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

ABSTRACT: 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.

SUBMITTER: Moore CJ

PROVIDER: S-EPMC10470949 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Moore Connor J CJ Holstege Christopher P CP Papin Jason A JA

PLoS computational biology 20230821 8

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 n ...[more]

PMID: 37603574

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Project 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 effect 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 androgen, ether lipid, glucocorticoid, tryptophan, and xenobiotic metabolism have more activity in the male liver, and serotonin, melatonin, pentose, glucuronate, and vitamin A metabolism have more activity in the female liver. When TIDEs is used to compare expression differences in treated and untreated hepatocytes, we see little response in those sex-altered subsystems, and the largest differences are in subsystems related to lipid metabolism. Finally, using sex-specific transcriptomic data, we create individual and averaged male and female liver models and find differences in the import of bile acids and salts. This result suggests that the sexually dimorphic behavior of the liver may be caused by differences in enterohepatic recirculation, and we suggest an investigation into sex-specific microbiome composition as an avenue of further research.Author summaryMale-bias in clinical testing of drugs has led to a disproportionate number of hepatotoxic events in women. Previous works use 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; however, when comparing these subsystems with those pathways altered by hepatotoxic agents, we find little 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 human cell metabolic model. In these models we find a difference in flux for the import of bile acids and salts, suggesting a potential difference in enterohepatic circulation. These findings can help guide future drug design, toxicological testing, and sex-specific research to better account for the entire human population.

Project description:BackgroundThe obesity-related risk of developing metabolic syndrome is higher in males than in females of reproductive age, likely due to estrogen-mediated reduced adipose tissue inflammation and fibrosis with hypertrophied adipocytes. Depletion of the ubiquitin ligase Siah2 reduced white adipose tissue inflammation and improved glucose metabolism in obese male mice. Siah2 is a transcriptional target of estrogen, but data is lacking about the effect of Siah2 on adipose tissue of females. We therefore evaluated the impact of Siah2 deficiency on white and brown adipose tissue in females of reproductive age.MethodsBody composition, adipose tissue morphology, brown adipose tissue gene, and protein expression and adipocyte sizing were evaluated in wild-type and Siah2KO female and male mice fed a low-fat or high-fat diet. Glucose and insulin tolerance, fasting glucose, insulin, fatty acids and triglycerides, and gene expression of inflammation markers in perigonadal fat were evaluated in wild-type and Siah2KO female mice. Microarray analysis of brown fat gene expression was carried out in both sexes. Statistical analysis was assessed by unpaired two-tailed t test and repeated measures ANOVA.ResultsSiah2 deficiency improves glucose and insulin tolerance in the presence of hypertrophied white adipocytes in high-fat-fed female mice with percent fat comparable to male mice. While previous studies showed Siah2KO reduces the white adipose tissue inflammatory response in male mice, the response in females is biased toward the upregulation of M2-like markers in white adipose tissue. In contrast, loss of Siah2 leads to increased whitening of brown fat in males, but not in females. This corresponded to increased expression of markers of inflammation (F4/80, Ccl2) and thermogenic genes (Pgc1alpha, Dio2, Ucp-1) and proteins (PGC-1α, UCP-1) in females. Contrary to expectations, increased expression of thermogenic markers in females was coupled with a downregulation of ERalpha and ERRgamma protein levels.ConclusionsThe most striking sex-related effect of Siah2 deficiency is reduced whitening of brown fat in high-fat-fed females. Protection from accumulating unilocular adipocytes in the brown fat corresponds to increased expression of thermogenic genes and proteins in female, but not in male mice. These results raise the possibility that Siah2 contributes to the estrogen-related effects on brown fat function in males and females.

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

Publications

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

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