# Sex-dimorphic reprogramming of fetal mouse brain development by maternal estradiol excess

## TL;DR

High maternal estradiol during pregnancy disrupts fetal brain development differently in male and female mice, potentially explaining why males are more vulnerable to certain disorders.

## Contribution

The study reveals sex-specific molecular and cellular mechanisms by which maternal estradiol excess reprograms fetal brain development.

## Key findings

- Maternal HE exposure altered gene expression more in male-biased genes, with changes proportional to their baseline male bias.
- HE disrupted the proliferation-differentiation balance of neural progenitor cells in the male cerebral cortex.
- Sex-opposed changes in intra-regional signaling pathways and regulon activity were observed in response to HE.

## Abstract

Gestational environmental perturbations can induce sex-specific developmental programming, increasing offspring susceptibility to chronic diseases. While prenatal high estradiol (HE) exposure has been associated with male-biased neurodevelopmental disorders, the underlying mechanisms remain poorly understood.

Using spatial transcriptomics in a murine HE exposure model, we systematically characterized sex-divergent molecular and cellular responses in fetal brains. Through cell type identification, spatial mapping, ligand-receptor interaction analysis, and transcription factor activity assessment, we examined gene expression profile, intra-regional signaling pathway, and regulon activity variations. Additionally, we performed immunofluorescence to characterize neural progenitor cell dynamics.

Our analysis revealed that maternal HE exposure differentially altered gene expression patterns between male and female fetal brain regions, with more pronounced effects on male-biased genes. Notably, HE-induced downregulation of male-biased genes was proportional to their baseline male-bias degree. We uncovered region-specific cellular responses to HE exposure and demonstrated sex-opposed alterations in intra-regional signaling pathway. Furthermore, we identified cell type- and brain region-restricted sex differences in regulon activity variations. Histological validation confirmed that maternal HE exposure specifically disrupts the proliferation-differentiation balance of neural progenitor cells in the male cerebral cortex.

These findings provide mechanistic insights into sex-dimorphic developmental reprogramming of fetal brain by maternal estradiol excess. They establish a framework for developing targeted interventions against gestational endocrine disruption-induced neurodevelopmental disorders.

The online version contains supplementary material available at 10.1186/s13293-025-00792-7.

During pregnancy, certain environmental factors can affect how a baby’s brain develops, sometimes leading to long-term health problems. High levels of maternal estradiol (HE) have been linked to brain development issues in offspring, especially in males, but scientists don’t fully understand why. This study investigated how HE exposure affects male and female fetal brains differently in mice. It found that HE changed different gene expression in two sexes, with more changes in genes that are normally highly expressed in males. Interestingly, the more a gene was typically male-biased, the more HE reduced its expression. It also discovered that different brain regions and cell types reacted to HE in unique ways, with males and females showing opposite changes in brain cell communication and specific alterations in gene regulation activity. Most importantly, HE disrupted the growth and maturation of brain-building cells (neural progenitors) in a certain region of male brain, which might explain why males are more vulnerable. These findings help explain how excess estradiol during pregnancy may harm brain development differently in male and female offsprings, they could lead to better ways to prevent or treat developmental disorders caused by maternal hormone imbalances.

The online version contains supplementary material available at 10.1186/s13293-025-00792-7.

High maternal estradiol (HE) induces distinct alteration of transcriptional profile and sex-biased gene expression in male and female fetal brains.HE dysregulates ligand-receptor interactions and transcription factor activities in specific brain regions and cell types in a sex-dimorphic manner.HE disrupts proliferation-differentiation balance of neural progenitors in the male cerebral cortex.Findings reveal how maternal hormone imbalances sex-specifically reprogram fetal brain development, paving the way for targeted prevention strategies.

High maternal estradiol (HE) induces distinct alteration of transcriptional profile and sex-biased gene expression in male and female fetal brains.

HE dysregulates ligand-receptor interactions and transcription factor activities in specific brain regions and cell types in a sex-dimorphic manner.

HE disrupts proliferation-differentiation balance of neural progenitors in the male cerebral cortex.

Findings reveal how maternal hormone imbalances sex-specifically reprogram fetal brain development, paving the way for targeted prevention strategies.

The online version contains supplementary material available at 10.1186/s13293-025-00792-7.