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Persistence of Epigenomic Effects After Recovery From Repeated Treatment With Two Nephrocarcinogens

Limonciel, Alice; van Breda, Simone G; Jiang, Xiaoqi; Tredwell, Greg; Wilmes, Anja; Aschauer, Lydia; Siskos, Alexandros P; Sachinidis, Agapios; Keun, Hector C.; Kopp-Schneider, Annette; de Kok, Theo M

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The discovery of the epigenetic regulation of transcription has provided a new source of mechanistic understanding to long lasting effects of chemicals. However, this information is still seldom exploited in a toxicological context and studies of chemical effect after washout remain rare. Here we studied the effects of two nephrocarcinogens on the human proximal tubule cell line RPTEC/TERT1 using high-content mRNA microarrays coupled with miRNA, histone acetylation (HA) and DNA methylation (DM)...[Show more]

dc.contributor.authorLimonciel, Alice
dc.contributor.authorvan Breda, Simone G
dc.contributor.authorJiang, Xiaoqi
dc.contributor.authorTredwell, Greg
dc.contributor.authorWilmes, Anja
dc.contributor.authorAschauer, Lydia
dc.contributor.authorSiskos, Alexandros P
dc.contributor.authorSachinidis, Agapios
dc.contributor.authorKeun, Hector C.
dc.contributor.authorKopp-Schneider, Annette
dc.contributor.authorde Kok, Theo M
dc.date.accessioned2020-06-02T02:14:24Z
dc.date.available2020-06-02T02:14:24Z
dc.identifier.urihttp://hdl.handle.net/1885/204742
dc.description.abstractThe discovery of the epigenetic regulation of transcription has provided a new source of mechanistic understanding to long lasting effects of chemicals. However, this information is still seldom exploited in a toxicological context and studies of chemical effect after washout remain rare. Here we studied the effects of two nephrocarcinogens on the human proximal tubule cell line RPTEC/TERT1 using high-content mRNA microarrays coupled with miRNA, histone acetylation (HA) and DNA methylation (DM) arrays and metabolomics during a 5-day repeat-dose exposure and 3 days after washout. The mycotoxin ochratoxin A (OTA) was chosen as a model compound for its known impact on HA and DM. The foremost effect observed was the modulation of thousands of mRNAs and histones by OTA during and after exposure. In comparison, the oxidant potassium bromate (KBrO3) had a milder impact on gene expression and epigenetics. However, there was no strong correlation between epigenetic modifications and mRNA changes with OTA while with KBrO3 the gene expression data correlated better with HA for both up-and down-regulated genes. Even when focusing on the genes with persistent epigenetic modifications after washout, only half were coupled to matching changes in gene expression induced by OTA, suggesting that while OTA causes a major effect on the two epigenetic mechanisms studied, these alone cannot explain its impact on gene expression. Mechanistic analysis confirmed the known activation of Nrf2 and p53 by KBrO3, while OTA inhibited most of the same genes, and genes involved in the unfolded protein response. A few miRNAs could be linked to these effects of OTA, albeit without clear contribution of epigenetics to the modulation of the pathways at large. Metabolomics revealed disturbances in amino acid balance, energy catabolism, nucleotide metabolism and polyamine metabolism with both chemicals. In conclusion, the large impact of OTA on transcription was confirmed at the mRNA level but also with two high-content epigenomic methodologies. Transcriptomic data confirmed the previously reported activation (by KBrO3) and inhibition (by OTA) of protective pathways. However, the integration of omic datasets suggested that HA and DM were not driving forces in the gene expression changes induced by either chemical.
dc.description.sponsorshipThe study was funded by the 7th Framework project DETECTIVE (grant no. 266838 to PJ, JK, AS, HK, and AK-S), the Long Range Initiative Innovative Science Award of the European Chemical Industry Council (CEFIC, 2015 to AL), the Horizon 2020 project EU-ToxRisk (http://www.eu-toxrisk.eu/ grant no. 681002, to PJ) and the Tiroler Wissenschaftfund (Grant no. UNI-0404/1768, to AW).
dc.format.extent15 pages
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherFrontiers Media
dc.rights© 2018 Limonciel, van Breda, Jiang, Tredwell, Wilmes, Aschauer, Siskos, Sachinidis, Keun, Kopp-Schneider, de Kok, Kleinjans and Jennings. Limonciel A, van Breda SG, Jiang X, Tredwell GD, Wilmes A, Aschauer L, Siskos AP, Sachinidis A, Keun HC, Kopp-Schneider A, de Kok TM, Kleinjans JCS and Jennings P (2018) Persistence of Epigenomic Effects After Recovery From Repeated Treatment With Two Nephrocarcinogens. Front. Genet. 9:558. doi: 10.3389/fgene.2018.00558
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceFrontiers in Genetics
dc.subjectrecovery, persistence, epigenomics, stress responses, ochratoxin A, potassium bromate, nephrotoxicity, metabolomics
dc.titlePersistence of Epigenomic Effects After Recovery From Repeated Treatment With Two Nephrocarcinogens
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume9
dcterms.dateAccepted2018-10-31
dc.date.issued2018-12-03
local.identifier.absfor060404 - Epigenetics (incl. Genome Methylation and Epigenomics)
local.identifier.ariespublicationu3102795xPUB2391
local.publisher.urlhttps://www.frontiersin.org/
local.type.statusPublished Version
local.contributor.affiliationLimonciel, Alice, Vrije Universiteit Amsterdam
local.contributor.affiliationvan Breda, Simone G, Maastricht University Medical Center
local.contributor.affiliationJiang, Xiaoqi, German Cancer Research Center
local.contributor.affiliationTredwell, Gregory, College of Science, The Australian National University
local.contributor.affiliationWilmes, Anja, Vrije Universiteit Amsterdam
local.contributor.affiliationAschauer, Lydia, Medical University of Innsbruck
local.contributor.affiliationSiskos, Alexandros P, Imperial College London
local.contributor.affiliationSachinidis, Agapios, University of Cologne
local.contributor.affiliationKeun, Hector C., Imperial College (London)
local.contributor.affiliationKopp-Schneider, Annette, German Cancer Research Center
local.contributor.affiliationde Kok, Theo M, Maastricht University Medical Center
local.identifier.essn1664-8021
local.bibliographicCitation.startpage558
local.identifier.doi10.3389/fgene.2018.00558
local.identifier.absseo970111 - Expanding Knowledge in the Medical and Health Sciences
dc.date.updated2019-12-19T07:06:50Z
local.identifier.thomsonID4.52099E+11
dcterms.accessRightsOpen Access
dc.rights.licenseThis is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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