高雌激素暴露通过降低Kdm6b的表达影响卵巢过度刺激小鼠H3K27me3的去甲基化

康诠敏; 乐芳; 徐夏苑; 陈李芳; 郑诗; 楼丽君; 江楠; 赵瑞敏; 周圆圆; 沈娟; 胡珉豪; 王宁; 黄琼晓; 金帆

doi:10.1631/jzus.B2300681

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高雌激素暴露通过降低Kdm6b的表达影响卵巢过度刺激小鼠H3K27me3的去甲基化

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Research Article | Updated：2025-03-13

高雌激素暴露通过降低Kdm6b的表达影响卵巢过度刺激小鼠H3K27me3的去甲基化
High-dose estrogen impairs demethylation of H3K27me3 by decreasing Kdm6b expression during ovarian hyperstimulation in mice
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2025年26卷第3期页码：269-285
Affiliations：

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.Laboratory of Reproductive Genetics, Jinhua Maternal & Child Health Care Hospital, Jinhua 321000, China
3.Department of Obstetrics, Lishui Maternal and Child Health Hospital, Lishui 323000, China
4.Department of Obstetrics and Gynecology, Women and Children’s Hospital of Ningbo University, Ningbo 315012, China
5.Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China
6.Department of Reproductive Endocrinology, Dongyang People’s Hospital, Dongyang 322100, China
7.Reproductive Medicine Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Funds：

the National Key Research and Development Program of China(2018YFC1004900);the National Natural Science Foundation of China(82101799);the Health Science and Technology Foundation of Zhejiang Province of China(2022KY186)
DOI：10.1631/jzus.B2300681
中图分类号：
CSTR：
收稿日期：2023-09-21，

修回日期：2024-01-25，

纸质出版日期：2025-03-13
Accepted：

康诠敏,乐芳,徐夏苑等.高雌激素暴露通过降低Kdm6b的表达影响卵巢过度刺激小鼠H3K27me3的去甲基化[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(03):269-285.

Quanmin KANG, Fang LE, Xiayuan XU, et al. High-dose estrogen impairs demethylation of H3K27me3 by decreasing Kdm6b expression during ovarian hyperstimulation in mice[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(3): 269-285.
康诠敏,乐芳,徐夏苑等.高雌激素暴露通过降低Kdm6b的表达影响卵巢过度刺激小鼠H3K27me3的去甲基化[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(03):269-285. DOI： 10.1631/jzus.B2300681.

Quanmin KANG, Fang LE, Xiayuan XU, et al. High-dose estrogen impairs demethylation of H3K27me3 by decreasing Kdm6b expression during ovarian hyperstimulation in mice[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(3): 269-285. DOI： 10.1631/jzus.B2300681.

摘要

促排卵是辅助生殖技术（ART）的关键环节之一，能导致母体血清雌二醇水平升高。因此，在促排卵过程中高浓度雌激素暴露对卵母细胞和胚胎的影响一直为人们所关注。本研究利用小鼠模型和小鼠胚胎干细胞（mESCs）探讨了促排卵对卵母细胞和胚胎的形态及基因表达的影响。在本研究中，我们建立了不同促排卵方案的C57BL/6J小鼠模型，其中包括一组超剂量促排卵导致卵巢过度刺激。研究结果显示，过度刺激组小鼠的血清雌激素水平显著升高，卵巢增大，异形卵母细胞增加，以及卵裂

率和成囊率均下降。卵母细胞信使RNA（mRNA）测序结果发现差异基因去甲基化酶

Kdm6b

在过度刺激组中显著下调，这提示其可能是过度刺激引起卵母细胞和胚胎发育异常的关键分子。细胞实验表明，高雌激素暴露可下调mESCs中Kdm6b的表达，而雌激素受体拮抗剂预处理可以逆转高雌激素对Kdm6b的影响。此外，

Kdm6b

的敲降和高雌激素暴露均可导致mESCs中组蛋白H3赖氨酸27的三甲基化（H3K27me3）和大鼠磷酸化组蛋白（γ-H2AX）的表达上调，并伴随拟胚体的形成受损。综上所述，过度刺激引起的高浓度雌激素暴露可通过降低Kdm6b的表达从而影响H3K27me3的去甲基化。因此，Kdm6b是预测卵巢过度刺激患者ART结局的重要指标。

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.

