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@ARTICLE{Limonciel:142080,
      author       = {A. Limonciel and S. G. van Breda and X. Jiang$^*$ and G. D.
                      Tredwell and A. Wilmes and L. Aschauer and A. P. Siskos and
                      A. Sachinidis and H. C. Keun and A. Kopp-Schneider$^*$ and
                      T. M. de Kok and J. C. S. Kleinjans and P. Jennings},
      title        = {{P}ersistence of {E}pigenomic {E}ffects {A}fter {R}ecovery
                      {F}rom {R}epeated {T}reatment {W}ith {T}wo
                      {N}ephrocarcinogens.},
      journal      = {Frontiers in genetics},
      volume       = {9},
      issn         = {1664-8021},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DKFZ-2018-02310},
      pages        = {558},
      year         = {2018},
      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.},
      cin          = {C060},
      ddc          = {570},
      cid          = {I:(DE-He78)C060-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30559759},
      pmc          = {pmc:PMC6286959},
      doi          = {10.3389/fgene.2018.00558},
      url          = {https://inrepo02.dkfz.de/record/142080},
}