| Abstrakt: |
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. Author summary: There is a male-bias in clinical testing of drugs and a disproportionate number of hepatotoxic events occur in women. Previous work uses gene-by-gene differences in biological sex to explain this discrepancy, but there is little focus on the systematic interactions of these differences. To this end, we use a combination of gene expression data and metabolic modeling to compare metabolic activity between the male and female liver and treated and untreated hepatocytes. We find several subsystems with differential activity in each sex, and when comparing these subsystems with those pathways altered by hepatotoxic agents, we identify several pathways that overlap. To explore these differences on a reaction-by-reaction basis, we use the same sex-specific transcriptomic data to contextualize the previously published Human1 metabolic model. In these models we find a difference in flux through the pentose phosphate pathway, suggesting a potential difference in response to oxidative stress. These findings can help guide future drug design, toxicological testing, and sex-specific research to better account for the entire human population. [ABSTRACT FROM AUTHOR] |
