Transcriptome-Metabolome Association Studies in Mouse Lungs Reveal Differences Between Sex and Strain in the Glutathione Antioxidant Pathway

Sex and strain significantly influence pathophysiological responses to environmental exposures in mice. Underlying sex and strain differences have not been clearly investigated but are essential to understanding unique molecular and pathological features of experimental pulmonary disease models. We used an integrated transcriptome and metabolome approach to test for sex and strain-based differences in functional pathway and network responses in lungs of C3H/HeN and C57Bl6 mice. Results from multivariate analysis at P< 0.05 and FDR at 0.05 revealed differentially expressed metabolites (m) and transcripts (t) between males and females (660 m, 484 t), C3H/Hen and C57Bl6 strains (921 m, 418 t) and as a result of interaction between sex and strain (374 m and 383 t). Metabolic pathway analysis using mummichog showed drug metabolism was the most common pathway affected by sex, strain and interaction. Oxidative stress related pathways such seleno amino acid metabolism reflected strain-based influence while cysteine/glutathione pathways were influenced by sex and the combined interaction of sex and strain. Gene set enrichment analysis revealed inflammatory response as the underlying differential pathway in sex, strain and interaction-based transcriptomic differences and several antioxidant genes were identified including glutamatecysteine ligase C, catalase, and peroxiredoxin 1. Overall, these results suggest that underlying metabolic and transcriptomic differences in antioxidant regulation and oxidation of key molecules may be responsible for the differences observed in sex and strain-based pulmonary susceptibilities.