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

Alice Limonciel, Simone G van Breda, Xiaoqi Jiang, Gregory D Tredwell, Anja Wilmes, Lydia Aschauer, Alexandros P Siskos, Agapios Sachinidis, Hector C Keun, Annette Kopp-Schneider, Theo M de Kok, Jos C S Kleinjans, P. Jennings

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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) 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.

Original languageEnglish
Article number558
Pages (from-to)1-15
Number of pages15
JournalFrontiers in Genetics
Volume9
Early online date3 Dec 2018
DOIs
Publication statusPublished - 2018

Funding

The authors would like to thank Margit Henry and Tamara Rothstein, University of Cologne, for the Affymetrix microarray analysis. Funding. The 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).

FundersFunder number
7th Framework project
Horizon 2020 project EU-ToxRisk
European Chemical Industry Council
Seventh Framework Programme681002, 266838
Universität zu Köln
Landes TirolsUNI-0404/1768

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