Mechanistic insights of sexual transmission of MPXV Clade I and II and associated impacts on the reproductive tissues: An integrated transcriptomic approach

Problem Monkeypox virus (MPXV) has recently been detected in semen and genital secretions, raising the possibility of increased sexual transmission. These questions on the plausible molecular impact of MPXV on human reproductive tissues, especially tissue-specific pathological changes, fertility risks, and pregnancy complications, remain poorly understood to date. Method of Study We applied an integrative bioinformatics approach using available transcriptomic datasets and protein interaction networks to assess MPXV’s effects on reproductive organs/tissues, including testis, epididymis, prostate, cervix, and placenta. Differentially expressed genes (DEGs) were examined through functional enrichment and hub gene identification. Results Clade II-associated genes mapped frequently to reproductive tissue expression datasets, whereas Clade I-associated genes showed minimal overlap. In males, the testis and epididymis revealed altered expression of chromatin regulators (CDC14A, PLK1, histone H4 variants) and cytoskeletal–centrosomal genes required for spermatogenesis. Enrichment of extracellular matrix (ECM) remodelling and TGF-β signalling was identified in the prostate targeted by DPP4 and PMEPA1 as potential host hub genes. In sperm, stress-chaperone responses, cytoskeletal reorganization, and innate immune activation were the most likely influenced pathways. In females, Clade II DEGs were associated with Wnt, TGF-β, ECM, and angiogenesis pathways. Maternal-fetal tolerance, regulated by these pathways, was altered in the placenta. Ovarian DEGs highlighted follicular ECM processing and developmental regulators (ADAMTS1, GATA6, LHX9). Conclusion Our study depicts clade-specific and tissue-associated perturbed transcriptional signatures following MPXV exposure, with the strongest in testis, epididymis, and placenta, supporting clinical evidence of semen shedding and pregnancy risks. These findings highlight probable predicted candidate pathways and genes that could be utilized to design therapeutics in the future, following experimental validation.