关键词

Keywords

references

Agger K , Cloos PAC , Christensen J , et al. , 2007 . UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development . Nature , 449 ( 7163 ): 731 - 734 . https://doi.org/10.1038/nature06145 https://doi.org/10.1038/nature06145

An JT , Wang J , Kong SM , et al. , 2024 . GametesOmics: a comprehensive multi-omics database for exploring the gametogenesis in humans and mice . Genom Proteom Bioinf , 22 ( 1 ): qzad004 . https://doi.org/10.1093/gpbjnl/qzad004 https://doi.org/10.1093/gpbjnl/qzad004

Baart EB , Martini E , Eijkemans MJ , et al. , 2007 . Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial . Hum Reprod , 22 ( 4 ): 980 - 988 . https://doi.org/10.1093/humrep/del484 https://doi.org/10.1093/humrep/del484

Beebeejaun Y , Athithan A , Copeland TP , et al. , 2021 . Risk of breast cancer in women treated with ovarian stimulation drugs for infertility: a systematic review and meta-analysis . Fertil Steril , 116 ( 1 ): 198 - 207 . https://doi.org/10.1016/j.fertnstert.2021.01.044 https://doi.org/10.1016/j.fertnstert.2021.01.044

Berntsen S , Söderström-Anttila V , Wennerholm UB , et al. , 2019 . The health of children conceived by ART: ‘the chicken or the egg?’ Hum Reprod Update , 25 ( 2 ): 137 - 158 . https://doi.org/10.1093/humupd/dmz001 https://doi.org/10.1093/humupd/dmz001

Bogliotti YS , Ross PJ , 2012 . Mechanisms of histone H3 lysine 27 trimethylation remodeling during early mammalian development . Epigenetics , 7 ( 9 ): 976 - 981 . https://doi.org/10.4161/epi.21615 https://doi.org/10.4161/epi.21615

Bortoletto P , Prabhu M , Baker VL , 2022 . Association between programmed frozen embryo transfer and hypertensive disorders of pregnancy . Fertil Steril , 118 ( 5 ): 839 - 848 . https://doi.org/10.1016/j.fertnstert.2022.07.025 https://doi.org/10.1016/j.fertnstert.2022.07.025

Burchfield JS , Li QT , Wang HY , et al. , 2015 . JMJD3 as an epigenetic regulator in development and disease . Int J Biochem Cell Biol , 67 : 148 - 157 . https://doi.org/10.1016/j.biocel.2015.07.006 https://doi.org/10.1016/j.biocel.2015.07.006

Cahill DJ , Wardle PG , Harlow CR , et al. , 2000 . Expected contribution to serum oestradiol from individual ovarian follicles in unstimulated cycles . Hum Reprod , 15 ( 9 ): 1909 - 1912 . https://doi.org/10.1093/humrep/15.9.1909 https://doi.org/10.1093/humrep/15.9.1909

Canovas S , Cibelli JB , Ross PJ , 2012 . Jumonji domain-containing protein 3 regulates histone 3 lysine 27 methylation during bovine preimplantation development . Proc Natl Acad Sci USA , 109 ( 7 ): 2400 - 2405 . https://doi.org/10.1073/pnas.1119112109 https://doi.org/10.1073/pnas.1119112109

Chambers GM , Dyer S , Zegers-Hochschild F , et al. , 2021 . International Committee for Monitoring Assisted Reproductive Technologies world report: assisted reproductive technology, 2014 . Hum Reprod , 36 ( 11 ): 2921 - 2934 . https://doi.org/10.1093/humrep/deab198 https://doi.org/10.1093/humrep/deab198

Chen SZ , Ma J , Wu FZ , et al. , 2012 . The histone H3 Lys 27 demethylase JMJD3 regulates gene expression by impacting transcriptional elongation . Genes Dev , 26 ( 12 ): 1364 - 1375 . https://doi.org/10.1101/gad.186056.111 https://doi.org/10.1101/gad.186056.111

Chou DM , Adamson B , Dephoure NE , et al. , 2010 . A chromatin localization screen reveals poly(ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage . Proc Natl Acad Sci USA , 107 ( 43 ): 18475 - 18480 . https://doi.org/10.1073/pnas.1012946107 https://doi.org/10.1073/pnas.1012946107

