Spatial transcriptomics for fetal mouse brain with high maternal estradiol exposure

An adverse maternal environment during pregnancy may program a higher risk of chronic diseases or disorders in the offspring, and this effect tends to be sex-specific. Published studies have reported that prenatal high estradiol (HE) exposure is associated with an increased risk of autism and hypothalamic insulin resistance in males but not in females, but the mechanisms of this sex difference have not been elucidated. We investigated the spatial transcriptome profile in male and female fetal brains of an HE mouse model to identify the critical molecular features involved in sex dimorphism. High maternal estradiol regulated distinct gene expression with different functional enrichment in male compared to female brain regions. More male-biased DEGs than female-biased DEGs were affected, and the male bias appeared to be negatively correlated with the effect of HE exposure. The major cell types were spatially mapped using a public single-cell RNA-seq dataset. High maternal estradiol induced different changes in cell-cell interactions in male and female brains, involving a number of oppositely regulated signaling pathways in four cell types across seven brain regions. The sex difference in prenatal HE exposure was also evident in regulon activity, with the major sex-specific regulons localized in three cell types from three brain regions and enriched mainly in neuronal differentiation and brain development. This study lays the groundwork for understanding the sex difference in fetal brain development driven by high maternal estradiol and provides evidence for targeted interventions in sex-linked fetal programmed diseases.