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Application of the in vivo oxidative stress reporter Hmox1 as mechanistic biomarker of arsenic toxicity

Francisco Inesta-Vaquera, Panida Navasumrit, Colin J. Henderson, Tanya G. Frangova, Tadashi Honda, Albena T. Dinkova-Kostova, Mathuros Ruchirawat, C. Roland Wolf
doi: https://doi.org/10.1101/2020.06.19.161117
Francisco Inesta-Vaquera
1Department of Systems Medicine. School of Medicine. University of Dundee, Ninewells Hospital, Dundee, DD1 9SY, UK
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  • For correspondence: f.inestavaquera@dundee.ac.uk
Panida Navasumrit
3Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand
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Colin J. Henderson
1Department of Systems Medicine. School of Medicine. University of Dundee, Ninewells Hospital, Dundee, DD1 9SY, UK
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Tanya G. Frangova
1Department of Systems Medicine. School of Medicine. University of Dundee, Ninewells Hospital, Dundee, DD1 9SY, UK
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Tadashi Honda
4Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA
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Albena T. Dinkova-Kostova
2Department of Molecular Medicine. School of Medicine. University of Dundee, Ninewells Hospital, Dundee, DD1 9SY, UK
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Mathuros Ruchirawat
3Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand
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C. Roland Wolf
1Department of Systems Medicine. School of Medicine. University of Dundee, Ninewells Hospital, Dundee, DD1 9SY, UK
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Abstract

Inorganic arsenic (iAs) is a naturally occurring metalloid present in drinking water and polluted air exposing millions of people globally. Epidemiological studies have linked iAs exposure to the development of numerous diseases including cognitive impairment, cardiovascular failure and cancer. Despite intense research, an effective therapy for chronic arsenicosis has yet to be developed. Laboratory studies have been of great benefit in establishing the pathways involved in iAs toxicity and providing insights into its mechanism of action. However, the in vivo analysis of arsenic toxicity mechanisms has been difficult by the lack of reliable in vivo biomarkers of the effects of iAs. To resolve this issue we have applied the use of our recently developed stress reporter models to study iAs toxicity. The reporter mice Hmox1 (oxidative stress/inflammation; HOTT) and p21 (DNA damage) were exposed to iAs at acute and chronic, environmentally relevant, doses. We observed induction of the oxidative stress reporters in several cell types and tissues, which was largely dependent on the activation of transcription factor NRF2. We propose that our HOTT reporter model can be used as a surrogate biomarker of iAs-induced oxidative stress, and it constitutes a first-inclass platform to develop treatments in arsenicosis. Indeed, in a proof of concept experiment, the HOTT reporter mice were able to predict the therapeutic utility of the antioxidant N-acetyl cysteine in the prevention of iAs associated toxicity.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 20, 2020.
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Application of the in vivo oxidative stress reporter Hmox1 as mechanistic biomarker of arsenic toxicity
Francisco Inesta-Vaquera, Panida Navasumrit, Colin J. Henderson, Tanya G. Frangova, Tadashi Honda, Albena T. Dinkova-Kostova, Mathuros Ruchirawat, C. Roland Wolf
bioRxiv 2020.06.19.161117; doi: https://doi.org/10.1101/2020.06.19.161117
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Application of the in vivo oxidative stress reporter Hmox1 as mechanistic biomarker of arsenic toxicity
Francisco Inesta-Vaquera, Panida Navasumrit, Colin J. Henderson, Tanya G. Frangova, Tadashi Honda, Albena T. Dinkova-Kostova, Mathuros Ruchirawat, C. Roland Wolf
bioRxiv 2020.06.19.161117; doi: https://doi.org/10.1101/2020.06.19.161117

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