Theresa L Barke1, Kelli M Money2, Liping Du3, Ana Serezani4, Maureen Gannon5, Karoly Mirnics6, David M Aronoff7. 1. Graduate Program in Microbiology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. 2. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. 3. Center for Quantitative Sciences, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. 4. Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. 5. Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. 6. Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, 68198, USA. 7. Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. Electronic address: d.aronoff@vanderbilt.edu.
Abstract
INTRODUCTION: Metabolic stress (e.g., gestational diabetes mellitus (GDM) and obesity) and infections are common during pregnancy, impacting fetal development and the health of offspring. Such antenatal stresses can differentially impact male and female offspring. We sought to determine how metabolic stress and maternal immune activation (MIA), either alone or in combination, alters inflammatory gene expression within the placenta and whether the effects exhibited sexual dimorphism. METHODS: Female C57BL/6 J mice were fed a normal diet or a high fat diet for 6 weeks prior to mating, with the latter diet inducing a GDM phenotype during pregnancy. Dams within each diet group at gestational day (GD) 12.5 received either an intraperitoneal injection of the viral mimic, polyinosinic:polycytidylic acid (poly(I:C)) or saline. Three hours post injection; placentae were collected and analyzed for changes in the expression of 248 unique immune genes. RESULTS: Placental immune gene expression was significantly altered by GDM, MIA and the combination of the two (GDM+MIA). mRNA expression was generally lower in placentae of mice exposed to GDM alone compared with the other experimental groups, while mice exposed to MIA exhibited the highest transcript levels. Notably, fetal/placental sex influenced the responses of many immune genes to both metabolic and inflammatory stress. DISCUSSION: GDM and MIA provoke inflammatory responses within the placenta and such effects exhibit sexual dimorphism. The combination of these stressors impacts the placenta differently than either condition alone. These findings may help explain sexual dimorphism observed in adverse pregnancy outcomes in human offspring exposed to similar stressors.
INTRODUCTION: Metabolic stress (e.g., gestational diabetes mellitus (GDM) and obesity) and infections are common during pregnancy, impacting fetal development and the health of offspring. Such antenatal stresses can differentially impact male and female offspring. We sought to determine how metabolic stress and maternal immune activation (MIA), either alone or in combination, alters inflammatory gene expression within the placenta and whether the effects exhibited sexual dimorphism. METHODS: Female C57BL/6 J mice were fed a normal diet or a high fat diet for 6 weeks prior to mating, with the latter diet inducing a GDM phenotype during pregnancy. Dams within each diet group at gestational day (GD) 12.5 received either an intraperitoneal injection of the viral mimic, polyinosinic:polycytidylic acid (poly(I:C)) or saline. Three hours post injection; placentae were collected and analyzed for changes in the expression of 248 unique immune genes. RESULTS: Placental immune gene expression was significantly altered by GDM, MIA and the combination of the two (GDM+MIA). mRNA expression was generally lower in placentae of mice exposed to GDM alone compared with the other experimental groups, while mice exposed to MIA exhibited the highest transcript levels. Notably, fetal/placental sex influenced the responses of many immune genes to both metabolic and inflammatory stress. DISCUSSION: GDM and MIA provoke inflammatory responses within the placenta and such effects exhibit sexual dimorphism. The combination of these stressors impacts the placenta differently than either condition alone. These findings may help explain sexual dimorphism observed in adverse pregnancy outcomes in human offspring exposed to similar stressors.
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