418 Paternal Programming of Offspring Health

There is now a significant body of human and animal model data identifying common associations between perturbed development during gestation, disproportionate fetal growth and poor adult cardiovascular and metabolic health. Typically, these studies have focused on the impact of poor maternal health on offspring development and well-being. However, a growing evidence base now indicates that sub-optimal paternal factors (such as diet) can also program adult offspring ill-health. While the link between paternal health and offspring well-being is becoming established, attention is being focused on defining the underlying mechanism(s). Here, the father may influence post-fertilization development through two main pathways, the integrity and status of the sperm genome (including epigenome) and through components of the seminal plasma. We have used a mouse model of paternal low protein diet to study the impact sub-optimal nutrition has on the quality and epigenetic status of the sperm, embryonic development and fetal growth. We have also used our model to study the relative seminal plasma and sperm contributions to adult offspring cardiovascular and metabolic health. Our studied highlight the role of a father’s diet at the time of conception for the development and well-being of his offspring.

Revealing grand-paternal programming of lipid metabolism using a novel computational tool

While the consequences of poor maternal diet on the offspring’s cardio-metabolic health have been studied in detail, the role of the father’s diet on the health of his offspring is poorly understood. We used a known mouse model to establish the impact of an isocaloric paternal low-protein high-carbohydrate diet on the offspring’s lipid metabolism. Detailed lipid profiles were acquired from F1 neonate (3 weeks), F1 adult (16 weeks) and F2 neonate male and female offspring, in serum, liver, brain, heart and abdominal adipose tissues by Mass Spectrometry and Nuclear Magnetic Resonance. Using a purpose-built computational tool for analysing lipid metabolism as a network, we characterised the number, type and abundance of lipid variables in and between tissues (Lipid Traffic Analysis), finding a variety of alterations associated with paternal diet. These elucidate a mechanism for the defective physiological behaviour of systems at risk of cardio-metabolic disease.

Paternal epigenetic programming: evolving metabolic disease risk

Parental health or exposures can affect the lifetime health outcomes of offspring, independently of inherited genotypes. Such ‘epigenetic’ effects occur over a broad range of environmental stressors, including defects in parental metabolism. Although maternal metabolic effects are well documented, it has only recently been established that that there is also an independent paternal contribution to long-term metabolic health. Both paternal undernutrition and overnutrition can induce metabolic phenotypes in immediate offspring, and in some cases, the induced phenotype can affect multiple generations, implying inheritance of an acquired trait. The male lineage transmission of metabolic disease risk in these cases implicates a heritable factor carried by sperm. Sperm-based transmission provides a tractable system to interrogate heritable epigenetic factors influencing metabolism, and as detailed here, animal models of paternal programming have already provided some significant insights. Here, we review the evidence for paternal programming of metabolism in humans and animal models, and the available evidence on potential underlying mechanisms. Programming by paternal metabolism can be observed in multiple species across animal phyla, suggesting that this phenomenon may have a unique evolutionary significance.