Parental health and diet at the time of conception determine the development and life-long disease risk of their offspring. While the association between poor maternal diet and offspring health is well established, the underlying mechanisms linking paternal diet with offspring health are poorly defined. Possible programming pathways include changes in testicular and sperm epigenetic regulation and status, seminal plasma composition, and maternal reproductive tract responses regulating early embryo development. In this study, we demonstrate that paternal low-protein diet induces sperm-DNA hypomethylation in conjunction with blunted female reproductive tract embryotrophic, immunological, and vascular remodeling responses. Furthermore, we identify sperm- and seminal plasma-specific programming effects of paternal diet with elevated offspring adiposity, metabolic dysfunction, and altered gut microbiota.Abstract
The association between poor paternal diet, perturbed embryonic development, and adult offspring ill health represents a new focus for the Developmental Origins of Health and Disease hypothesis. However, our understanding of the underlying mechanisms remains ill-defined. We have developed a mouse paternal low-protein diet (LPD) model to determine its impact on semen quality, maternal uterine physiology, and adult offspring health. We observed that sperm from LPD-fed male mice displayed global hypomethylation associated with reduced testicular expression of DNA methylation and folate-cycle regulators compared with normal protein diet (NPD) fed males. Furthermore, females mated with LPD males display blunted preimplantation uterine immunological, cell signaling, and vascular remodeling responses compared to controls. These data indicate paternal diet impacts on offspring health through both sperm genomic (epigenetic) and seminal plasma (maternal uterine environment) mechanisms. Extending our model, we defined sperm- and seminal plasma-specific effects on offspring health by combining artificial insemination with vasectomized male mating of dietary-manipulated males. All offspring derived from LPD sperm and/or seminal plasma became heavier with increased adiposity, glucose intolerance, perturbed hepatic gene expression symptomatic of nonalcoholic fatty liver disease, and altered gut bacterial profiles. These data provide insight into programming mechanisms linking poor paternal diet with semen quality and offspring health.