Autophagy-related neurotoxicity is mediated via AHR and CAR in mouse neurons exposed to DDE

Wnuk, Agnieszka; Rzemieniec, Joanna; Przepiórska, Karolina; Wesołowska, Julita; Wójtowicz, Anna K.; Kajta, Małgorzata

doi:10.1016/j.scitotenv.2020.140599

Cited by 12 publications

(5 citation statements)

References 57 publications

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“…As an organochlorine pesticide strongly associated with AD, DDT has been extensively used as a broad-spectrum insecticide in agriculture since World War II (Davies et al, 2007 ; Greenwood, 2014 ). The common use of DDT in agriculture was banned in the 1970s–1980s, but DDT is still used for controlling disease vectors responsible for malaria and the Zika virus in developing countries (Wnuk et al, 2020 ). DDT is known to bioaccumulate in human and is negatively associated with cognitive scores (Kiyosawa et al, 2008 ; Kim et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression

Song

et al. 2021

Front. Aging Neurosci.

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Abnormal amyloid beta (Aβ) clearance is a distinctive pathological mechanism for Alzheimer’s disease (AD). ATP-binding cassette transporter A1 (ABCA1), which mediates the lipidation of apolipoprotein E, plays a critical role in Aβ clearance. As an environmental factor for AD, dichlorodiphenyltrichloroethane (DDT) can decrease ATP-binding cassette transporter A1 (ABCA1) expression and disrupt Aβ clearance. Liver X receptor α (LXRα) is an autoregulatory transcription factor for ABCA1 and a target of some environmental pollutants, such as organophosphate pesticides. In this study, we aimed to investigate whether DDT could affect Aβ clearance by targeting LXRα. The DDT-pretreated H4 human neuroglioma cells and immortalized astrocytes were incubated with exogenous Aβ to evaluate Aβ consumption. Meanwhile, cytotoxicity and LXRα expression were determined in the DDT-treated cells. Subsequently, the antagonism of DDT on LXRα agonist T0901317 was determined in vitro. The interaction between DDT and LXRα was predicted by molecular docking and molecular dynamics simulation technology. We observed that DDT could inhibit Aβ clearance and decrease the levels of LXRα mRNA and LXRα protein. Moreover, DDT is supposed to strongly bind to LXRα and exert antagonistic effects on LXRα. In conclusion, this study firstly presented that DDT could inhibit LXRα expression, which would contribute to Aβ clearance decline in vitro. It provides an experimental basis to search for potential therapeutic targets of AD.

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Section: Discussionmentioning

confidence: 99%

Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression

Song

et al. 2021

Front. Aging Neurosci.

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“…The amounts of RNA were determined spectrophotometrically at 260 nm and 260/280 nm (ND/1000 UV/Vis; Thermo Fisher NanoDrop, Waltham, MA, USA). Reverse transcription (RT) and quantitative polymerase chain reaction (qPCR) were performed using the CFX96 Real-Time System (Bio-Rad, Hercules, CA, USA) as previously described [ 34 , 35 , 36 ]. High-capacity cDNA reverse transcription kits, the TaqMan Gene Expression Master Mix kit and TaqMan probes (Thermo Fisher Scientific, Waltham, MA, USA), were used to transcribe and amplify the specific genes.…”

Section: Methodsmentioning

confidence: 99%

“…To prepare samples for Western blot analyses, mouse prefrontal cortices were lysed, sonicated, and centrifuged for 20 min. Individual samples containing 40 µg of total protein were reconstituted in appropriate amounts of sample buffer, denatured, and separated on 7.5% SDS-polyacrylamide gels using a Bio-Rad Mini-Protean II Electrophoresis Cell as previously described [ 36 , 41 , 42 ]. The separated proteins were electrotransferred to PVDF membranes using a Bio-Rad Mini Trans-Blot apparatus, and nonspecific binding sites were blocked with 5% dry milk and 0.2% Tween-20 in 0.02 M TBS (Tris-buffered saline) for 2 h with shaking.…”

Section: Methodsmentioning

confidence: 99%

Prenatal Exposure to Triclocarban Impairs ESR1 Signaling and Disrupts Epigenetic Status in Sex-Specific Ways as Well as Dysregulates the Expression of Neurogenesis- and Neurotransmitter-Related Genes in the Postnatal Mouse Brain

Wnuk

Rzemieniec

Przepiórska

et al. 2021

IJMS

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Triclocarban is a highly effective and broadly used antimicrobial agent. Humans are continually exposed to triclocarban, but the safety of prenatal exposure to triclocarban in the context of neurodevelopment remains unknown. In this study, we demonstrated for the first time that mice that had been prenatally exposed to environmentally relevant doses of triclocarban had impaired estrogen receptor 1 (ESR1) signaling in the brain. These mice displayed decreased mRNA and protein expression levels of ESR1 as well as hypermethylation of the Esr1 gene in the cerebral cortex. Prenatal exposure to triclocarban also diminished the mRNA expression of Esr2, Gper1, Ahr, Arnt, Cyp19a1, Cyp1a1, and Atg7, and the protein levels of CAR, ARNT, and MAP1LC3AB in female brains and decreased the protein levels of BCL2, ARNT, and MAP1LC3AB in male brains. In addition, exposure to triclocarban caused sex-specific alterations in the methylation levels of global DNA and estrogen receptor genes. Microarray and enrichment analyses showed that, in males, triclocarban dysregulated mainly neurogenesis-related genes, whereas, in females, the compound dysregulated mainly neurotransmitter-related genes. In conclusion, our data identified triclocarban as a neurodevelopmental risk factor that particularly targets ESR1, affects apoptosis and autophagy, and in sex-specific ways disrupts the epigenetic status of brain tissue and dysregulates the postnatal expression of neurogenesis- and neurotransmitter-related genes.

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“…132 Metabolites of the pesticide DDT induce AHR-dependent neurotoxicity. 137 Finally, AHR has been proposed to participate in oligodendrocyte differentiation. 138 These findings indicate that AHR participates in the regulation of endothelial cells, neurons and oligodendrocytes in health and disease, though further studies are needed to identify the specific mechanisms involved.…”

Section: Modulation Of Inflammation In the Central Nervous System (Cns)mentioning

confidence: 99%

The aryl hydrocarbon receptor and the gut–brain axis

et al. 2021

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor initially identified as the receptor for dioxin. Almost half a century after its discovery, AHR is now recognized as a receptor for multiple physiological ligands, with important roles in health and disease. In this review, we discuss the role of AHR in the gut–brain axis and its potential value as a therapeutic target for immune-mediated diseases.

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Autophagy-related neurotoxicity is mediated via AHR and CAR in mouse neurons exposed to DDE

Cited by 12 publications

References 57 publications

Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression

Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression

Prenatal Exposure to Triclocarban Impairs ESR1 Signaling and Disrupts Epigenetic Status in Sex-Specific Ways as Well as Dysregulates the Expression of Neurogenesis- and Neurotransmitter-Related Genes in the Postnatal Mouse Brain

The aryl hydrocarbon receptor and the gut–brain axis

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