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Sex modifies placental gene expression in response to metabolic and inflammatory stress
Theresa L Barke1, Kelli M Money2, Liping Du3
1Graduate 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.
Insights
Pregnancy metabolic stress (gestational diabetes mellitus) and maternal immune activation alter placental inflammation differently in male and female fetuses. These combined effects impact fetal development and offspring health.
Area of Science:
- Reproductive biology
- Immunology
- Developmental biology
Background:
- Pregnancy involves metabolic stress (e.g., gestational diabetes mellitus, GDM) and infections, impacting fetal development.
- Antenatal stresses can differentially affect male and female offspring.
- Understanding placental responses to these stressors is crucial for offspring health.
Purpose of the Study:
- To investigate how metabolic stress and maternal immune activation (MIA), alone or combined, alter placental inflammatory gene expression.
- To determine if these alterations exhibit sexual dimorphism.
Main Methods:
- Mice were fed a high-fat diet to induce GDM or a normal diet.
- Maternal immune activation was induced using poly(I:C) injection at gestational day 12.5.
- Placentae were collected 3 hours post-injection for immune gene expression analysis (248 genes).
Main Results:
- GDM, MIA, and their combination significantly altered placental immune gene expression.
- GDM alone generally lowered mRNA expression, while MIA elevated it.
- Fetal/placental sex influenced immune gene responses to both metabolic and inflammatory stress.
Conclusions:
- GDM and MIA provoke distinct placental inflammatory responses with sexual dimorphism.
- Combined stressors have unique effects compared to individual stressors.
- Findings may explain sex-specific adverse pregnancy outcomes in humans exposed to similar antenatal 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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