A novel nuclear xenobiotic receptors (AhR/PXR/CAR)-mediated mechanism of DEHP-induced cerebellar toxicity in quails ( Coturnix japonica ) via disrupting CYP enzyme system homeostasis

Du, Zheng-Hai; Xia, Jun; Sun, Xiaochen; Li, Xue-Nan; Zhang, Cong; Zhao, Hua-Shan; Zhu, Shi-Yong; Li, Jinlong

doi:10.1016/j.envpol.2017.04.015

Cited by 75 publications

(35 citation statements)

References 51 publications

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“…We also provided evidence for an essential role of AHR signaling in the propagation of deleterious effects of the pesticide DDT, triclosan, and hypoxia [ 16 – 18 ] and a participation of CAR in nonylphenol-induced apoptosis and neurotoxicity [ 22 ]. Recently, Du et al [ 23 ] showed that AHR and CAR play roles in di-(2-ethylhexyl)-phthalate-induced cerebellar toxicity in quails. In the present study, triclocarban-stimulated functioning of the receptors was correlated with an increase in their protein levels after a prolonged 24-h exposure and a disruption of neurite outgrowth in neocortical neurons.…”

Section: Discussionmentioning

confidence: 99%

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Triclocarban Disrupts the Epigenetic Status of Neuronal Cells and Induces AHR/CAR-Mediated Apoptosis

et al. 2018

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Triclocarban is a phenyl ether that has recently been classified as a contaminant of emerging concern. Evidence shows that triclocarban is present in human tissues, but little is known about the impact of triclocarban on the nervous system, particularly at early developmental stages. This study demonstrated that triclocarban that was used at environmentally relevant concentrations induced apoptosis in mouse embryonic neurons, inhibited sumoylation, and changed the epigenetic status, as evidenced by impaired activities of HDAC, sirtuins, and DNMT, global DNA hypomethylation, and alterations of methylation levels of bax, bcl2, Ahr, and Car genes. The use of selective antagonists and specific siRNAs, which was followed by the co-localization of aryl hydrocarbon receptor (AHR) and constitutive androstane receptor (CAR) in mouse neurons, points to the involvement of AHR and CAR in triclocarban-induced neurotoxicity. A 24-h treatment with triclocarban enhanced protein levels of the receptors which was paralleled by Car hypomethylation and Ahr hypermethylation. Car hypomethylation is in line with global DNA hypomethylation and explains the increased mRNA and protein levels of CAR in response to triclocarban. Ahr hypermethylation could reflect reduced Ahr mRNA expression and corresponds to lowered protein levels after 3- and 6-h exposures to triclocarban that is likely related to proteasomal degradation of activated AHR. We hypothesize that the triclocarban-induced apoptosis in mouse neurons and the disruption of epigenetic status involve both AHR- and CAR-mediated effects, which may substantiate a fetal basis of the adult onset of neurological diseases; however, the expression of the receptors is regulated in different ways.

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Section: Discussionmentioning

confidence: 99%

“…Our previous data demonstrated the presence of CAR in mouse neurons undergoing nonylphenol-induced apoptosis [ 22 ]. Recently, a novel mechanism that involves AHR and CAR signaling in di-(2-ethylhexyl)-phthalate-induced cerebellar toxicity has been recognized [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Triclocarban Disrupts the Epigenetic Status of Neuronal Cells and Induces AHR/CAR-Mediated Apoptosis

et al. 2018

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“…CYP3A4 is a well-known oxidative enzyme that is mostly involved in the metabolism of xenobiotics, and is the most expressed isoform in human liver [ 30 ]. Its metabolic role in the CNS is still unclear, yet its genetic regulation can be mediated by the pregnane X receptor in both the liver and brain [ 31 , 32 ]. Due to its wide range of metabolic activity, it has been also related with drug–drug interaction of CNS-drugs, such as co-administration of sertraline and carbamazepine [ 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

β-Naphtoflavone and Ethanol Induce Cytochrome P450 and Protect towards MPP+ Toxicity in Human Neuroblastoma SH-SY5Y Cells

