene microplastic group (MP group, mice were fed normal food and water containing 10 mg/L MPs), and DEHP +MPs group (mice were fed food containing 200 mg/kg DEHP and water containing 10 mg/L MPs). For the dosage of DEHP and MPs, previous studies were used as a reference. − DEHP was purchased from Adamas-β company (Shanghai, China) and its structural formula is shown in Figure A. MPs (1–10 μm in size) were bought from Mingshuo Chemical Company (Linyi, China).…”

Section: Methodsmentioning

confidence: 99%

Di-(2-Ethylhexyl) Phthalate and Microplastics Induced Neuronal Apoptosis through the PI3K/AKT Pathway and Mitochondrial Dysfunction

Zhang

Sun

et al. 2022

J. Agric. Food Chem.

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Di-(2-Ethylhexyl) phthalate (DEHP) and microplastics (MPs) have released widespread residues to the environment and possess the ability to cause damage to humans and animals. However, there are still gaps in the study of damage to neurons caused by DEHP and MPs in mice cerebra and whether they have combined toxic effects. To investigate the underlying mechanism of action, mice were fed 200 mg/kg DEHP and 10 mg/L MPs in vivo. In vitro, NS20Y (CBNumber: CB15474825) cells were treated with 25 μM DEHP and 775 mg/L MPs. Next, qRT-PCR and western blot analysis were performed to evaluate PI3K/AKT pathway genes, mitochondrial dynamics-related genes, apoptosis-related genes, and GSK-3β and its associated genes, mRNA, and protein expression. To determine pathological changes in the mice cerebra, hematoxylin and eosin (H&E) staining, transmission electron microscopy, and TUNEL staining were employed. To determine the levels of reactive oxygen species (ROS) and apoptosis cells in vitro, ROS staining, acridine orange/ethidium bromide (AO/EB) staining, and flow cytometry were performed. Our results demonstrated that DEHP and MPs caused changes in mitochondrial function, and GSK-3β and its associated gene expression in mice through the PI3K/AKT pathway, which eventually led to apoptosis of neurons. Moreover, our findings showed that DEHP and MPs have a combined toxic effect on mice cerebra. Our findings facilitate the understanding of the neurotoxic effects of DEHP and MPs on neurons in the cerebra of mice and help identify the important role of maintaining normal mitochondrial function in protecting cerebrum health.

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Mitigating effect of ferulic acid on di-(2-ethylhexyl) phthalate-induced neurocognitive dysfunction in male rats with a comprehensive in silico survey

Khalifa,

Fayed,

Ahmed

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Di-(2-ethylhexyl) phthalate (DEHP) is the most abundant phthalate threatening public health-induced neurotoxicity. This neurotoxicity is associated with behavioral and biochemical deficits in male rats. Our study investigated the neuroprotective effect of ferulic acid (FA) on male rats exposed to DEHP. Thirty-two male Wistar rats were assigned to four groups. Group I control rats received corn oil, group II intoxicated rats received 300 mg/kg of DEHP, group III received 300 mg/kg of DEHP + 50 mg/kg of FA, and group IV received 50 mg/kg of FA, all agents administrated daily per os for 30 days. Anxiety-like behavior, spatial working memory, and recognition memory were assessed. Also, brain oxidative stress biomarkers, including brain malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), brain-derived neurotrophic factor (BDNF) as well as heme oxygenase-1 (HO-1) were measured. Moreover, brain histopathology examinations associated with immunohistochemistry determination of brain caspase-3 were also evaluated. Furthermore, docking simulation was adapted to understand the inhibitory role of FA on caspase-3 and NO synthase. Compared to DEHP-intoxicated rats, FA-treated rats displayed improved cognitive memory associated with a reduced anxious state. Also, the redox state was maintained with increased BNDF levels. These changes were confirmed by restoring the normal architecture of brain tissue and a decrement in the immunohistochemistry caspase-3. In conclusion, FA has potent antioxidant and antiapoptotic properties that confirm the neuroprotective activity of FA, with a possible prospect for its therapeutic capabilities and nutritional supplement value.

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Ingestion of Bis(2-ethylhexyl) phthalate (DEHP) during adolescence causes depressive-like behaviors through hypoactive glutamatergic signaling in the medial prefrontal cortex

Cited by 16 publications

References 51 publications

Long-Term Hyperglycemia Causes Depressive Behaviors in Mice with Hypoactive Glutamatergic Activity in the Medial Prefrontal Cortex, Which Is Not Reversed by Insulin Treatment

Long-Term Hyperglycemia Causes Depressive Behaviors in Mice with Hypoactive Glutamatergic Activity in the Medial Prefrontal Cortex, Which Is Not Reversed by Insulin Treatment

Di-(2-Ethylhexyl) Phthalate and Microplastics Induced Neuronal Apoptosis through the PI3K/AKT Pathway and Mitochondrial Dysfunction

Mitigating effect of ferulic acid on di-(2-ethylhexyl) phthalate-induced neurocognitive dysfunction in male rats with a comprehensive in silico survey

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