Editorial: "Sperm Epigenetic Code: Implications in Reproductive Health and Paternal Contribution to Embryo Development"

Marta Lombó¹Gilda Cobellis^2*Francesco Manfrevola^2,3

• ¹Universita Politecnica delle Marche Dipartimento di Scienze Agrarie Alimentari ed Ambientali, Ancona, Italy
• ²Universita degli Studi della Campania Luigi Vanvitelli Dipartimento di Medicina Sperimentale, Naples, Italy
• ³University of Campania Luigi Vanvitelli, Caserta, Italy

chromatin remodeling which arises during spermiogenesis. The hyperacetylation of lysine residues on histone H4 (notably H4K5, H4K8, H4K12, and H4K16) underlie the histone-to-protamine exchange in elongating spermatids. Precise regulation of these histone PTMs is indispensable for the acquisition of a functional paternal epigenome. In this regard, Porreca et al. have provided novel insights into the mechanistic involvement of histone -acetyltransferases (HATs) anddeacetylases (HDACs) in modulating H4 hyperacetylation. By exploiting the cannabinoid receptor 1 (CB1) knockout mice (Cb1 -/-) as a model of impaired histone displacement, the authors demonstrate how the aberrant interaction between deacetylase SIRT1 and the MOF acetyltransferase disrupts MOF-dependent H4K16 acetylation in elongating spermatids, leading to defective histone displacement and production of spermatozoa with abnormally retained chromatin H3-binding sites.The sperm epigenetic code is responsive to external environmental and lifestyle stressors such as pollutants, diet, stress and smoking (Chioccarelli et al., 2010;Pastore et al., 2024). In this light, the work of Porreca et al. also clarifies the putative adverse effects on sperm epigenetic landscape deriving from cannabis use. Mounting evidence suggests that alterations in the sperm epigenetic marks, such as DNA methylation, sperm-borne small RNAs, and histone PTMs (particularly acetylation of histones H3 and H4) may arise from metabolic disorders and environmental contaminants and can be transmitted to the following generations (Akhatova et al., 2025;Ma et al., 2020;Lombó et al., 2019;Al Khaled et al., 2018;Hammer et al., 2021;Yuan et al., 2017;Rothstein et al., 2017;Lismer et al., 2020;Terashima et al., 2015;Swanson et al., 2020;Chen et al., 2016). Hence, the study by Pastore et al. sheds As the burden of male infertility continues to rise globally, the urgency to decode the sperm epigenome grows. This emerging topic requires a paradigm shift: moving beyond genetic determinism to embrace a more integrative view of heredity, one that acknowledges the epigenetic memory embedded in the paternal germline. Supporting this notion, Lin et al. provide encouraging evidence that germ cells retain an intrinsic epigenetic memory. The authors demonstrate that although in vitro induced pluripotent stem cells (iPSCs) retain residual gene expression and epigenetic features of their source cell type, this memory is largely erased upon their differentiation into primordial germ cell-like cells (PGCLCs), faithfully recapitulating the epigenetic reprogramming triggered in vivo during embryonic PGC specification. This study confirms a selective germ cell epigenetic memory and holds great promise for reproductive medicine. In line with the concept of paternal epigenetic memory, Capra et al. performed a comparative study in Montbéliarde and Holstein bull sperm. Despite breed-specific epigenetic variations, the authors reveal the presence of conserved methylated regions across the genetically distinct breeds. Such evolutionary conserved epigenetic signature appears essential for maintaining genomic integrity, silencing transposable elements, and regulating key genes required for spermatogenesis and early embryonic development.In conclusion, the concept of the sperm epigenetic code radically reshapes our understanding on paternal heredity, extending it beyond DNA sequence to include dynamic, heritable, and environmentally sensitive epigenetic modifications. The vulnerability of sperm epigenome to external stressors, alongside rising global infertility rates, underscores the urgent need to integrate epigenetic knowledge into reproductive medicine and public health strategies. Decoding and ultimately modulating the sperm epigenome offers a promising avenue to improve fertility outcomes and safeguard the health of future generations.