Alcohol-Induced Spleen Atrophy

Background: Spleen is the largest immune organ. It battles against any invading germs in the blood and control level of white blood cells, red blood cells and platelets. Organ weight change is widely accepted as a measure of toxicologic pathology. We have previously shown that binge exposure to ethanol (EtOH) decreases spleen size in adolescent rats. Using meta-analysis, this study is to explore the mechanisms underlying alcohol-induced spleen atrophy. QIAGEN Ingenuity Pathway Analysis (IPA) and Mammalian Phenotype (MP) Ontology were used to identify alcohol-related molecules associated with the small spleen phenotype. STRING and IPA bioinformatics tools were then used to analyze the biological processes and enriched signaling pathways engaging these molecules. In addition, “downstream effects analysis” algorithm was used to quantitatively demonstrate how alcohol has caused the small spleen phenotype by modulating the expression of these molecules. IPA “Grow” tool was used to identify 623 molecules associated with EtOH and Venn Diagram tool was used to reveal 26 of these molecules overlapped with those associated with the MP Ontology of small spleen. These 26 molecules include transcription regulators, enzymes, kinases, peptidase, G-protein coupled receptors, ligand dependent nuclear receptors, transmembrane receptors, transporters, ion channel and growth factor. A portion of these 26 molecules were also associated with the MP Ontology of abnormal white pulp and red pulp morphology of the spleen, abnormal splenic cell ratio, decreased splenocyte number, abnormal spleen physiology, increased splenocyte apoptosis, and reduced splenocyte proliferation. STRING and IPA “Core Analysis” showed that these molecules were mainly involved in pathway related with cell apoptosis, proliferation, migration, and immune responses. IPA “Molecular Activity Predictor” (MAP) tool was used to reveal that increased exposure to EtOH elevated expression of Esr1, Rora, Casp8, Pebp1, Atm, Camk4, Mtor, Ednrb, Cxcr4, Fas, Tlr7, Alox5, Nfkbia, and Tgfb1 and inhibited expression of Prf1, Bcl2, Il15, Ifng, Glra1, Drd2 and Ighm. However, concurrent effects of activation and inhibition of these molecules led to decreased spleen size by modulating apoptosis, proliferation and migration of splenocyte. Our network meta-analysis revealed that excessive exposure to alcohol induced spleen atrophy through a variety of molecular mechanisms and pathways.