# Sex Differences in Fetal Brain-Placental Immune Programming in Maternal Obesity

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $168,385

## Abstract

PROJECT SUMMARY
In the United States, one in three women of reproductive age is obese. In epidemiologic studies, maternal obesity
is associated with neurodevelopmental morbidity in children, including cognitive deficits, autism spectrum
disorder, anxiety and depression, disordered eating, and attention deficit hyperactivity disorder. Many of these
disorders have a sex bias, and aberrant brain immune activation (microglial priming, or “trained immunity”), has
been implicated in their pathogenesis. While direct evaluation of microglial function in a living human fetus or
neonate is impossible, resident placental macrophages (Hofbauer cells) and microglia have a common origin in
the fetal yolk sac. “Fetal Brain-Placental Immune Activation in Maternal Obesity” is a pre-clinical R01 that tests
the hypothesis that maternal obesity-associated inflammatory priming of fetal brain microglia and placental
Hofbauer cells is a targetable mechanism underlying offspring cognitive deficits. A key translational aspect of
the funded project is the use of single-cell RNA sequencing (scRNA-Seq) to determine whether Hofbauer cells
represent a novel biologic surrogate for microglial immunoreactivity in the setting of maternal obesity. In 2019,
we were funded to complete the following specific aims: Aim 1a: Determine whether maternal obesity primes
fetal brain and placental resident macrophages to overrespond to an immune challenge. Aim 1b: Evaluate
whether Hofbauer cells can serve as a biologic surrogate for brain microglial priming, using scRNA-Seq and flow
cytometry. Aim 2: Determine if targeted ablation of pro-inflammatory signaling in fetal resident tissue
macrophages (including microglia and placental Hofbauer cells) rescues hippocampal learning deficits in
offspring, using a novel Cx3cr1-CreBT:MyD88f/f transgenic mouse. Both sexes are evaluated in all experiments,
except the scRNA-Seq in Aim 1b. We have completed initial sequencing for 16 male brain and placental
macrophage samples from obese and lean dams. We have demonstrated novel gene programs and cell states
that define male microglia and Hofbauer cells in the context of maternal obesity.
This administrative supplement proposal aims to expand the scRNA-Seq experiments in Aim 1b of the parent
grant to include female fetal microglia and placental macrophages. This will allow us to test whether maternal
obesity induces sex-specific alterations in fetal microglial and Hofbauer cell programs, and whether Hofbauer
cell subsets can serve as a biologic surrogate for fetal brain microglial priming in the setting of maternal obesity.
Determination of how fetal sex impacts microglial and placental macrophage gene programs and cell states will
generate key insights into how obesity-associated brain and placental immune activation influences sex-specific
neurodevelopmental outcomes. If Hofbauer cells can serve as a more accessible cell type that provides
information about brain microglial function in maternal obesity, t...

## Key facts

- **NIH application ID:** 10093233
- **Project number:** 3R01HD100022-02S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Andrea Goldberg Edlow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,385
- **Award type:** 3
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093233

## Citation

> US National Institutes of Health, RePORTER application 10093233, Sex Differences in Fetal Brain-Placental Immune Programming in Maternal Obesity (3R01HD100022-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10093233. Licensed CC0.

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