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Yeast Deletomics to Uncover Gadolinium Toxicity Targets and Resistance Mechanisms

Among the rare earth elements (REEs), a crucial group of metals for high-technologies. Gadolinium (Gd) is the only REE intentionally injected to human patients. The use of Gd-based contrasting agents for magnetic resonance imaging (MRI) is the primary route for Gd direct exposure and accumulation in...

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Autores principales: Grosjean, Nicolas, Le Jean, Marie, Ory, Jordan, Blaudez, Damien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10459663/
https://www.ncbi.nlm.nih.gov/pubmed/37630673
http://dx.doi.org/10.3390/microorganisms11082113
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author Grosjean, Nicolas
Le Jean, Marie
Ory, Jordan
Blaudez, Damien
author_facet Grosjean, Nicolas
Le Jean, Marie
Ory, Jordan
Blaudez, Damien
author_sort Grosjean, Nicolas
collection PubMed
description Among the rare earth elements (REEs), a crucial group of metals for high-technologies. Gadolinium (Gd) is the only REE intentionally injected to human patients. The use of Gd-based contrasting agents for magnetic resonance imaging (MRI) is the primary route for Gd direct exposure and accumulation in humans. Consequently, aquatic environments are increasingly exposed to Gd due to its excretion through the urinary tract of patients following an MRI examination. The increasing number of reports mentioning Gd toxicity, notably originating from medical applications of Gd, necessitates an improved risk–benefit assessment of Gd utilizations. To go beyond toxicological studies, unravelling the mechanistic impact of Gd on humans and the ecosystem requires the use of genome-wide approaches. We used functional deletomics, a robust method relying on the screening of a knock-out mutant library of Saccharomyces cerevisiae exposed to toxic concentrations of Gd. The analysis of Gd-resistant and -sensitive mutants highlighted the cell wall, endosomes and the vacuolar compartment as cellular hotspots involved in the Gd response. Furthermore, we identified endocytosis and vesicular trafficking pathways (ESCRT) as well as sphingolipids homeostasis as playing pivotal roles mediating Gd toxicity. Finally, tens of yeast genes with human orthologs linked to renal dysfunction were identified as Gd-responsive. Therefore, the molecular and cellular pathways involved in Gd toxicity and detoxification uncovered in this study underline the pleotropic consequences of the increasing exposure to this strategic metal.
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spelling pubmed-104596632023-08-27 Yeast Deletomics to Uncover Gadolinium Toxicity Targets and Resistance Mechanisms Grosjean, Nicolas Le Jean, Marie Ory, Jordan Blaudez, Damien Microorganisms Article Among the rare earth elements (REEs), a crucial group of metals for high-technologies. Gadolinium (Gd) is the only REE intentionally injected to human patients. The use of Gd-based contrasting agents for magnetic resonance imaging (MRI) is the primary route for Gd direct exposure and accumulation in humans. Consequently, aquatic environments are increasingly exposed to Gd due to its excretion through the urinary tract of patients following an MRI examination. The increasing number of reports mentioning Gd toxicity, notably originating from medical applications of Gd, necessitates an improved risk–benefit assessment of Gd utilizations. To go beyond toxicological studies, unravelling the mechanistic impact of Gd on humans and the ecosystem requires the use of genome-wide approaches. We used functional deletomics, a robust method relying on the screening of a knock-out mutant library of Saccharomyces cerevisiae exposed to toxic concentrations of Gd. The analysis of Gd-resistant and -sensitive mutants highlighted the cell wall, endosomes and the vacuolar compartment as cellular hotspots involved in the Gd response. Furthermore, we identified endocytosis and vesicular trafficking pathways (ESCRT) as well as sphingolipids homeostasis as playing pivotal roles mediating Gd toxicity. Finally, tens of yeast genes with human orthologs linked to renal dysfunction were identified as Gd-responsive. Therefore, the molecular and cellular pathways involved in Gd toxicity and detoxification uncovered in this study underline the pleotropic consequences of the increasing exposure to this strategic metal. MDPI 2023-08-19 /pmc/articles/PMC10459663/ /pubmed/37630673 http://dx.doi.org/10.3390/microorganisms11082113 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Grosjean, Nicolas
Le Jean, Marie
Ory, Jordan
Blaudez, Damien
Yeast Deletomics to Uncover Gadolinium Toxicity Targets and Resistance Mechanisms
title Yeast Deletomics to Uncover Gadolinium Toxicity Targets and Resistance Mechanisms
title_full Yeast Deletomics to Uncover Gadolinium Toxicity Targets and Resistance Mechanisms
title_fullStr Yeast Deletomics to Uncover Gadolinium Toxicity Targets and Resistance Mechanisms
title_full_unstemmed Yeast Deletomics to Uncover Gadolinium Toxicity Targets and Resistance Mechanisms
title_short Yeast Deletomics to Uncover Gadolinium Toxicity Targets and Resistance Mechanisms
title_sort yeast deletomics to uncover gadolinium toxicity targets and resistance mechanisms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10459663/
https://www.ncbi.nlm.nih.gov/pubmed/37630673
http://dx.doi.org/10.3390/microorganisms11082113
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