Assessing the epigenetic consequences of ART in male infertility: what risks to embryo and offspring health?

Abstract

Male infertility affects approximately 7 to 8% of men worldwide and is influenced by both genetic and epigenetic factors. Epigenetic mechanisms - including DNA methylation, histone modifications, and non-coding RNAs - are essential for spermatogenesis, sperm function, and early embryonic development. Disruptions in these processes can impair fertility and embryo viability. Assisted reproductive technologies (ART), particularly intracytoplasmic sperm injection (ICSI), have enabled conception in previously untreatable cases; however, by bypassing natural selection barriers, they may facilitate the transmission of epigenetic abnormalities. This narrative review summarizes recent clinical and experimental evidence on sperm epigenetics, emphasizing paternal health, sperm epigenetic signatures, and ART-associated developmental risks. During spermatogenesis, extensive epigenetic remodeling occurs, including protamine-histone exchange, selective histone retention, and RNA packaging, all critical for embryogenesis. Conditions such as varicocele, obesity, advanced paternal age, toxin exposure, and malignancy have been linked to abnormal DNA methylation, altered chromatin structure, and dysregulated small RNAs. Seminal extracellular vesicles also mediate environmental influences on implantation and immune modulation. Because ART coincides with windows of epigenetic vulnerability, laboratory procedures - including sperm selection, cryopreservation, and embryo culture - may contribute to imprinting disturbances. Understanding these mechanisms is essential to optimize reproductive safety while preserving ART efficacy.