Fernandez-Abascal

Ripullone

Valeri

et al. 2018

IJMS

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Cytochrome P450 (CYP) isozymes vary their expression depending on the brain area, the cell type, and the presence of drugs. Some isoforms are involved in detoxification and/or toxic activation of xenobiotics in central nervous system. However, their role in brain metabolism and neurodegeneration is still a subject of debate. We have studied the inducibility of CYP isozymes in human neuroblastoma SH-SY5Y cells, treated with β-naphtoflavone (β-NF) or ethanol (EtOH) as inducers, by qRT-PCR, Western blot (WB), and metabolic activity assays. Immunohistochemistry was used to localize the isoforms in mitochondria and/or endoplasmic reticulum (ER). Tetrazolium (MTT) assay was performed to study the role of CYPs during methylphenyl pyridine (MPP+) exposure. EtOH increased mRNA and protein levels of CYP2D6 by 73% and 60% respectively. Both β-NF and EtOH increased CYP2E1 mRNA (4- and 1.4-fold, respectively) and protein levels (64% both). The 7-ethoxycoumarin O-deethylation and dextromethorphan O-demethylation was greater in treatment samples than in controls. Furthermore, both treatments increased by 22% and 18%, respectively, the cell viability in MPP+-treated cells. Finally, CYP2D6 localized at mitochondria and ER. These data indicate that CYP is inducible in SH-SY5Y cells and underline this in vitro system for studying the role of CYPs in neurodegeneration.

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“…This gene encodes monooxygenases, one of the cytochrome P450 proteins which catalyze reactions involved in drug metabolism and in the synthesis of steroid hormone signaling [ 118 ]. Moreover, the CYP system is one of the main targets of different nuclear xenobiotic receptors, directing different pathways of xenobiotics metabolism [ 119 , 120 ]. These processes may also have an indirect link to endocrine disruption by binding to estrogenic hormone receptors in the worm [ 121 ], especially since BPA is an estrogen-receptor ligand [ 122 ] that has been shown to transcriptionally activate the CYP2C9 promoter [ 123 ].…”

Section: Discussionmentioning

confidence: 99%

Toxic Effects of Bisphenol A, Propyl Paraben, and Triclosan on Caenorhabditis elegans

Espiñeira

Benítez

Olívero-Verbel

2018

IJERPH

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Bisphenol A (BPA) is a ubiquitous plasticizer which is absorbed by ingestion and dermal contact; propyl paraben (PPB) inhibits the microbiome and extends the shelf life of many personal care products, whereas triclosan (TCS) is commonly found in antiseptics, disinfectants, or additives. In this work, Caenorhabditis elegans was used as a biological model to assess the toxic effects of BPA, PPB, and TCS. The wild type strain, Bristol N2, was used in bioassays with the endpoints of lethality, growth, and reproduction; green fluorescent protein (GFP) transgenic strains with the hsp-3, hsp-4, hsp-16.2, hsp-70, sod-1, sod-4, cyp-35A4, cyp-29A2, and skn-1 genes were evaluated for their mRNA expression through fluorescence measurement; and quick Oil Red O (q ORO) was utilized to stain lipid deposits. Lethality was concentration-dependent, while TCS and PPB showed more toxicity than BPA. BPA augmented worm length, while PPB reduced it. All toxicants moderately increased the width and the width–length ratio. BPA and PPB promoted reproduction, in contrast to TCS, which diminished it. All toxicants affected the mRNA expression of genes related to cellular stress, control of reactive oxygen species, and nuclear receptor activation. Lipid accumulation occurred in exposed worms. In conclusion, BPA, PPB, and TCS alter the physiology of growth, lipid accumulation, and reproduction in C. elegans, most likely through oxidative stress mechanisms.

show abstract

A novel nuclear xenobiotic receptors (AhR/PXR/CAR)-mediated mechanism of DEHP-induced cerebellar toxicity in quails ( Coturnix japonica ) via disrupting CYP enzyme system homeostasis

Cited by 75 publications

References 51 publications

Triclocarban Disrupts the Epigenetic Status of Neuronal Cells and Induces AHR/CAR-Mediated Apoptosis

Triclocarban Disrupts the Epigenetic Status of Neuronal Cells and Induces AHR/CAR-Mediated Apoptosis

β-Naphtoflavone and Ethanol Induce Cytochrome P450 and Protect towards MPP+ Toxicity in Human Neuroblastoma SH-SY5Y Cells

Toxic Effects of Bisphenol A, Propyl Paraben, and Triclosan on Caenorhabditis elegans

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