Transcriptomic-Metabolomic Profiling in Mouse Lung Tissues Reveals Sex- and Strain-Based Differences
Jolyn Fernandes,
Katelyn Dunigan-Russell,
Hua Zhong,
Vivian Lin,
Mary Silverberg,
Stephanie B. Moore,
ViLinh Tran,
Dean P. Jones,
Peter F. Vitiello,
Lynette K. Rogers,
Trent E. Tipple
Affiliations
Jolyn Fernandes
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Katelyn Dunigan-Russell
Pulmonary, Critical Care and Sleep Medicine, Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Hua Zhong
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Vivian Lin
Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Mary Silverberg
Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Stephanie B. Moore
Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
ViLinh Tran
Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, GA 30322, USA
Dean P. Jones
Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, GA 30322, USA
Peter F. Vitiello
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Lynette K. Rogers
Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH 43215, USA
Trent E. Tipple
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Omics analyses are commonly used for identifying pathways and genes responsible for physiologic and pathologic processes. Though sex is considered a biological variable in rigorous assessments of pulmonary responses to oxidant exposures, the contribution of the murine strain is largely ignored. This study utilized an unbiased integrated assessment of high-resolution metabolomic profiling and RNA-sequencing to explore sex- and strain-dependent pathways in adult mouse lungs. The results indicated that strain exhibited a greater influence than sex on pathways associated with inflammatory and oxidant/antioxidant responses and that interaction metabolites more closely resembled those identified as differentially expressed by strain. Metabolite analyses revealed that the components of the glutathione antioxidant pathway were different between strains, specifically in the formation of mixed disulfides. Additionally, selenium metabolites such as selenohomocystiene and selenocystathionine were similarly differentially expressed. Transcriptomic analysis revealed similar findings, as evidenced by differences in glutathione peroxidase, peroxiredoxin, and the inflammatory transcription factors RelA and Jun. In summary, an multi-omics integrated approach identified that murine strain disproportionately impacts baseline expression of antioxidant systems in lung tissues. We speculate that strain-dependent differences contribute to discrepant pulmonary responses in preclincal mouse models, with deleterious effects on clinical translation.
