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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9059368/ https://www.ncbi.nlm.nih.gov/pubmed/35491423 http://dx.doi.org/10.1186/s12915-022-01293-4 |
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author | Zhou, Yuping Gu, Baoxia Brichant, Geraldine Singh, Jay Prakash Yang, Huan Chang, Hao Zhao, Yanding Cheng, Chao Liu, Zhong-Wu Alderman, Myles H. Lu, Lingeng Yang, Xiaoyong Gao, Xiao-Bing Taylor, Hugh S. |
author_facet | Zhou, Yuping Gu, Baoxia Brichant, Geraldine Singh, Jay Prakash Yang, Huan Chang, Hao Zhao, Yanding Cheng, Chao Liu, Zhong-Wu Alderman, Myles H. Lu, Lingeng Yang, Xiaoyong Gao, Xiao-Bing Taylor, Hugh S. |
author_sort | Zhou, Yuping |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9059368 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-90593682022-05-03 The steroid hormone estriol (E(3)) regulates epigenetic programming of fetal mouse brain and reproductive tract Zhou, Yuping Gu, Baoxia Brichant, Geraldine Singh, Jay Prakash Yang, Huan Chang, Hao Zhao, Yanding Cheng, Chao Liu, Zhong-Wu Alderman, Myles H. Lu, Lingeng Yang, Xiaoyong Gao, Xiao-Bing Taylor, Hugh S. BMC Biol Research Article 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. BioMed Central 2022-05-02 /pmc/articles/PMC9059368/ /pubmed/35491423 http://dx.doi.org/10.1186/s12915-022-01293-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Zhou, Yuping Gu, Baoxia Brichant, Geraldine Singh, Jay Prakash Yang, Huan Chang, Hao Zhao, Yanding Cheng, Chao Liu, Zhong-Wu Alderman, Myles H. Lu, Lingeng Yang, Xiaoyong Gao, Xiao-Bing Taylor, Hugh S. The steroid hormone estriol (E(3)) regulates epigenetic programming of fetal mouse brain and reproductive tract |
title | The steroid hormone estriol (E(3)) regulates epigenetic programming of fetal mouse brain and reproductive tract |
title_full | The steroid hormone estriol (E(3)) regulates epigenetic programming of fetal mouse brain and reproductive tract |
title_fullStr | The steroid hormone estriol (E(3)) regulates epigenetic programming of fetal mouse brain and reproductive tract |
title_full_unstemmed | The steroid hormone estriol (E(3)) regulates epigenetic programming of fetal mouse brain and reproductive tract |
title_short | The steroid hormone estriol (E(3)) regulates epigenetic programming of fetal mouse brain and reproductive tract |
title_sort | steroid hormone estriol (e(3)) regulates epigenetic programming of fetal mouse brain and reproductive tract |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9059368/ https://www.ncbi.nlm.nih.gov/pubmed/35491423 http://dx.doi.org/10.1186/s12915-022-01293-4 |
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