D'Angelo A , Davies R , Salah E , et al. , 2004 . Value of the serum estradiol level for preventing ovarian hyperstimulation syndrome: a retrospective case control study . Fertil Steril , 81 ( 2 ): 332 - 336 . https://doi.org/10.1016/j.fertnstert.2003.06.016 https://doi.org/10.1016/j.fertnstert.2003.06.016

Delvigne A , 2009 . Symposium: update on prediction and management of OHSS . Epidemiology of OHSS. Reprod Biomed Online , 19 ( 1 ): 8 - 13 . https://doi.org/10.1016/s1472-6483(10)60040-5 https://doi.org/10.1016/s1472-6483(10)60040-5

Diamond MP , Legro RS , Coutifaris C , et al. , 2015 . Letrozole, gonadotropin, or clomiphene for unexplained infertility . N Engl J Med , 373 ( 13 ): 1230 - 1240 . https://doi.org/10.1056/NEJMoa1414827 https://doi.org/10.1056/NEJMoa1414827

Ding YJ , Yao YC , Gong XM , et al. , 2021 . JMJD3: a critical epigenetic regulator in stem cell fate . Cell Commun Signal , 19 : 72 . https://doi.org/10.1186/s12964-021-00753-8 https://doi.org/10.1186/s12964-021-00753-8

Engmann L , Sladkevicius P , Agrawal R , et al. , 1999 . Value of ovarian stromal blood flow velocity measurement after pituitary suppression in the prediction of ovarian responsiveness and outcome of in vitro fertilization treatment . Fertil Steril , 71 ( 1 ): 22 - 29 . https://doi.org/10.1016/S0015-0282(98)00406-3 https://doi.org/10.1016/S0015-0282(98)00406-3

Filicori M , Cognigni GE , Gamberini E , et al. , 2005 . Efficacy of low-dose human chorionic gonadotropin alone to complete controlled ovarian stimulation . Fertil Steril , 84 ( 2 ): 394 - 401 . https://doi.org/10.1016/j.fertnstert.2005.02.036 https://doi.org/10.1016/j.fertnstert.2005.02.036

Fleming TP , Kwong WY , Porter R , et al. , 2004 . The embryo and its future . Biol Reprod , 71 ( 4 ): 1046 - 1054 . https://doi.org/10.1095/biolreprod.104.030957 https://doi.org/10.1095/biolreprod.104.030957

Gardner EE , Lok BH , Schneeberger VE , et al. , 2017 . Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis . Cancer Cell , 31 ( 2 ): 286 - 299 . https://doi.org/10.1016/j.ccell.2017.01.006 https://doi.org/10.1016/j.ccell.2017.01.006

Greene AD , Patounakis G , Segars JH , 2014 . Genetic associations with diminished ovarian reserve: a systematic review of the literature . J Assist Reprod Genet , 31 ( 8 ): 935 - 946 . https://doi.org/10.1007/s10815-014-0257-5 https://doi.org/10.1007/s10815-014-0257-5

Guo TW , Han X , He JZ , et al. , 2022 . KDM6B interacts with TFDP1 to activate P53 signaling in regulating mouse palatogenesis . eLife , 11 : e74595 . https://doi.org/10.7554/eLife.74595 https://doi.org/10.7554/eLife.74595

Harikumar A , Meshorer E , 2015 . Chromatin remodeling and bivalent histone modifications in embryonic stem cells . EMBO Rep , 16 ( 12 ): 1609 - 1619 . https://doi.org/10.15252/embr.201541011 https://doi.org/10.15252/embr.201541011

Hofstetter C , Kampka JM , Huppertz S , et al. , 2016 . Inhibition of KDM6 activity during murine ESC differentiation induces DNA damage . J Cell Sci , 129 ( 4 ): 788 - 803 . https://doi.org/10.1242/jcs.175174 https://doi.org/10.1242/jcs.175174

Huang X , Yan J , Zhang M , et al. , 2018 . Targeting epigenetic crosstalk as a therapeutic strategy for EZH2-aberrant solid tumors . Cell , 175 ( 1 ): 186 - 199.e19 . https://doi.org/10.1016/j.cell.2018.08.058 https://doi.org/10.1016/j.cell.2018.08.058

Huang ZW , Wells D , 2010 . The human oocyte and cumulus cells relationship: new insights from the cumulus cell transcriptome . Mol Hum Reprod , 16 ( 10 ): 715 - 725 . https://doi.org/10.1093/molehr/gaq031 https://doi.org/10.1093/molehr/gaq031

