Effects of Trigger-Day hCG Usage on DNA Methylation Alterations

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.