# Fetal Brain-Placental Immune Activation in Maternal Obesity

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $394,602

## Abstract

PROJECT SUMMARY
In the United States, one in three women of reproductive age is obese. In large epidemiologic studies, maternal
obesity is associated with cognitive deficits in children, including reduced and low IQ (<70), and lower reading
and math scores. Underlying mechanisms remain unclear. What is known is that maternal obesity is a state of
chronic low-level immune activation, and both placental and brain inflammation have been reported in fetuses
and offspring of obese women. Microglia, the resident immune cells of the brain, have been implicated in the
pathogenesis of many of the neurodevelopmental morbidities noted with increased frequency in offspring of
obese women. Despite this, there is a gap in knowledge about if/how placental inflammation affects fetal brain
development in the setting of maternal obesity. We have demonstrated sex-specific fetal brain transcriptomes in
the setting of maternal obesity, with dysregulated immune and inflammatory signaling highlighted as key effects
of maternal obesity on both the male and female embryonic brain. We subsequently demonstrated a significant
and sexually dimorphic effect of maternal obesity on microglial antigen (Iba-1) density in the embryonic
hippocampus, and hippocampal learning deficits in obesity-exposed offspring, with male offspring more
significantly affected. These data support the hypothesis that aberrant brain immune activation in embryonic life
is one mechanism underlying enduring cognitive deficits.
Inappropriate fetal microglial priming may therefore have lifelong neurodevelopmental consequences, but direct
evaluation of microglial function in a living human fetus or neonate is impossible. Fortunately, placental
macrophages (Hofbauer cells) and microglia have a common origin in the fetal yolk sac. Yolk-sac-derived
macrophages comprise the permanent pool of brain microglia throughout an individual’s lifetime. Therefore,
placental Hofbauer cells represent a potentially novel biologic sentinel that may mirror microglial
immunoreactivity. Here, we seek to test the following hypotheses: (1a) maternal obesity will prime both Hofbauer
cells and fetal brain microglia to overrespond to an immune challenge (1b) Maternal obesity will induce key
alterations in the fetal microglial single cell transcriptome which will be recapitulated in the Hofbauer cell
transcriptome (2) Selective ablation of pro-inflammatory macrophage signaling in the fetal brain and placenta
using an innovative transgenic mouse will rescue maternal obesity-associated hippocampal learning deficits.
The proposed experiments will fill a knowledge gap by ascertaining whether increased pro-inflammatory
macrophage signaling in the placenta and fetal brain is a mechanism underlying offspring hippocampal learning
deficits in maternal obesity. Demonstrating a causal link between fetal placental and brain macrophage-mediated
inflammation and neurodevelopmental morbidity has potential therapeutic applications. If Hofbauer cells...

## Key facts

- **NIH application ID:** 10229462
- **Project number:** 5R01HD100022-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Andrea Goldberg Edlow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $394,602
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229462

## Citation

> US National Institutes of Health, RePORTER application 10229462, Fetal Brain-Placental Immune Activation in Maternal Obesity (5R01HD100022-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10229462. Licensed CC0.

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