Ikeda S , Yamada M , 2014 . Midkine and cytoplasmic maturation of mammalian oocytes in the context of ovarian follicle physiology . Br J Pharmacol , 171 ( 4 ): 827 - 836 . https://doi.org/10.1111/bph.12311 https://doi.org/10.1111/bph.12311

Kalthur G , Salian SR , Nair R , et al. , 2016 . Distribution pattern of cytoplasmic organelles, spindle integrity, oxidative stress, octamer-binding transcription factor 4 (Oct4) expression and developmental potential of oocytes following multiple superovulation . Reprod Fertil Dev , 28 ( 12 ): 2027 - 2038 . https://doi.org/10.1071/RD15184 https://doi.org/10.1071/RD15184

Kartikasari AER , Zhou JX , Kanji MS , et al. , 2013 . The histone demethylase Jmjd3 sequentially associates with the transcription factors Tbx3 and Eomes to drive endoderm differentiation . EMBO J , 32 ( 10 ): 1393 - 1408 . https://doi.org/10.1038/emboj.2013.78 https://doi.org/10.1038/emboj.2013.78

Klose RJ , Zhang Y , 2007 . Regulation of histone methylation by demethylimination and demethylation . Nat Rev Mol Cell Biol , 8 ( 4 ): 307 - 318 . https://doi.org/10.1038/nrm2143 https://doi.org/10.1038/nrm2143

Lass A , Brinsden P , 1999 . The role of ovarian volume in reproductive medicine . Hum Reprod Update , 5 ( 3 ): 256 - 266 . https://doi.org/10.1093/humupd/5.3.256 https://doi.org/10.1093/humupd/5.3.256

Lee MG , Villa R , Trojer P , et al. , 2007 . Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination . Science , 318 ( 5849 ): 447 - 450 . https://doi.org/10.1126/science.1149042 https://doi.org/10.1126/science.1149042

Liu XY , Wang CF , Liu WQ , et al. , 2016 . Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos . Nature , 537 ( 7621 ): 558 - 562 . https://doi.org/10.1038/nature19362 https://doi.org/10.1038/nature19362

Liu ZQ , Lee HL , Suh JS , et al. , 2022 . The ERα/KDM6B regulatory axis modulates osteogenic differentiation in human mesenchymal stem cells . Bone Res , 10 : 3 . https://doi.org/10.1038/s41413-021-00171-z https://doi.org/10.1038/s41413-021-00171-z

Lundin K , Ahlström A , 2015 . Quality control and standardization of embryo morphology scoring and viability markers . Reprod Biomed Online , 31 ( 4 ): 459 - 471 . https://doi.org/10.1016/j.rbmo.2015.06.026 https://doi.org/10.1016/j.rbmo.2015.06.026

Ma WG , Song H , Das SK , et al. , 2003 . Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation . Proc Natl Acad Sci USA , 100 ( 5 ): 2963 - 2968 . https://doi.org/10.1073/pnas.0530162100 https://doi.org/10.1073/pnas.0530162100

Macrae TA , Fothergill-Robinson J , Ramalho-Santos M , 2023 . Regulation, functions and transmission of bivalent chromatin during mammalian development . Nat Rev Mol Cell Biol , 24 ( 1 ): 6 - 26 . https://doi.org/10.1038/s41580-022-00518-2 https://doi.org/10.1038/s41580-022-00518-2

Maekawa R , Lee L , Okada M , et al. , 2016 . Changes in gene expression of histone modification enzymes in rat granulosa cells undergoing luteinization during ovulation . J Ovarian Res , 9 : 15 . https://doi.org/10.1186/s13048-016-0225-z https://doi.org/10.1186/s13048-016-0225-z

Market-Velker BA , Zhang LY , Magri LS , et al. , 2010 . Dual effects of superovulation: loss of maternal and paternal imprinted methylation in a dose-dependent manner . Hum Mol Genet , 19 ( 1 ): 36 - 51 . https://doi.org/10.1093/hmg/ddp465 https://doi.org/10.1093/hmg/ddp465

Minocherhomji S , Athalye AS , Madon PF , et al. , 2009 . A case-control study identifying chromosomal polymorphic variations as forms of epigenetic alterations associated with the infertility phenotype . Fertil Steril , 92 ( 1 ): 88 - 95 . https://doi.org/10.1016/j.fertnstert.2008.05.071 https://doi.org/10.1016/j.fertnstert.2008.05.071

