Dad's Diet Shapes the Future: How Paternal Nutrition Impacts Placental Development and Childhood Metabolic Health
David A. Skerrett‐Byrne, Anne-Sophie Pépin, Katharina Laurent, Johannes Beckers, Robert Schneider, Martin Hrabě de Angelis, Raffaele Teperino
Abstract
Early-life programming is a major determinant of lifelong metabolic health, yet current preventive strategies focus almost exclusively on maternal factors. Emerging experimental and preclinical data reveal that a father's diet before conception, particularly high-fat intake, also shapes offspring physiology. Here, we synthesize the latest evidence on how such diets remodel the sperm epigenome during two discrete windows of vulnerability: (i) testicular spermatogenesis, via DNA methylation and histone modifications, and (ii) post-testicular epididymal maturation, where small non-coding RNAs are selectively gained. We examine how these epigenetic signals influence pregnancy, placental development, and ultimately, metabolic trajectories in progeny. To extend published work, we sourced publicly available diet-induced sperm epigenome datasets and provide new potential connections of these changes to genes governing placental development, vascularization and size using the International Mouse Phenotyping Consortium data. Moreover, we further interrogate these overlaps with intricate in-silico analyses to examine their potential consequences. To foster meaningful interactions with these findings, we have developed a web application for ease (ShinySpermPlacenta). Collectively, these findings support a biparental model of preconception care and position the sperm epigenome as a promising tractable biomarker platform for personalized paternal nutrition counselling aimed at improving fertility and reducing intergenerational metabolic disease risk.