Fernandes Jolyn, Dunigan-Russell Katelyn, Zhong Hua, Lin Vivian, Silverberg Mary, Moore Stephanie B, Tran ViLinh, Jones Dean P, Vitiello Peter F, Rogers Lynette K, Tipple Trent E
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Pulmonary, Critical Care and Sleep Medicine, Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
Metabolites. 2022 Sep 30;12(10):932. doi: 10.3390/metabo12100932.
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.
组学分析通常用于识别参与生理和病理过程的信号通路及相关基因。尽管在对肺部氧化应激反应的严格评估中，性别被视为一个生物学变量，但小鼠品系的影响在很大程度上被忽视了。本研究采用了高分辨率代谢组学分析和RNA测序的无偏整合评估方法，以探索成年小鼠肺组织中性别和品系依赖性信号通路。结果表明，品系对与炎症和氧化/抗氧化反应相关的信号通路的影响大于性别，且相互作用代谢物更类似于那些被鉴定为品系差异表达的代谢物。代谢物分析显示，谷胱甘肽抗氧化信号通路的成分在不同品系之间存在差异，特别是在混合二硫键的形成方面。此外，硒代谢物如硒代高半胱氨酸和硒代胱硫醚也存在类似的差异表达。转录组分析也得出了类似的结果，谷胱甘肽过氧化物酶、过氧化物酶和炎症转录因子RelA和Jun的差异就证明了这一点。总之，多组学整合方法表明小鼠品系对肺组织抗氧化系统的基线表达有不成比例的影响。我们推测品系依赖性差异导致临床前小鼠模型中肺部反应的差异，对临床转化产生有害影响。
