Applicability of a keratinocyte gene signature to predict skin sensitizing potential

Jochem W. van der Veen*, Tessa E. Pronk, Henk van Loveren, Janine Ezendam

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

30 Citations (Web of Science)

Abstract

There is a need to replace animal tests for the identification of skin sensitizers and currently many alternative assays are being developed that have very promising results. In this study a gene signature capable of very accurate identification of sensitizers was established in the HaCaT human keratinocyte cell line. This signature was evaluated in a separate study using six chemicals that are either local lymph node (LLNA) false-positive or false-negative chemicals in addition to nine sensitizers and four non-sensitizers. Similar studies do not apply these more difficult to classify chemicals, which show the true potential for human predictions of an assay. Although the gene signature has improved prediction accuracy compared to the LLNA, the misclassified compounds were comparable between the two assays. Gene profiling also showed a sensitizer specific response of the Nrf2-keap1 and Toll-like receptor signaling pathways. After exposure to non-sensitizing chemicals that induce either of the pathways the signature misclassified all Nr12-inducers, while the Toll-like receptor ligands were correctly classified. In conclusion, we confirm that keratinocyte based prediction assays may provide essential information on the properties of compounds. Furthermore, chemical selection is critical for assessment of the performance of in vitro alternative assays.
Original languageEnglish
Pages (from-to)314-322
JournalToxicology in Vitro
Volume27
Issue number1
DOIs
Publication statusPublished - Feb 2013

Keywords

  • Skin sensitization
  • Alternative methods
  • In vitro
  • Keratinocytes
  • Toxicogenomics

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