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Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses

Male subjects in animal and human studies are disproportionately used for toxicological testing. This discrepancy is evidenced in clinical medicine where females are more likely than males to experience liver-related adverse events in response to xenobiotics. While previous work has shown gene expre...

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Autores principales: Moore, Connor J., Holstege, Christopher P., Papin, Jason A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10470949/
https://www.ncbi.nlm.nih.gov/pubmed/37603574
http://dx.doi.org/10.1371/journal.pcbi.1010927
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author Moore, Connor J.
Holstege, Christopher P.
Papin, Jason A.
author_facet Moore, Connor J.
Holstege, Christopher P.
Papin, Jason A.
author_sort Moore, Connor J.
collection PubMed
description Male subjects in animal and human studies are disproportionately used for toxicological testing. This discrepancy is evidenced in clinical medicine where females are more likely than males to experience liver-related adverse events in response to xenobiotics. While previous work has shown gene expression differences between the sexes, there is a lack of systems-level approaches to understand the direct clinical impact of these differences. Here, we integrate gene expression data with metabolic network models to characterize the impact of transcriptional changes of metabolic genes in the context of sex differences and drug treatment. We used Tasks Inferred from Differential Expression (TIDEs), a reaction-centric approach to analyzing differences in gene expression, to discover that several metabolic pathways exhibit sex differences including glycolysis, fatty acid metabolism, nucleotide metabolism, and xenobiotics metabolism. When TIDEs is used to compare expression differences in treated and untreated hepatocytes, we find several subsystems with differential expression overlap with the sex-altered pathways such as fatty acid metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Finally, using sex-specific transcriptomic data, we create individual and averaged male and female liver models and find differences in the pentose phosphate pathway and other metabolic pathways. These results suggest potential sex differences in the contribution of the pentose phosphate pathway to oxidative stress, and we recommend further research into how these reactions respond to hepatotoxic pharmaceuticals.
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spelling pubmed-104709492023-09-01 Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses Moore, Connor J. Holstege, Christopher P. Papin, Jason A. PLoS Comput Biol Research Article Male subjects in animal and human studies are disproportionately used for toxicological testing. This discrepancy is evidenced in clinical medicine where females are more likely than males to experience liver-related adverse events in response to xenobiotics. While previous work has shown gene expression differences between the sexes, there is a lack of systems-level approaches to understand the direct clinical impact of these differences. Here, we integrate gene expression data with metabolic network models to characterize the impact of transcriptional changes of metabolic genes in the context of sex differences and drug treatment. We used Tasks Inferred from Differential Expression (TIDEs), a reaction-centric approach to analyzing differences in gene expression, to discover that several metabolic pathways exhibit sex differences including glycolysis, fatty acid metabolism, nucleotide metabolism, and xenobiotics metabolism. When TIDEs is used to compare expression differences in treated and untreated hepatocytes, we find several subsystems with differential expression overlap with the sex-altered pathways such as fatty acid metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Finally, using sex-specific transcriptomic data, we create individual and averaged male and female liver models and find differences in the pentose phosphate pathway and other metabolic pathways. These results suggest potential sex differences in the contribution of the pentose phosphate pathway to oxidative stress, and we recommend further research into how these reactions respond to hepatotoxic pharmaceuticals. Public Library of Science 2023-08-21 /pmc/articles/PMC10470949/ /pubmed/37603574 http://dx.doi.org/10.1371/journal.pcbi.1010927 Text en © 2023 Moore et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Moore, Connor J.
Holstege, Christopher P.
Papin, Jason A.
Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses
title Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses
title_full Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses
title_fullStr Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses
title_full_unstemmed Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses
title_short Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses
title_sort metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10470949/
https://www.ncbi.nlm.nih.gov/pubmed/37603574
http://dx.doi.org/10.1371/journal.pcbi.1010927
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