Title
Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds
Author
van de Briel, R.J.
Pennings, J.L.A.
Baken, K.A.
Pronk, T.E.
Boorsma, A.
Gottschalk, R.
van Loveren, H.
TNO Kwaliteit van Leven
Publication year
2010
Abstract
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.
Subject
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
To reference this document use:
http://resolver.tudelft.nl/uuid:7f7947b5-4953-4fa1-bbf2-6b32bad5e732
TNO identifier
409300
ISSN
1096-6080
Source
Toxicological Sciences, 117 (1), 81-89
Document type
article