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bioRxiv · 10.1101/2025.09.24.677934

Uterine immune dysregulation after asynchronous transfer induced embryonic apoptosis in mice

Yang, N.·Zhao, H.·Sun, S.·Zhang, J.·Li, M.·Li, X.·Wu, X.
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Abstract

Asynchronous embryo transfer is widely used in assisted reproduction, yet its adverse effects and mechanisms remain unclear. This study investigates implantation failure in D1.5 pseudopregnant mice to elucidate mechanisms underlying asynchronous transfer. Blastocysts were transferred into uterine horns of D1.5 (Group A), D2.5 (Group B), and D3.5 (Group C) recipients. Implantation sites were counted at D7.5, and embryos were recovered within 3 hours post-transfer for analysis. Multibarcode single-cell RNA sequencing was applied to embryos and uterine tissues. Embryo recovery rate in Group A was significantly lower than in Groups B and C (p<0.01), with an abnormal embryo rate of 68.67%. Hoechst 33342/PI double staining revealed dead-cell features in abnormal embryos. Transcriptomic analysis of embryos showed downregulated DNA damage repair and structural maintenance genes in Group A. GO and KEGG analyses highlighted enrichment in transcriptional regulation and cell cycle pathways. GSEA identified activated apoptosis pathways, with intrinsic (mitochondrial) and extrinsic (death receptor TNFR-mediated) apoptosis genes significantly upregulated (p<0.05). Uterine transcriptome analysis revealed downregulated collagen family genes (ECM maintenance) but upregulated immune-related genes (IL family, CDs, C3) in Group A. Functional enrichment confirmed ECM and immune regulation pathway involvement. Gene network analysis identified Clca1, Smpdl3a, Tmprss4, Muc4, Cfb, and Nupr1 as key regulators of D1.5 uterine immunity/inflammation. D1.5 uterine immune dysregulation induces embryonic stress and inflammation. Impaired DNA damage repair activates intrinsic apoptosis, while upregulated TNFR signaling triggers extrinsic apoptosis, collectively blocking embryonic development toward implantation competence. These findings provide mechanistic insights into optimizing embryo transfer timing and improving reproductive outcomes.

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Yang, N., Zhao, H., Sun, S., Zhang, J., Li, M., Li, X., Wu, X.. 2025-09-25. Uterine immune dysregulation after asynchronous transfer induced embryonic apoptosis in mice. https://doi.org/10.1101/2025.09.24.677934

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