The steroid hormone estriol (E(3)) regulates epigenetic programming of fetal mouse brain and reproductive tract

BACKGROUND: Estriol (E(3)) is a steroid hormone formed only during pregnancy in primates including humans. Although E(3) is synthesized at large amounts through a complex pathway involving the fetus and placenta, it is not required for the maintenance of pregnancy and has classically been considered virtually inactive due to associated very weak canonical estrogen signaling. However, estrogen exposure during pregnancy may have an effect on organs both within and outside the reproductive system, and compounds with binding affinity for estrogen receptors weaker than E(3) have been found to impact reproductive organs and the brain. Here, we explore potential effects of E(3) on fetal development using mouse as a model system. RESULTS: We administered E(3) to pregnant mice, exposing the fetus to E(3). Adult females exposed to E(3) in utero (E(3)-mice) had increased fertility and superior pregnancy outcomes. Female and male E(3)-mice showed decreased anxiety and increased exploratory behavior. The expression levels and DNA methylation patterns of multiple genes in the uteri and brains of E(3)-mice were distinct from controls. E(3) promoted complexing of estrogen receptors with several DNA/histone modifiers and their binding to target genes. E(3) functions by driving epigenetic change, mediated through epigenetic modifier interactions with estrogen receptors rather than through canonical nuclear transcriptional activation. CONCLUSIONS: We identify an unexpected functional role for E(3) in fetal reproductive system and brain. We further identify a novel mechanism of estrogen action, through recruitment of epigenetic modifiers to estrogen receptors and their target genes, which is not correlated with the traditional view of estrogen potency. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-022-01293-4.