Epigenetic safety of in vitro maturation in PCOS: genome-wide DNA methylation profiling of cord blood from a randomized controlled trial.

IF 5.3 3区医学 Q1 REPRODUCTIVE BIOLOGY

Journal of Ovarian Research Pub Date : 2026-06-27 DOI:10.1186/s13048-026-02179-7

Wei Guo, Yi Yang, Meng Qin, Siming Kong, Linlin Wang, Xiaoying Zheng, Rui Yang, Shuo Yang, Xiumei Zhen, Xiaohui Zhu, Rong Li, Liying Yan, Jie Qiao, Zhiqiang Yan

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引用次数: 0

Abstract

Background: In vitro maturation (IVM) provides a safer alternative to conventional in vitro fertilization (IVF) for women with polycystic ovary syndrome (PCOS) by mitigating the risk of ovarian hyperstimulation. However, concerns persist regarding whether IVM perturbs epigenetic reprogramming in the offspring. Current evidence is constrained by candidate-gene approaches or a lack of parental controls. This study aimed to evaluate the genome-wide DNA methylation safety of IVM compared with conventional IVF using a rigorous trio-based design.

Methods: This secondary epigenetic analysis was nested within a randomized controlled trial (RCT) (ClinicalTrials.gov: NCT03463772). We included 10 nuclear families (trios), comprising five IVM-conceived and five IVF-conceived singleton offspring alongside their biological parents. Both groups utilized a uniform freeze-only single-blastocyst transfer strategy to minimize hormonal confounding. Genomic DNA from umbilical cord blood (UCB) and parental peripheral blood was analyzed using reduced representation bisulfite sequencing (RRBS). Genome-wide methylation patterns and differentially methylated regions (DMRs) were subsequently compared between the groups.

Results: Clinical characteristics were comparable between the IVM and IVF groups. Genome-wide analyses demonstrated high concordance in UCB methylation patterns, revealing no significant differences in global CpG methylation levels or distributions across key genomic features (promoters, CpG islands, and gene bodies). Only three rare DMRs were identified in UCB (representing ~ 0.0001% of the genome), none of which mapped to imprinted or developmentally critical loci. Furthermore, methylation variability remained consistent between the groups.

Conclusions: Our findings provide robust mechanistic evidence supporting the epigenetic safety of IVM. The remarkable stability of the neonatal methylome confirms that specific IVM conditions do not compromise early developmental programming, thereby endorsing IVM as a safe and viable alternative for women with PCOS.

Trial registration: ClinicalTrials.gov registry, NCT03463772. Registered on March 13, 2018.

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PCOS体外成熟的表观遗传安全性：来自一项随机对照试验的脐带血全基因组DNA甲基化分析

背景：体外成熟（IVM）通过降低卵巢过度刺激的风险，为患有多囊卵巢综合征（PCOS）的女性提供了一种比传统体外受精（IVF）更安全的选择。然而，对于IVM是否会干扰后代的表观遗传重编程，人们仍然存在担忧。目前的证据受到候选基因方法或缺乏父母控制的限制。本研究旨在评估IVM与传统IVF相比的全基因组DNA甲基化安全性，采用严格的三组设计。方法：该二级表观遗传学分析采用随机对照试验（RCT）（ClinicalTrials.gov: NCT03463772）。我们纳入了10个核心家庭（三胞胎），包括5个体外受精和5个体外受精的单胎后代及其亲生父母。两组均采用统一的单囊胚冷冻移植策略，以尽量减少激素干扰。采用亚硫酸氢盐还原序列（RRBS）分析了脐带血（UCB）和亲代外周血的基因组DNA。随后比较了两组之间的全基因组甲基化模式和差异甲基化区域（DMRs）。结果：IVM组和IVF组的临床特征具有可比性。全基因组分析显示，UCB甲基化模式高度一致，显示全球CpG甲基化水平或关键基因组特征（启动子、CpG岛和基因体）之间的分布没有显著差异。在UCB中仅鉴定出3个罕见的DMRs（约占基因组的0.0001%），其中没有一个映射到印迹或发育关键位点。此外，甲基化变异性在各组之间保持一致。结论：我们的研究结果为支持IVM的表观遗传安全性提供了强有力的机制证据。新生儿甲基组的显著稳定性证实，特定的IVM条件不会影响早期发育计划，因此支持IVM作为PCOS妇女安全可行的替代方案。试验注册：ClinicalTrials.gov注册中心，NCT03463772。2018年3月13日注册。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Ovarian Research REPRODUCTIVE BIOLOGY-

CiteScore

6.20

自引率

2.50%

发文量

125

审稿时长

>12 weeks

期刊介绍： Journal of Ovarian Research is an open access, peer reviewed, online journal that aims to provide a forum for high-quality basic and clinical research on ovarian function, abnormalities, and cancer. The journal focuses on research that provides new insights into ovarian functions as well as prevention and treatment of diseases afflicting the organ. Topical areas include, but are not restricted to: Ovary development, hormone secretion and regulation Follicle growth and ovulation Infertility and Polycystic ovarian syndrome Regulation of pituitary and other biological functions by ovarian hormones Ovarian cancer, its prevention, diagnosis and treatment Drug development and screening Role of stem cells in ovary development and function.