O'Hagan HM , Mohammad HP , Baylin SB , 2008 . Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island . PLoS Genet , 4 ( 8 ): e1000155 . https://doi.org/10.1371/journal.pgen.1000155 https://doi.org/10.1371/journal.pgen.1000155

Pinborg A , Wennerholm UB , Romundstad LB , et al. , 2013 . Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis . Hum Reprod Update , 19 ( 2 ): 87 - 104 . https://doi.org/10.1093/humupd/dms044 https://doi.org/10.1093/humupd/dms044

Practice Committee of the American Society for Reproductive Medicine , 2016 . Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline . Fertil Steril , 106 ( 7 ): 1634 - 1647 . https://doi.org/10.1016/j.fertnstert.2016.08.048 https://doi.org/10.1016/j.fertnstert.2016.08.048

Qin JB , Liu XY , Sheng XQ , et al. , 2016 . Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies: a meta-analysis of cohort studies . Fertil Steril , 105 ( 1 ): 73 - 85.e6 . https://doi.org/10.1016/j.fertnstert.2015.09.007 https://doi.org/10.1016/j.fertnstert.2015.09.007

Satoh T , Takeuchi O , Vandenbon A , et al. , 2010 . The Jmjd3- Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection . Nat Immunol , 11 ( 10 ): 936 - 944 . https://doi.org/10.1038/ni.1920 https://doi.org/10.1038/ni.1920

Seki Y , Hayashi K , Itoh K , et al. , 2005 . Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice . Dev Biol , 278 ( 2 ): 440 - 458 . https://doi.org/10.1016/j.ydbio.2004.11.025 https://doi.org/10.1016/j.ydbio.2004.11.025

Shi YH , Sun Y , Hao CF , et al. , 2018 . Transfer of fresh versus frozen embryos in ovulatory women . N Engl J Med , 378 ( 2 ): 126 - 136 . https://doi.org/10.1056/NEJMoa1705334 https://doi.org/10.1056/NEJMoa1705334

Sousa M , Cunha M , Teixeira da Silva J , et al. , 2015 . Ovarian hyperstimulation syndrome: a clinical report on 4894 consecutive ART treatment cycles . Reprod Biol Endocrinol , 13 : 66 . https://doi.org/10.1186/s12958-015-0067-3 https://doi.org/10.1186/s12958-015-0067-3

Svotelis A , Bianco S , Madore J , et al. , 2011 . H3 K 27 demethylation by JMJD 3 at a poised enhancer of anti-apoptotic gene BCL2 determines ERα ligand dependency . EMBO J , 30 ( 19 ): 3947 - 3961 . https://doi.org/10.1038/emboj.2011.284 https://doi.org/10.1038/emboj.2011.284

Syrop CH , Willhoite A , van Voorhis BJ , 1995 . Ovarian volume: a novel outcome predictor for assisted reproduction . Fertil Steril , 64 ( 6 ): 1167 - 1171 . https://doi.org/10.1016/S0015-0282(16)57979-5 https://doi.org/10.1016/S0015-0282(16)57979-5

Tang SB , Yang LL , Zhang TT , et al. , 2019 . Multiple superovulations alter histone modifications in mouse early embryos . Reproduction , 157 ( 6 ): 511 - 523 . https://doi.org/10.1530/REP-18-0495 https://doi.org/10.1530/REP-18-0495

Trakarnphornsombat W , Kimura H , 2023 . Live-cell tracking of γ‍-H2AX kinetics reveals the distinct modes of ATM and DNA-PK in the immediate response to DNA damage . J Cell Sci , 136 ( 8 ): jcs260698 . https://doi.org/10.1242/jcs.260698 https://doi.org/10.1242/jcs.260698

Vandamme J , Lettier G , Sidoli S , et al. , 2012 . The C . elegans H3K27 demethylase UTX-1 is essential for normal development, independent of its enzymatic activity . PLoS Genet , 8 ( 5 ): e1002647 . https://doi.org/10.1371/journal.pgen.1002647 https://doi.org/10.1371/journal.pgen.1002647

