Defining the impact of paternal nutrition on fetal growth regulation

点击翻译按钮获取中文摘要

We know that what a mother eats during pregnancy is important for the development and growth of her child. We also know that a poor diet during pregnancy can increase the risk that her child grows up being overweight, having type-2 diabetes or osteoporosis in adulthood. While the relationship between a mother's diet and the health of her child has been studied in detail, the relationship between a father's diet and his child's health has been neglected.To begin to address this knowledge gap, I conducted a series of experiments in which male mice were fed a low protein diet (LPD; a poor, nutritionally imbalanced diet). I found that adult offspring of LPD fed male mice became over weight, had more body fat and developed symptoms of heart disease and type-2 diabetes. As all the female (mothers) mice were fed the same good quality diet during pregnancy, these changes in offspring health are solely caused by the poor diet of their fathers. Of specific interest was the observation that a paternal LPD increased the weight of his offspring at birth. In human and animal studies we know that being significantly heavier at birth increases the chances of developing heart disease, obesity, diabetes and osteoporosis in adulthood. Therefore, understanding how a father's diet affects the growth of his offspring before birth is central to preventing the development of poor health in adult life. Using my mouse model, I am uniquely positioned to address the question of how a father's diet affects the growth of his offspring before birth. Mice are an excellent model to use for such studies as many of the biological processes regulating metabolism, reproduction, embryo development and offspring health are the same between mice and humans. Using my mouse model, I have identified key changes in embryonic gene expression, fetal growth, bone formation and placental development in response to paternal LPD. These data suggest poor paternal diet affects a range of fundamental biological processes and identify key mechanisms for study in the regulation of offspring development. Therefore, this proposal will expand on my existing mouse paternal diet studies establishing the precise mechanisms through which poor paternal diet affects the development and growth of his offspring prior to birth. In addition, I will determine whether supplementing a poor paternal diet with specific combinations of vitamins can be beneficial for both paternal health and the health of his offspring. Under this proposal, I will first determine how a father's diet affects the development and metabolism of the early embryo. I will measure what the embryo metabolises, the rate at which the embryo develops and look at which proteins the embryo is expressing. This is because we know that changes in early embryo development can affect the growth of the fetus and offspring health in adult life. My second objective is to determine whether offspring growth is influenced by the function of the placenta. Here, I will measure the transport of key nutrients from the mother to her fetus and relate this to all the genes that are expressed within the placenta. These studies will inform on whether a father 'hijacks' the placenta, programming it to enhance the growth of his offspring. A third objective will be to relate paternal diet to the development of his offspring's skeleton. Here, I will use state-of-the-art imaging techniques to measure how offspring skeletons are built, organised and structured, giving important insight into their bone strength in later-life. Finally, I will characterise how a father's diet affects the development of his sperm and the genetic information that is passed from one generation to the next.This work is timely in its focus on the role of a father's diet for the growth and well-being of his offspring. Findings from this study will help men, wishing to become a father, improve their diet and lifestyle for the benefit of their children's health.