Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency

BMC Clinical Pharmacology

Malin Lindstedt²  Carl Borrebaeck²  Anna Börje¹  Henrik Johansson²  Ann-Sofie Albrekt² 

[1] Department of Chemistry and Molecular Biology, Dermatochemistry and Skin Allergy, University of Gothenburg, SE-412 96 Gothenburg, Sweden;Department of Immunotechnology, Lund University, Medicon Village building 406, 223 81 Lund, Sweden

关键词: Metabolic pathways;    Signaling pathways;    in vitro assay;    Skin sensitizer;    Pathways in skin sensitization;   

Others  :  860432
DOI  :  10.1186/2050-6511-15-5

 received in 2013-07-11, accepted in 2014-01-27,  发布年份 2014

【 摘 要 】

Background

Due to the recent European legislations posing a ban of animal tests for safety assessment within the cosmetic industry, development of in vitro alternatives for assessment of skin sensitization is highly prioritized. To date, proposed in vitro assays are mainly based on single biomarkers, which so far have not been able to classify and stratify chemicals into subgroups, related to risk or potency.

Methods

Recently, we presented the Genomic Allergen Rapid Detection (GARD) assay for assessment of chemical sensitizers. In this paper, we show how the genome wide readout of GARD can be expanded and used to identify differentially regulated pathways relating to individual chemical sensitizers. In this study, we investigated the mechanisms of action of a range of skin sensitizers through pathway identification, pathway classification and transcription factor analysis and related this to the reactive mechanisms and potency of the sensitizing agents.

Results

By transcriptional profiling of chemically stimulated MUTZ-3 cells, 33 canonical pathways intimately involved in sensitization to chemical substances were identified. The results showed that metabolic processes, cell cycling and oxidative stress responses are the key events activated during skin sensitization, and that these functions are engaged differently depending on the reactivity mechanisms of the sensitizing agent. Furthermore, the results indicate that the chemical reactivity groups seem to gradually engage more pathways and more molecules in each pathway with increasing sensitizing potency of the chemical used for stimulation. Also, a switch in gene regulation from up to down regulation, with increasing potency, was seen both in genes involved in metabolic functions and cell cycling. These observed pathway patterns were clearly reflected in the regulatory elements identified to drive these processes, where 33 regulatory elements have been proposed for further analysis.

Conclusions

This study demonstrates that functional analysis of biomarkers identified from our genomics study of human MUTZ-3 cells can be used to assess sensitizing potency of chemicals in vitro, by the identification of key cellular events, such as metabolic and cell cycling pathways.

【 授权许可】

   
2014 Albrekt et al.; licensee BioMed Central Ltd.

【 图 表 】

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