SAT-175 Beyond DNA: Impact of Sperm IGF2 mRNA on Early Embryo Development and Fertility

Abstract Disclosure: R. Cannarella: None. M. Suryavanshi: None. A. Miller: None. A.E. Calogero: None. Background: Spermatozoa carry RNAs that may influence early embryo development. A pilot study (PMID: 39312692) suggests that sperm Insulin-like growth factor 2 (IGF2) mRNA levels impact embryo development timing. This study aims to validate these findings with a larger cohort and introduce a control group of fertile men to explore sperm IGF2 mRNA’s role in human fertility and embryogenesis. Methods: This 3-year prospective study included 50 infertile couples undergoing assisted reproductive technique (ART) for idiopathic or male factor infertility. Excluding female factor infertility due to impaired oocyte reserve, we included those with tubal factor or anovulation. Sperm samples used in ART were tested for IGF2 mRNA, and levels were compared to a control group of men with recent fatherhood (within 12 months). Embryo kinetic parameters were correlated with sperm IGF2 mRNA, adjusting for female age, body mass index (BMI), and anti-Müllerian hormone (AMH). Correlation analysis was conducted on the full cohort, embryos reaching blastocyst, and transferred blastocysts. A ROC curve was used to assess IGF2 mRNA’s predictive value for normal embryo development timing. Results: Fifty infertile patients and ten controls were enrolled. Sperm IGF2 mRNA levels were significantly lower in patients (0.0319 ± 0.04807) than in controls (1.0493 ± 0.75410; p<0.0001), with no significant correlation to conventional sperm parameters. In the full embryo cohort (n=505), IGF2 mRNA levels negatively correlated with the time to pronucleus fading (r=-0.12, p=0.0075) and positively correlated with key milestones of embryo development, including compaction (r=0.27, p<0.0001), morula formation (r=0.22, p<0.0001), blastulation (r=0.23, p<0.0001), full blastocyst (r=0.30, p<0.0001), and expanded blastocyst formation (r=0.27, p<0.0001). These correlations remained significant after adjusting for female factors and were further confirmed in embryos that reached the blastocyst stage (n=268) and in the group of transferred blastocysts (n=231). Embryos that reached the two-cell stage (t2) within the normal time range (21.4 h< t2< 34.8 h, PMID: 23585186) exhibited higher IGF2 mRNA levels (0.0364±0.0451) compared to those with altered t2 timing (0.02206±0.0341; p=0.03). An IGF2 mRNA threshold of >0.0207 predicted normal t2 timing with 44.2% sensitivity and 86% specificity (AUC 0.572, p=0.036). Conclusion: Sperm IGF2 mRNA levels vary between infertile and fertile individuals and play a positive role in early embryo kinetics. These findings challenge the view that spermatozoa only carry paternal DNA, suggesting that IGF2 mRNA in healthy sperm is crucial for early embryo development. This may represent a novel aspect of reproductive biology, offer insights into infertility mechanisms, and provide diagnostic and therapeutic opportunities for infertile couples. Presentation: Saturday, July 12, 2025