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

Connor J. Moore, Christopher P. Holstege, Jason A. Papin

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.