Trigger-day hCG effects on DNA methylation and neurodevelopment in ART offspring

Area of Science:

• Reproductive Biology
• Developmental Neuroscience
• Epigenetics

Background:

• Assisted reproductive technology (ART) may alter offspring epigenetics.
• The impact of trigger-day pharmacotherapy on epigenetics and neurodevelopment is not well understood.

Purpose of the Study:

• To investigate the association between trigger-day human chorionic gonadotropin (hCG) dose and offspring epigenetics and neurodevelopment.
• To explore the effects of hCG exposure on neurodevelopment and epigenetic markers in a mouse model.

Main Methods:

• Prospective birth cohort studies of families conceived via ART.
• Neurodevelopmental assessments in offspring.
• Mouse models to study effects of hCG exposure on neurogenesis, behavior, and epigenetic markers.
• In vivo rescue experiments using mRNA microinjection.

Main Results:

• Higher trigger-day hCG dose correlated with reduced global DNA methylation in ART-conceived offspring.
• Increased maternal hCG dose was associated with a higher risk of suboptimal neurodevelopment.
• In mice, hCG exposure impaired neurocognitive behaviors, reduced hippocampal neurogenesis, and decreased histone methylation.
• Restoring euchromatic histone lysine methyltransferase 1 (EHMT1) expression normalized neurogenesis and improved behavior in mouse offspring.

Conclusions:

• Higher hCG doses in ART may pose epigenetic and neurodevelopmental risks.
• Findings support optimizing hCG trigger protocols to ensure long-term offspring health.
• Further research into ART pharmacotherapy and its long-term consequences is warranted.