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Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds

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Author: Briel, R.J. van de · Pennings, J.L.A. · Baken, K.A. · Pronk, T.E. · Boorsma, A. · Gottschalk, R. · Loveren, H. van
Institution: TNO Kwaliteit van Leven
Source:Toxicological Sciences, 1, 117, 81-89
Identifier: 409300
Keywords: Biology · Biomedical Research · Gene profiling · HaCaT · Irritant oxidative stress · Keratinocytes · Sensitizer · 1 chloro 2,4 dinitrobenzene · 2 propanol · benzoic acid · cinnamyl alcohol · collagen type 16 · disulfiram · dodecyl sulfate sodium · eugenol · ferritin · ferrochelatase · glucose 6 phosphate dehydrogenase · glucuronosyltransferase 1A6 · glutamate cysteine ligase · glutathione reductase · heat shock protein · heme oxygenase 1 · hexane · interleukin 6 receptor · irritant agent · isoeugenol · lactic acid · mitogen activated protein kinase · nickel sulfate · phosphogluconate dehydrogenase · salicylic acid methyl ester · thioredoxin 2 · thioredoxin reductase 1 · thioredoxin reductase 2 · transcription factor Nrf2 · article · cell viability · gene control · gene expression profiling · human · human cell · human cell culture · in vitro study · keratinocyte · oxidative stress · random forest · sensitization · support vector machine


Many chemicals can induce allergic contact dermatitis. Because evaluation of skin sensitizing potential by animal testing is prohibited for cosmetics, and screening of many chemicals is required within Registration, Evaluation, Authorisation and Restriction of Chemicals, urgent need exists for predictive in vitro assays to identify contact allergens. Keratinocytes (KC) are the first cells encountered when chemicals land on the skin. Therefore, KC form an important site of haptenization and their metabolism is likely to be important. Moreover, KC secrete mediators that affect processing and presentation of haptenized proteins by dendritic cells. To develop a KC-based in vitro assay to predict sensitizing potential of chemicals, in vitro exposure effects of eight contact sensitizers and six irritants on the KC cell line HaCaT were examined by gene profiling. Classifiers predictive of the class sensitizers or irritants were calculated, based on support vector machine (SVM) and random forest (RF) algorithms. Classifiers using high-ranking genes were 70% (SVM) and 62% (RF) accurate, based on three (SVM) and two to five (RF) features. Classifiers using oxidative stress pathway gene sets were 68-73% (SVM) and 69-71% (RF) accurate. Crossvalidation showed that the top-3 of most discriminating genes added up to 13 genes and included oxidative stress gene HMOX1 irrespective of the chemical left out. Moreover, HMOX1 was the most significantly regulated gene. Gene Set Enrichment Analysis showed upregulation of "Keap1 dependent" and "oxidative stress" gene lists. In conclusion, KC expression profiling can identify contact sensitizers, providing opportunities for nonanimal testing for sensitizing potential. Moreover, our data suggest that contact sensitizers induce the oxidative stress pathway in KC. © The Author 2010. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.