Behavior; DNA methylation; Developmental programming; E3; Epigenetics; Estriol; Pregnancy; Reproduction; Estrogens; Receptors, Estrogen; Steroids; Animals; Brain/metabolism; Epigenesis, Genetic; Female; Fetus/metabolism; Male; Mice; Estrogens/genetics; Estrogens/metabolism; Receptors, Estrogen/genetics; Receptors, Estrogen/metabolism; Brain; Fetus; Biotechnology; Structural Biology; Ecology, Evolution, Behavior and Systematics; Physiology; Biochemistry, Genetics and Molecular Biology (all); Agricultural and Biological Sciences (all); Plant Science; Developmental Biology; Cell Biology; General Agricultural and Biological Sciences; General Biochemistry, Genetics and Molecular Biology
Abstract :
[en] BACKGROUND: Estriol (E3) is a steroid hormone formed only during pregnancy in primates including humans. Although E3 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 E3 have been found to impact reproductive organs and the brain. Here, we explore potential effects of E3 on fetal development using mouse as a model system.
RESULTS: We administered E3 to pregnant mice, exposing the fetus to E3. Adult females exposed to E3 in utero (E3-mice) had increased fertility and superior pregnancy outcomes. Female and male E3-mice showed decreased anxiety and increased exploratory behavior. The expression levels and DNA methylation patterns of multiple genes in the uteri and brains of E3-mice were distinct from controls. E3 promoted complexing of estrogen receptors with several DNA/histone modifiers and their binding to target genes. E3 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 E3 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.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
Author, co-author :
Zhou, Yuping; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA
Gu, Baoxia; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA ; Present Address: Reproductive Medicine Center of Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China, 450003
Brichant, Géraldine ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gynécologie-obstétrique (CHR) ; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA
Singh, Jay Prakash; Department of Comparative Medicine and of Cellular and Molecular Physiology, Yale University, New Haven, CT, 06520, USA
Yang, Huan; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA
Chang, Hao; Department of Genetics, Yale University, New Haven, CT, 06520, USA
Zhao, Yanding; Department of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
Cheng, Chao; Department of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
Liu, Zhong-Wu; Present Address: Reproductive Medicine Center of Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China, 450003
Alderman, Myles H; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA ; Department of Genetics, Yale University, New Haven, CT, 06520, USA ; Present Address: Yale Stem Cell Center, Yale University, New Haven, CT, 06520, USA
Lu, Lingeng; Department of Chronic Disease Epidemiology, Yale University, New Haven, CT, 06520, USA
Yang, Xiaoyong; Department of Comparative Medicine and of Cellular and Molecular Physiology, Yale University, New Haven, CT, 06520, USA
Gao, Xiao-Bing; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA ; Department of Comparative Medicine and of Cellular and Molecular Physiology, Yale University, New Haven, CT, 06520, USA
Taylor, Hugh S ; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA. hugh.taylor@yale.edu
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