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.

Details

Title
Deducing signaling pathways from parallel actions of arsenite and antimonite in human epidermal keratinocytes
Author
Phillips, Marjorie A 1 ; Cánovas, Angela 2 ; Rea, Miguel A 3 ; Islas-Trejo Alma 4 ; Medrano, Juan F 4 ; Durbin-Johnson, Blythe 5 ; Rocke, David M 5 ; Rice, Robert H 1 

 University of California, Department of Environmental Toxicology, Davis, USA (GRID:grid.27860.3b) (ISNI:0000 0004 1936 9684) 
 University of Guelph, Centre for Genetic Improvement of Livestock, Department of Animal Biosciences, Guelph, Canada (GRID:grid.34429.38) (ISNI:0000 0004 1936 8198) 
 Universidad Autónoma Querétaro, Department of Chemistry, Querétaro, Mexico (GRID:grid.412861.8) (ISNI:0000 0001 2207 2097) 
 University of California, Department of Animal Science, Davis, USA (GRID:grid.27860.3b) (ISNI:0000 0004 1936 9684) 
 University of California, Division of Biostatistics, Department of Public Health Sciences, Clinical and Translational Science Center Biostatistics Core, Davis, USA (GRID:grid.27860.3b) (ISNI:0000 0004 1936 9684) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2358521069
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.