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Effects of Trigger-Day hCG Usage on DNA Methylation Alterations

ABSTRACT: Assisted reproductive technology (ART) addresses infertility through supraphysiological procedures, yet the effects of trigger-day pharmacotherapy on epigenetic stability and offspring neurodevelopment remain unclear. We demonstrate that ART-conceived offspring exhibit relatively lower global methylation compared to naturally conceived (NC) peers. For the first time, we identify that human chorionic gonadotropin (hCG) exposure on trigger day might exacerbate oocyte DNA methylation loss, further increasing risk of suboptimal neurodevelopment performance at age three in ART-conceived offspring. In a controlled mouse model, transient hCG-triggered exposure downregulates Ehmt1 and perturbs oocyte DNA methylation, potentially reducing neurogenesis and neurodevelopmental alterations in the offspring. Our findings reveal previously unrecognized epigenetic risks associated with higher dose hCG exposure in ART protocols, highlighting the need for optimized trigger protocols that balance treatment efficacy with long-term offspring health.

ORGANISM(S): Mus musculus

PROVIDER: GSE315316 | GEO | 2026/05/14

REPOSITORIES: GEO

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Project description:Background: With the rapid development of assisted reproductive technology (ART), although ovulation induction has made great progress, the accompanying health risks should not be ignored. Epigenetic modifications play an important role during the development of gametes and embryos. Recently, the epigenetic abnormalities caused by superovulation have attracted increasing attention. The follicle-stimulating hormone (FSH) and human menopausal gonadotropin (hMG) are common gonadotropins used for superovulation and appropriate concentration of them might be necessary. However, there is still no systematic study on the similarities and differences of DNA methylation alterations induced by superovulation with different dosage of FSH/hMG at the single cell levels. Methods: In the current study, the different doses of FSH/hMG combined with (add hcg full name here) hCG were used in C57BL/6 strain female mice to get experimental group oocytes while naturally matured oocytes and superovulated oocytes with only hCG were respectively set as controls. Single-cell level DNA methylation sequencing was carried out to all the mature oocytes to investigate the effect of superovulation with different dosage of FSH/hMG on DNA methylation during oocyte maturation. Results: In this study, we found that the hypo differentially methylated regions (DMRs) number of FSH/hMG 200 IU group both increased significantly although the whole genome methylation pattern of mature oocytes derived from superovulation were unaffected as compared with the control matured oocytes, suggesting that high dosage of FSH/hMG might lead to increased genomic methylation instability. At the same time, some of the DMRs annotated genes related to oocyte quality and embryonic development potential were disturbed in all dosage of FSH/hMG group (including Twist2, Cdk1, Ntrk2, Slc22a4, Sstr2, Wnt2, Cntnap5a, Gm2087, Slc16a7, and so on) as well as the certain ones (containing Abcc3, Zfp532, Atp1a1, Zfp804a, and so on) were impaired after high dosage of gonadotropins. We speculated that the effect of superovulation on DNA methylation during oocyte maturation might be dose-dependent to a certain extent, and such effect might affect oocyte quality and embryonic development competency. Conclusions: The current study firstly analyzed the differential impacts of different doses of gonadotropins on single-cell level DNA methylation of mouse oocytes, indicating a dose-dependent effect of superovulation with FSH/hMG and hCG on the epigenetic variations in mouse oocytes. Furthermore, some important genes that play a critical role in oocyte quality and embryo development were indicated to form the possible molecular basis of the corresponding regulation. This study laid a foundation for evaluating the safety of superovulation and highlighted the need for more and further research into ART.

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Effects of Trigger-Day hCG Usage on DNA Methylation Alterations

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