Triclocarban Disrupts the Epigenetic Status of Neuronal Cells and Induces AHR/CAR-Mediated Apoptosis
M. Kajta , A. Wnuk , J. Rzemieniec , W. Lasoń , M. Maćkowiak , E. Chwastek , M. Staniszewska , I. Nehring , Anna K. Wójtowicz
AbstractTriclocarban 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.
|Journal series||Molecular Neurobiology, ISSN 0893-7648, e-ISSN 1559-1182, (N/A 100 pkt)|
|Publication size in sheets||0.9|
|Keywords in English||Apoptosis, DNA methylation, Primary neurons, Sumoylation, Triclocarban|
|License||Journal (articles only); author's original; ; after publication|
|Publication indicators||: 2017 = 0.993; : 2018 = 4.586 (2) - 2018=4.643 (5)|
|Finansowanie||This study was financially supported by grant no. 2015/19/B/NZ7/02449 from the National Science Centre of Poland and the statutory fund of the Institute of Pharmacology at the Polish Academy of Sciences in Krakow, Poland. The publication charge was supported by KNOW funds MNiSW-DS-6002-4693-26/WA/12.|
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