High-dose estrogen impairs demethylation of H3K27me3 by decreasing Kdm6b expression during ovarian hyperstimulation in mice.

Quanmin KANG; Fang LE; Xiayuan XU; Lifang CHEN; Shi ZHENG; Lijun LOU; Nan JIANG; Ruimin ZHAO; Yuanyuan ZHOU; Juan SHEN; Minhao HU; Ning WANG; Qiongxiao HUANG; Fan JIN

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High-dose estrogen impairs demethylation of H3K27me3 by decreasing Kdm6b expression during ovarian hyperstimulation in mice.

Author: Quanmin KANG ¹ ; Fang LE ¹ ; Xiayuan XU ¹ ; Lifang CHEN ¹ ; Shi ZHENG ¹ ; Lijun LOU ² ; Nan JIANG ³ ; Ruimin ZHAO ¹ ; Yuanyuan ZHOU ¹ ; Juan SHEN ¹ ; Minhao HU ¹ ; Ning WANG ¹ ; Qiongxiao HUANG ⁴ ; Fan JIN ⁵
Author Information

1. Department of Reproductive Endocrinology, Key Laboratory of Reproductive Genetics of National Ministry of Education, Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
2. Department of Reproductive Endocrinology, Dongyang People's Hospital, Dongyang 322100, China.
3. Reproductive Medicine Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
4. Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China. huangqiongxiao@hmc.edu.cn.
5. Department of Reproductive Endocrinology, Key Laboratory of Reproductive Genetics of National Ministry of Education, Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China. jinfan@zju.edu.cn.
Publication Type:Journal Article
Keywords: Assisted reproductive technology (ART); Histone methylation; Ovarian stimulation
MeSH: Female; Mice; Demethylation/drug effects*; Embryonic Stem Cells; Estrogens/administration & dosage*; Gene Expression/drug effects*; Histones/metabolism*; Jumonji Domain-Containing Histone Demethylases/metabolism*; Mice, Inbred C57BL; Oocytes; Ovary/drug effects*; Reproductive Techniques, Assisted; Animals
From: Journal of Zhejiang University. Science. B 2025;26(3):269-285
CountryChina
Language:English
Abstract: Given that ovarian stimulation is vital for assisted reproductive technology (ART) and results in elevated serum estrogen levels, exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary. We investigated the effects of various ovarian stimulation treatments on oocyte and embryo morphology and gene expression using a mouse model and estrogen-treated mouse embryonic stem cells (mESCs). Female C57BL/6J mice were subjected to two types of conventional ovarian stimulation and ovarian hyperstimulation; mice treated with only normal saline served as controls. Hyperstimulation resulted in high serum estrogen levels, enlarged ovaries, an increased number of aberrant oocytes, and decreased embryo formation. The messenger RNA (mRNA)‍-sequencing of oocytes revealed the dysregulated expression of lysine-specific demethylase 6b (Kdm6b), which may be a key factor indicating hyperstimulation-induced aberrant oocytes and embryos. In vitro, Kdm6b expression was downregulated in mESCs treated with high-dose estrogen; treatment with an estrogen receptor antagonist could reverse this downregulated expression level. Furthermore, treatment with high-dose estrogen resulted in the upregulated expression of histone H3 lysine 27 trimethylation (H3K27me3) and phosphorylated H2A histone family member X (γ-H2AX). Notably, knockdown of Kdm6b and high estrogen levels hindered the formation of embryoid bodies, with a concomitant increase in the expression of H3K27me3 and γ-H2AX. Collectively, our findings revealed that hyperstimulation-induced high-dose estrogen could impair the demethylation of H3K27me3 by reducing Kdm6b expression. Accordingly, Kdm6b could be a promising marker for clinically predicting ART outcomes in patients with ovarian hyperstimulation syndrome.