title: Applicability of a keratinocyte gene signature to predict skin sensitizing potential.
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 Nrf2-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.
authors.affiliation: Department of Toxicogenomics, Maastricht University, PO Box 616, NL-6200 MD Maastricht, The Netherlands. Jochem.van.der.Veen@rivm.nl
authors.forename: Jochem W
authors.initials: JW
authors.lastname: van der Veen
authors.forename: Tessa E
authors.initials: TE
authors.lastname: Pronk
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
authors.forename: Janine
authors.initials: J
authors.lastname: Ezendam
mesh_terms: D000485:Allergens / Q000633:toxicity*; D001681:Biological Assay; D002460:Cell Line; D017449:Dermatitis, Allergic Contact; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D023422:Skin Irritancy Tests
chemical_list: D000485:Allergens; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human