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In Vitro Scratch Assay to Demonstrate Effects of Arsenic on Skin Cell Migration
Published on: February 23, 2019
Deducing signaling pathways from parallel actions of arsenite and antimonite in human epidermal keratinocytes
Marjorie A Phillips1, Angela Cánovas2, Miguel A Rea3
1Department of Environmental Toxicology, University of California, Davis, CA, USA.
Abstract:
Inorganic arsenic oxides have been identified as carcinogens in several human tissues, including epidermis. Due to the chemical similarity between trivalent inorganic arsenic (arsenite) and antimony (antimonite), we hypothesized that common intracellular targets lead to similarities in cellular responses. Indeed, transcriptional and proteomic profiling revealed remarkable similarities in differentially expressed genes and proteins resulting from exposure of cultured human epidermal keratinocytes to arsenite and antimonite in contrast to comparisons of arsenite with other metal compounds. These data were analyzed to predict upstream regulators and affected signaling pathways following arsenite and antimonite treatments. A majority of the top findings in each category were identical after treatment with either compound. Inspection of the predicted upstream regulators led to previously unsuspected roles for oncostatin M, corticosteroids and ephrins in mediating cellular response. The influence of these predicted mediators was then experimentally verified. Together with predictions of transcription factor effects more generally, the analysis has led to model signaling networks largely accounting for arsenite and antimonite action. The striking parallels between responses to arsenite and antimonite indicate the skin carcinogenic risk of exposure to antimonite merits close scrutiny.
Insights
Trivalent inorganic arsenic (arsenite) and antimony (antimonite) cause similar cellular responses in human skin cells. This suggests antimonite may also pose a skin carcinogenic risk, warranting further investigation.
Area of Science:
- Toxicology
- Dermatology
- Molecular Biology
Background:
- Inorganic arsenic oxides are known human skin carcinogens.
- Chemical similarity exists between trivalent inorganic arsenic (arsenite) and antimony (antimonite).
Purpose of the Study:
- To investigate if arsenite and antimonite induce similar cellular responses in human epidermal keratinocytes.
- To identify common intracellular targets and signaling pathways affected by arsenite and antimonite.
Main Methods:
- Transcriptional and proteomic profiling of cultured human epidermal keratinocytes exposed to arsenite and antimonite.
- Bioinformatic analysis to predict upstream regulators and affected signaling pathways.
- Experimental verification of predicted mediator roles.
Main Results:
- Arsenite and antimonite exposure resulted in remarkably similar gene and protein expression profiles.
- Predicted upstream regulators and signaling pathways were largely identical for both compounds.
- Oncostatin M, corticosteroids, and ephrins were identified as key mediators, with their roles experimentally confirmed.
Conclusions:
- Arsenite and antimonite share common intracellular targets and induce similar cellular responses in skin keratinocytes.
- The findings suggest a potential skin carcinogenic risk associated with antimonite exposure.
- This study provides a model signaling network for arsenite and antimonite action and highlights the need for scrutiny of antimonite's risks.
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