# Sex-Biased Mitochondrial Alterations Underlying Male Susceptibility to Neurodevelopmental Disorders

> **NIH NIH F32** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $29,358

## Abstract

PROJECT SUMMARY
 Autism Spectrum Disorders (ASD) are a collection of complex neurodevelopmental disorders
characterized by repetitive behaviors and alterations in social interaction and communication that currently
affect 1 in 68 children in the United States. Although it is clear that ASD prevalence is biased towards males
(~4:1 male to female ratio), the mechanisms behind this male susceptibility remain elusive. While ASDs are
quite heterogenous, evidence suggests a role for neuroinflammation in the development of these neurological
abnormalities. Microglia, the resident immune cells of the brain, are key regulators of the neural response to
immune activation and developmental organization of neural circuits, uniquely positioning them to translate
early-life challenges into neural outcomes. Additionally, emerging evidence suggests that mitochondrial
dysfunction plays an important role in neuropsychiatric/neurodevelopmental disorders such as ASD, and that
inhibition of mitochondrial function may be critical in the processes of microglial activation. The emerging
understanding of sex differences in mitochondrial and microglial physiology suggest that further study into their
potential roles in the development of neurodevelopmental disorders such as ASD are warranted. To that end, I
will first characterize the effect of early-life immune challenge (an established model for ASD in mice that
presents with a strong sex bias) on mitochondrial gene/protein levels and functions. Building upon this, I will
then assess how an early-life immune stimulus affects epigenetic regulation of mitochondrial DNA in males and
females. Finally, I will ask what could be occurring during early development that may mediate these early-
onset sex differences. There is a surge in gonadal hormone levels that occurs only in males during a ‘critical
period’ of days surrounding birth that is responsible for masculinizing male brains. Injections of these
hormones into females during this ‘critical period’ has been shown to ‘masculinize’ their brains to a male-like
state. Using this model, I will determine if male sex hormones present during a critical period surrounding birth
(‘masculinizing’ female mice) will impart susceptibility to subsequent immune challenge. I expect this project to
result in several novel implications by bridging three bodies of research that are only beginning to collaborate:
(i) the role of mitochondrial biology in neurodevelopment and disease, (ii) the role of neuroimmune dysfunction
and microglial function in neurodevelopment and disease, and (iii) the striking differences in male and female
responses to pathophysiological insults.

## Key facts

- **NIH application ID:** 10374457
- **Project number:** 3F32MH116604-03S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Evan Andrew Bordt
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $29,358
- **Award type:** 3
- **Project period:** 2021-09-21 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374457

## Citation

> US National Institutes of Health, RePORTER application 10374457, Sex-Biased Mitochondrial Alterations Underlying Male Susceptibility to Neurodevelopmental Disorders (3F32MH116604-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10374457. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*