Triclocarban disrupts the epigenetic status of neuronal cells and induces AHR/CAR-mediated apoptosis

M. Kajta , A. Wnuk , J. Rzemieniec , W. Lason , M. Mackowiak , E. Chwastek , Marta Staniszewska , Iga Nehring , A. K. Wojtowicz

Abstract

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.
Author M. Kajta
M. Kajta,,
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, A. Wnuk
A. Wnuk,,
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, J. Rzemieniec
J. Rzemieniec,,
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, W. Lason
W. Lason,,
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, M. Mackowiak
M. Mackowiak,,
-
, E. Chwastek
E. Chwastek,,
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, Marta Staniszewska (FOG / IO / DMChEP)
Marta Staniszewska,,
- Division of Marine Chemistry and Environmental Protection
, Iga Nehring (FOG / IO / DMChEP)
Iga Nehring,,
- Division of Marine Chemistry and Environmental Protection
, A. K. Wojtowicz
A. K. Wojtowicz,,
-
Journal seriesMolecular Neurobiology, ISSN 0893-7648, (N/A 100 pkt)
Issue year2019
Vol56
No5
Pages3113-3131
Publication size in sheets0.9
Keywords in Englishapoptosis, DNA methylation, primary neurons, sumoylation, triclocarban
ASJC Classification2804 Cellular and Molecular Neuroscience
DOIDOI:10.1007/s12035-018-1285-4
URL https://doi.org/10.1007/s12035-018-1285-4
Languageen angielski
LicenseOther; published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)100
Score sourcejournalList
ScoreMinisterial score = 100.0, 17-11-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2017 = 0.993; WoS Impact Factor: 2018 = 4.586 (2) - 2018=4.643 (5)
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