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Arsenic is a potent co-mutagen of ultraviolet light

Environmental co-exposures are widespread and are major contributors to carcinogenic mechanisms. Two well-established environmental agents causing skin cancer are ultraviolet radiation (UVR) and arsenic. Arsenic is a known co-carcinogen that enhances UVR’s carcinogenicity. However, the mechanisms of...

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Autores principales: Speer, Rachel M., Nandi, Shuvro P., Cooper, Karen L., Zhou, Xixi, Yu, Hui, Guo, Yan, Hudson, Laurie G., Alexandrov, Ludmil B., Liu, Ke Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980120/
https://www.ncbi.nlm.nih.gov/pubmed/36865271
http://dx.doi.org/10.1101/2023.02.22.529578
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author Speer, Rachel M.
Nandi, Shuvro P.
Cooper, Karen L.
Zhou, Xixi
Yu, Hui
Guo, Yan
Hudson, Laurie G.
Alexandrov, Ludmil B.
Liu, Ke Jian
author_facet Speer, Rachel M.
Nandi, Shuvro P.
Cooper, Karen L.
Zhou, Xixi
Yu, Hui
Guo, Yan
Hudson, Laurie G.
Alexandrov, Ludmil B.
Liu, Ke Jian
author_sort Speer, Rachel M.
collection PubMed
description Environmental co-exposures are widespread and are major contributors to carcinogenic mechanisms. Two well-established environmental agents causing skin cancer are ultraviolet radiation (UVR) and arsenic. Arsenic is a known co-carcinogen that enhances UVR’s carcinogenicity. However, the mechanisms of arsenic co-carcinogenesis are not well understood. In this study, we utilized primary human keratinocytes and a hairless mouse model to investigate the carcinogenic and mutagenic properties of co-exposure to arsenic and UVR. In vitro and in vivo exposures revealed that, on its own, arsenic is neither mutagenic nor carcinogenic. However, in combination with UVR, arsenic exposure has a synergistic effect leading to an accelerated mouse skin carcinogenesis as well as to more than 2-fold enrichment of UVR mutational burden. Notably, mutational signature ID13, previously found only in UVR-associated human skin cancers, was observed exclusively in mouse skin tumors and cell lines jointly exposed to arsenic and UVR. This signature was not observed in any model system exposed purely to arsenic or purely to UVR, making ID13 the first co-exposure signature to be reported using controlled experimental conditions. Analysis of existing genomics data from basal cell carcinomas and melanomas revealed that only a subset of human skin cancers harbor ID13 and, consistent with our experimental observations, these cancers exhibited an elevated UVR mutagenesis. Our results provide the first report of a unique mutational signature caused by a co-exposure to two environmental carcinogens and the first comprehensive evidence that arsenic is a potent co-mutagen and co-carcinogen of UVR. Importantly, our findings suggest that a large proportion of human skin cancers are not formed purely due to UVR exposure but rather due to a co-exposure of UVR and other co-mutagens such as arsenic.
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spelling pubmed-99801202023-03-03 Arsenic is a potent co-mutagen of ultraviolet light Speer, Rachel M. Nandi, Shuvro P. Cooper, Karen L. Zhou, Xixi Yu, Hui Guo, Yan Hudson, Laurie G. Alexandrov, Ludmil B. Liu, Ke Jian bioRxiv Article Environmental co-exposures are widespread and are major contributors to carcinogenic mechanisms. Two well-established environmental agents causing skin cancer are ultraviolet radiation (UVR) and arsenic. Arsenic is a known co-carcinogen that enhances UVR’s carcinogenicity. However, the mechanisms of arsenic co-carcinogenesis are not well understood. In this study, we utilized primary human keratinocytes and a hairless mouse model to investigate the carcinogenic and mutagenic properties of co-exposure to arsenic and UVR. In vitro and in vivo exposures revealed that, on its own, arsenic is neither mutagenic nor carcinogenic. However, in combination with UVR, arsenic exposure has a synergistic effect leading to an accelerated mouse skin carcinogenesis as well as to more than 2-fold enrichment of UVR mutational burden. Notably, mutational signature ID13, previously found only in UVR-associated human skin cancers, was observed exclusively in mouse skin tumors and cell lines jointly exposed to arsenic and UVR. This signature was not observed in any model system exposed purely to arsenic or purely to UVR, making ID13 the first co-exposure signature to be reported using controlled experimental conditions. Analysis of existing genomics data from basal cell carcinomas and melanomas revealed that only a subset of human skin cancers harbor ID13 and, consistent with our experimental observations, these cancers exhibited an elevated UVR mutagenesis. Our results provide the first report of a unique mutational signature caused by a co-exposure to two environmental carcinogens and the first comprehensive evidence that arsenic is a potent co-mutagen and co-carcinogen of UVR. Importantly, our findings suggest that a large proportion of human skin cancers are not formed purely due to UVR exposure but rather due to a co-exposure of UVR and other co-mutagens such as arsenic. Cold Spring Harbor Laboratory 2023-02-23 /pmc/articles/PMC9980120/ /pubmed/36865271 http://dx.doi.org/10.1101/2023.02.22.529578 Text en https://creativecommons.org/licenses/by-nc/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Speer, Rachel M.
Nandi, Shuvro P.
Cooper, Karen L.
Zhou, Xixi
Yu, Hui
Guo, Yan
Hudson, Laurie G.
Alexandrov, Ludmil B.
Liu, Ke Jian
Arsenic is a potent co-mutagen of ultraviolet light
title Arsenic is a potent co-mutagen of ultraviolet light
title_full Arsenic is a potent co-mutagen of ultraviolet light
title_fullStr Arsenic is a potent co-mutagen of ultraviolet light
title_full_unstemmed Arsenic is a potent co-mutagen of ultraviolet light
title_short Arsenic is a potent co-mutagen of ultraviolet light
title_sort arsenic is a potent co-mutagen of ultraviolet light
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980120/
https://www.ncbi.nlm.nih.gov/pubmed/36865271
http://dx.doi.org/10.1101/2023.02.22.529578
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