Venetis CA , Storr A , Chua SJ , et al. , 2023 . What is the optimal GnRH antagonist protocol for ovarian stimulation during ART treatment? A systematic review and network meta-analysis . Hum Reprod Update , 29 ( 3 ): 307 - 326 . https://doi.org/10.1093/humupd/dmac040 https://doi.org/10.1093/humupd/dmac040

Wakimoto Y , Pors SE , Cadenas J , et al. , 2020 . The precise ovarian volume is significantly associated with serum concentrations of antimüllerian hormone, the luteinizing hormone/follicle-stimulating hormone ratio, and total testosterone . Fertil Steril , 113 ( 2 ): 453 - 459 . https://doi.org/10.1016/j.fertnstert.2019.09.029 https://doi.org/10.1016/j.fertnstert.2019.09.029

Wang HB , Dey SK , 2006 . Roadmap to embryo implantation: clues from mouse models . Nat Rev Genet , 7 ( 3 ): 185 - 199 . https://doi.org/10.1038/nrg1808 https://doi.org/10.1038/nrg1808

Wassarman PM , Litscher ES , 2022 . Female fertility and the zona pellucida . eLife , 11 : e76106 . https://doi.org/10.7554/eLife.76106 https://doi.org/10.7554/eLife.76106

Whitmill A , Liu Y , Timani KA , et al. , 2017 . Tip110 deletion impaired embryonic and stem cell development involving downregulation of stem cell factors Nanog, Oct4, and Sox2 . Stem Cells , 35 ( 7 ): 1674 - 1686 . https://doi.org/10.1002/stem.2631 https://doi.org/10.1002/stem.2631

Wolf XA , Serup P , Hyttel P , 2011 . Three-dimensional localisation of NANOG, OCT4, and E-cadherin in porcine pre- and peri-implantation embryos . Dev Dyn , 240 ( 1 ): 204 - 210 . https://doi.org/10.1002/dvdy.22491 https://doi.org/10.1002/dvdy.22491

Xu GF , Zhang JY , Pan HT , et al. , 2014 . Cardiovascular dysfunction in offspring of ovarian-hyperstimulated women and effects of estradiol and progesterone: a retrospective cohort study and proteomics analysis . J Clin Endocrinol Metab , 99 ( 12 ): E2494 - E2503 . https://doi.org/10.1210/jc.2014-2349 https://doi.org/10.1210/jc.2014-2349

Xu J , Yu B , Hong C , et al. , 2013 . KDM6B epigenetically regulates odontogenic differentiation of dental mesenchymal stem cells . Int J Oral Sci , 5 ( 4 ): 200 - 205 . https://doi.org/10.1038/ijos.2013.77 https://doi.org/10.1038/ijos.2013.77

Yang WJ , Ma YR , Jin JM , et al. , 2021 . Cyclophosphamide exposure causes long-term detrimental effect of oocytes developmental competence through affecting the epigenetic modification and maternal factors’ transcription during oocyte growth . Front Cell Dev Biol , 9 : 682060 . https://doi.org/10.3389/fcell.2021.682060 https://doi.org/10.3389/fcell.2021.682060

Zenk F , Loeser E , Schiavo R , et al. , 2017 . Germ line-inherited H3K27Me3 restricts enhancer function during maternal-to-zygotic transition . Science , 357 ( 6347 ): 212 - 216 . https://doi.org/10.1126/science.aam5339 https://doi.org/10.1126/science.aam5339

Zhang M , Wang FC , Kou ZH , et al. , 2009 . Defective chromatin structure in somatic cell cloned mouse embryos . J Biol Chem , 284 ( 37 ): 24981 - 24987 . https://doi.org/10.1074/jbc.M109.011973 https://doi.org/10.1074/jbc.M109.011973

Zhang YY , Yan ZQ , Qin QY , et al. , 2018 . Transcriptome landscape of human folliculogenesis reveals oocyte and granulosa cell interactions . Mol Cell , 72 ( 6 ): 1021 - 1034.e4 . https://doi.org/10.1016/j.molcel.2018.10.029 https://doi.org/10.1016/j.molcel.2018.10.029

Zhou VW , Goren A , Bernstein BE , 2011 . Charting histone modifications and the functional organization of mammalian genomes . Nat Rev Genet , 12 ( 1 ): 7 - 18 . https://doi.org/10.1038/nrg2905 https://doi.org/10.1038/nrg2905

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Hepatitis B virus infection, infertility, and assisted reproduction