Cargando…

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

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 biomarker...

Descripción completa

Detalles Bibliográficos
Autores principales: Albrekt, Ann-Sofie, Johansson, Henrik, Börje, Anna, Borrebaeck, Carl, Lindstedt, Malin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932014/
https://www.ncbi.nlm.nih.gov/pubmed/24517095
http://dx.doi.org/10.1186/2050-6511-15-5
_version_ 1782304740302913536
author Albrekt, Ann-Sofie
Johansson, Henrik
Börje, Anna
Borrebaeck, Carl
Lindstedt, Malin
author_facet Albrekt, Ann-Sofie
Johansson, Henrik
Börje, Anna
Borrebaeck, Carl
Lindstedt, Malin
author_sort Albrekt, Ann-Sofie
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3932014
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-39320142014-02-23 Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency Albrekt, Ann-Sofie Johansson, Henrik Börje, Anna Borrebaeck, Carl Lindstedt, Malin BMC Pharmacol Toxicol Research Article 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. BioMed Central 2014-02-11 /pmc/articles/PMC3932014/ /pubmed/24517095 http://dx.doi.org/10.1186/2050-6511-15-5 Text en Copyright © 2014 Albrekt et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Albrekt, Ann-Sofie
Johansson, Henrik
Börje, Anna
Borrebaeck, Carl
Lindstedt, Malin
Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency
title Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency
title_full Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency
title_fullStr Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency
title_full_unstemmed Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency
title_short Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency
title_sort skin sensitizers differentially regulate signaling pathways in mutz-3 cells in relation to their individual potency
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932014/
https://www.ncbi.nlm.nih.gov/pubmed/24517095
http://dx.doi.org/10.1186/2050-6511-15-5
work_keys_str_mv AT albrektannsofie skinsensitizersdifferentiallyregulatesignalingpathwaysinmutz3cellsinrelationtotheirindividualpotency
AT johanssonhenrik skinsensitizersdifferentiallyregulatesignalingpathwaysinmutz3cellsinrelationtotheirindividualpotency
AT borjeanna skinsensitizersdifferentiallyregulatesignalingpathwaysinmutz3cellsinrelationtotheirindividualpotency
AT borrebaeckcarl skinsensitizersdifferentiallyregulatesignalingpathwaysinmutz3cellsinrelationtotheirindividualpotency
AT lindstedtmalin skinsensitizersdifferentiallyregulatesignalingpathwaysinmutz3cellsinrelationtotheirindividualpotency