A genome-wide portrait of pervasive drug contaminants

Abstract Using a validated yeast chemogenomic platform, we characterized the genome-wide effects of several pharmaceutical contaminants, including three N-nitrosamines (NDMA, NDEA and NMBA), two related compounds (DMF and 4NQO) and several of their metabolites. A collection of 4800 non-essential hom...

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Autores principales:	Joseph Uche Ogbede, Guri Giaever, Corey Nislow
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4bd709ce55c34412964c9e590340ba41
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spelling	oai:doaj.org-article:4bd709ce55c34412964c9e590340ba412021-12-02T16:04:13ZA genome-wide portrait of pervasive drug contaminants10.1038/s41598-021-91792-12045-2322https://doaj.org/article/4bd709ce55c34412964c9e590340ba412021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91792-1https://doaj.org/toc/2045-2322Abstract Using a validated yeast chemogenomic platform, we characterized the genome-wide effects of several pharmaceutical contaminants, including three N-nitrosamines (NDMA, NDEA and NMBA), two related compounds (DMF and 4NQO) and several of their metabolites. A collection of 4800 non-essential homozygous diploid yeast deletion strains were screened in parallel and the strain abundance was quantified by barcode sequencing. These data were used to rank deletion strains representing genes required for resistance to the compounds to delineate affected cellular pathways and to visualize the global cellular effects of these toxins in an easy-to-use searchable database. Our analysis of the N-nitrosamine screens uncovered genes (via their corresponding homozygous deletion mutants) involved in several evolutionarily conserved pathways, including: arginine biosynthesis, mitochondrial genome integrity, vacuolar protein sorting and DNA damage repair. To investigate why NDMA, NDEA and DMF caused fitness defects in strains lacking genes of the arginine pathway, we tested several N-nitrosamine metabolites (methylamine, ethylamine and formamide), and found they also affected arginine pathway mutants. Notably, each of these metabolites has the potential to produce ammonium ions during their biotransformation. We directly tested the role of ammonium ions in N-nitrosamine toxicity by treatment with ammonium sulfate and we found that ammonium sulfate also caused a growth defect in arginine pathway deletion strains. Formaldehyde, a metabolite produced from NDMA, methylamine and formamide, and which is known to cross-link free amines, perturbed deletion strains involved in chromatin remodeling and DNA repair pathways. Finally, co-administration of N-nitrosamines with ascorbic or ferulic acid did not relieve N-nitrosamine toxicity. In conclusion, we used parallel deletion mutant analysis to characterize the genes and pathways affected by exposure to N-nitrosamines and related compounds, and provide the data in an accessible, queryable database.Joseph Uche OgbedeGuri GiaeverCorey NislowNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Joseph Uche Ogbede Guri Giaever Corey Nislow A genome-wide portrait of pervasive drug contaminants
description	Abstract Using a validated yeast chemogenomic platform, we characterized the genome-wide effects of several pharmaceutical contaminants, including three N-nitrosamines (NDMA, NDEA and NMBA), two related compounds (DMF and 4NQO) and several of their metabolites. A collection of 4800 non-essential homozygous diploid yeast deletion strains were screened in parallel and the strain abundance was quantified by barcode sequencing. These data were used to rank deletion strains representing genes required for resistance to the compounds to delineate affected cellular pathways and to visualize the global cellular effects of these toxins in an easy-to-use searchable database. Our analysis of the N-nitrosamine screens uncovered genes (via their corresponding homozygous deletion mutants) involved in several evolutionarily conserved pathways, including: arginine biosynthesis, mitochondrial genome integrity, vacuolar protein sorting and DNA damage repair. To investigate why NDMA, NDEA and DMF caused fitness defects in strains lacking genes of the arginine pathway, we tested several N-nitrosamine metabolites (methylamine, ethylamine and formamide), and found they also affected arginine pathway mutants. Notably, each of these metabolites has the potential to produce ammonium ions during their biotransformation. We directly tested the role of ammonium ions in N-nitrosamine toxicity by treatment with ammonium sulfate and we found that ammonium sulfate also caused a growth defect in arginine pathway deletion strains. Formaldehyde, a metabolite produced from NDMA, methylamine and formamide, and which is known to cross-link free amines, perturbed deletion strains involved in chromatin remodeling and DNA repair pathways. Finally, co-administration of N-nitrosamines with ascorbic or ferulic acid did not relieve N-nitrosamine toxicity. In conclusion, we used parallel deletion mutant analysis to characterize the genes and pathways affected by exposure to N-nitrosamines and related compounds, and provide the data in an accessible, queryable database.
format	article
author	Joseph Uche Ogbede Guri Giaever Corey Nislow
author_facet	Joseph Uche Ogbede Guri Giaever Corey Nislow
author_sort	Joseph Uche Ogbede
title	A genome-wide portrait of pervasive drug contaminants
title_short	A genome-wide portrait of pervasive drug contaminants
title_full	A genome-wide portrait of pervasive drug contaminants
title_fullStr	A genome-wide portrait of pervasive drug contaminants
title_full_unstemmed	A genome-wide portrait of pervasive drug contaminants
title_sort	genome-wide portrait of pervasive drug contaminants
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4bd709ce55c34412964c9e590340ba41
work_keys_str_mv	AT josephucheogbede agenomewideportraitofpervasivedrugcontaminants AT gurigiaever agenomewideportraitofpervasivedrugcontaminants AT coreynislow agenomewideportraitofpervasivedrugcontaminants AT josephucheogbede genomewideportraitofpervasivedrugcontaminants AT gurigiaever genomewideportraitofpervasivedrugcontaminants AT coreynislow genomewideportraitofpervasivedrugcontaminants
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A genome-wide portrait of pervasive drug contaminants

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