In This Article
- In a mouse model of maternal obesity, placental macrophages mirror the increased responsiveness of fetal brain microglia to an immune challenge, suggesting the potential to noninvasively assess microglial priming using placental macrophages
- Increased proinflammatory behavior of fetal microglia may contribute to adverse neurodevelopment in offspring of obese mice
- Male fetuses may be more vulnerable to the inflammatory priming effects of maternal obesity
- Findings may have implications for understanding adverse neurodevelopmental outcomes in children of obese women that have been noted in large epidemiologic studies, including autism spectrum disorder, developmental delay, ADHD, anxiety and depression
Maternal obesity is a well-documented epidemic in the United States and, increasingly, around the world. Both human epidemiological studies and animal research show that maternal obesity can negatively impact the neurodevelopment of offspring, impacting both behavior and cognitive ability. Maternal obesity has been associated with increased incidence of a number of conditions in children, including:
- Autism spectrum disorder
- Developmental delay
- Attention-deficit/hyperactivity disorder
- Anxiety and depression
Despite the prevalence of maternal obesity and the possible concerning neurodevelopmental outcomes, little is known about the mechanisms that underlie the association. However, animal model studies can help tease apart the contribution of the in utero versus the postnatal environment to these adverse neurodevelopmental outcomes.
Pioneering In Utero Insights
Andrea G. Edlow, MD, MSc, an investigator in the Vincent Center for Reproductive Biology at Massachusetts General Hospital, is conducting new research that seeks to better understand the role of brain and placental immune cells in mediating adverse neurodevelopmental outcomes in the setting of maternal obesity. She hopes to fill a knowledge gap about the early in utero processes that may lead to fetal brain dysregulation. Dr. Edlow, along with her collaborator Staci Bilbo, PhD, director of research for the Lurie Center for Autism, are among the first to examine the developmental impact of maternal obesity on in utero fetal brain and placental development in both sexes of mice.
Dr. Edlow reports intriguing results from her animal model in the International Journal of Developmental Neuroscience. Her team demonstrated that resident fetal placental macrophages, also called Hofbauer cells, may provide information about the behavior of resident fetal brain macrophages, also known as microglia. Dr. Edlow became interested in examining Hofbauer cells as a potential biomarker of microglial function due to their shared embryonic origin with microglia.
Results from this initial study support the hypothesis that microglial proinflammatory activity during development may be one mechanism by which maternal obesity predisposes postnatal neurodevelopmental morbidity in offspring. The increased vulnerability of microglia in males to proinflammatory priming may help explain sex differences in the risk for developmental delay, autism spectrum disorders and ADHD, among other morbidities.
"The use of a mouse model permitted direct examination of the fetal brain in obese pregnancy, which is not possible with human fetuses," Dr. Edlow says. "This, in turn, allowed us to definitively address possible in utero origins of the postnatal neurodevelopmental morbidities noted in epidemiological studies. It also differentiates the in utero effects of maternal obesity on microglia from postnatal environmental effects."
Researchers induced obesity in adult female mice by feeding them a 60% high-fat diet. On day 17.5 of embryonic development, researchers isolated microglia from fetal brains and Hofbauer cells from fetal placentas in parallel for examination. These isolated cells were then treated with lipopolysaccharide as an immune challenge, and the production of the proinflammatory cytokine TNF-a was quantified. Results showed that maternal obesity primed both cell types to overproduce TNF-a and that the response of Hofbauer cells and brain microglia were highly correlated.
By evaluating the placental macrophage-microglial connection in both obese and lean pregnant mice and both sexes of offspring, the team determined that maternal obesity had significant effects on the fetal brain and placental immune response. They also determined that the placental immune response closely mirrored that of fetal brain microglia.
"Maternal obesity primed both placental macrophages and fetal brain microglia to overrespond to ex vivo immune challenges," says Dr. Edlow.
Enhanced Sensitivity in Males
The researchers also found that the male fetal brain might be more vulnerable to proinflammatory priming in the setting of maternal obesity, with male microglia and Hofbauer cells producing more TNF-alpha. This male predisposition was consistent with other research into environmental influences during pregnancy.
"Males have traditionally been viewed as more vulnerable to gestational and perinatal exposures compared with females," says Dr. Edlow.
By investigating in utero origins of maternal obesity-linked neuroimmune dysregulation, Dr. Edlow hopes to identify brain development gone awry at an early stage.
The next step in this research is to validate the findings in further animal studies and, ultimately, to devise ways to safely determine if human fetal brain development is similarly impacted in utero. If validated, these findings could identify possible targets for a pharmacologic intervention, or lifestyle and dietary changes, to ensure healthy fetal brain development.
"Inappropriate fetal microglial priming may have lifelong neurodevelopmental consequences," says Dr. Edlow. "Because direct evaluation of microglial function in a living human fetus or neonate is impossible, our mouse studies showing a close correlation between the proinflammatory behavior of fetal brain and placental macrophages fill an important knowledge gap."
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