# Perinatal Gonadal Hormones Impart Male-Biased Neuroimmune, Mitochondrial, and Behavioral Vulnerabilities.

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $584,610

## Abstract

PROJECT SUMMARY
 This R01 proposal tests the central hypothesis that gonadal hormones present during a critical window of
perinatal brain organization result in distinct sex-specific microglial and mitochondrial phenotypes that increase
male vulnerability to perinatal immune stimuli. There is a strong male bias in the incidence of many early-onset
neurodevelopmental disorders. Although neurodevelopmental disorders are quite heterogeneous, growing
evidence demonstrates immune and mitochondrial abnormalities in a subset of these patients. Microglia, the
innate immune cells of the brain, have emerged as key effectors of this neuroimmune communication. We find
that microglia isolated from mice exposed to an early-life immune challenge show significant downregulation of
genes encoding mitochondrial electron transport genes, specifically in males. Additionally, we find that this
early-life immune challenge results in male-biased social behavior deficits, and specifically induces dysfunction
in other aspects of male microglial mitochondrial functionality. To determine what could be mediating these
early-onset sex differences, we first used the knowledge that there is a surge of gonadal hormones that occurs
only in males during a perinatal critical period of brain development. Injecting female mouse pups during this
perinatal critical period with estradiol, the aromatized form of the androgen testosterone that directly
masculinizes the male brain, results in a male-typical phenotype. We have found that masculinized females
subjected to early-life immune challenge display similar deficits in social behavior as did immune-challenged
males, with similar microglial mitochondrial alterations as were observed in immune-challenged males. We
have also demonstrated that estrogen receptors known to influence mitochondrial function are differentially
expressed on microglia between males and females. Using this knowledge, we can alter estrogen receptor
signaling in a cell-specific manner to study the importance of microglial estrogen receptors to male-biased
neurodevelopmental disorder vulnerabilities.
 In this proposal, we will assess whether microglia-specific alterations in mitochondrial morphology, gene
expression, and bioenergetic function are dependent upon microglia-specific estrogen or androgen receptor
signaling, as well as assess whether early-life immune challenge impacts social behavior through aberrant
microglial phagocytosis of synapses, as well as the impact of the perinatal gonadal hormone surge and
microglial estrogen/androgen receptors on these processes. This proposal will be the first to examine a
mechanistic relationship between perinatal gonadal hormone exposure through microglial estrogen and
androgen receptors and the establishment of sex-biased neurodevelopment that induce male-biased
vulnerabilities to neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 10912803
- **Project number:** 5R01HD110467-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Evan Andrew Bordt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $584,610
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912803

## Citation

> US National Institutes of Health, RePORTER application 10912803, Perinatal Gonadal Hormones Impart Male-Biased Neuroimmune, Mitochondrial, and Behavioral Vulnerabilities. (5R01HD110467-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10912803. Licensed CC0.

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