Uneven impacts: how male diet modulates the sperm epigenome and impacts embryo development and pregnancy health†

While maternal health has long been the focus of reproductive and developmental research, increasing attention is being given to the father's preconception health. Over the past two decades, growing evidence supports the Paternal Origins of Health and Disease (POHaD) paradigm, highlighting how paternal environmental factors prior to conception can significantly influence offspring development and long-term health. Rodent models have provided critical mechanistic insights into how paternal environmental exposure can alter the sperm epigenetic cargo. Emerging evidence indicates that paternal nutrition not only impacts the embryo but also the placenta. This review synthesizes current knowledge on how different types of paternal diet influence the sperm epigenome and the downstream consequences for the feto-placental unit and for pregnancy outcomes. We provide essential context: first, on the placenta's sensitivity to environmental influences, and second, on the variability across studies exploring paternal dietary exposures, highlighting key factors that may modulate paternal effects. We then examine how an altered diet affects the sperm epigenome and describe the physiological and molecular consequences on embryonic and placental development. Importantly, these modifications are linked to adverse outcomes including fetal growth restriction and placental insufficiency, and may therefore contribute to maternal complications such as preeclampsia, known for its long-term cardiovascular impact on women. Our review underscores the need to integrate paternal health into preconception care strategies, alongside maternal health, as it could significantly improve pregnancy outcomes and long-term health of both mothers and offspring.