Defining the impact of paternal nutrition on fetal growth regulation

我们知道母亲在怀孕期间吃的东西对孩子的发育和成长很重要。我们还知道，怀孕期间的不良饮食会增加孩子长大后超重、成年后患2型糖尿病或骨质疏松症的风险。虽然母亲的饮食和孩子的健康之间的关系已被详细研究，父亲的饮食和孩子的健康之间的关系一直被忽视。为了解决这一知识差距，我进行了一系列实验，给雄性老鼠喂食低蛋白饮食（LPD；营养不良，营养不均衡的饮食）。我发现LPD喂养的雄性小鼠的成年后代变得超重，体脂更多，并出现心脏病和2型糖尿病的症状。由于所有的雌性（母）老鼠在怀孕期间都被喂食同样优质的饮食，这些后代健康的变化完全是由它们父亲的不良饮食引起的。特别有趣的是观察到父亲的LPD增加了他的后代出生时的体重。在对人类和动物的研究中，我们知道，出生时体重明显增加会增加成年后患心脏病、肥胖、糖尿病和骨质疏松症的几率。因此，了解父亲的饮食如何影响其子女出生前的生长发育，对于防止子女在成年后出现健康状况不佳的情况至关重要。使用我的老鼠模型，我有独特的优势来解决父亲的饮食如何影响他的后代在出生前的生长。小鼠是用于此类研究的极好模型，因为小鼠和人类之间调节代谢、繁殖、胚胎发育和后代健康的许多生物过程是相同的。使用我的小鼠模型，我已经确定了胚胎基因表达、胎儿生长、骨形成和胎盘发育在父亲LPD反应中的关键变化。这些数据表明，不良的父亲饮食影响了一系列基本的生物学过程，并确定了研究调节后代发育的关键机制。因此，本提案将扩展我现有的小鼠父系饮食研究，建立不良父系饮食影响其后代在出生前发育和生长的确切机制。此外，我将确定在父亲的不良饮食中补充特定的维生素组合是否对父亲的健康和后代的健康都有益。根据这个提议，我将首先确定父亲的饮食如何影响早期胚胎的发育和代谢。我将测量胚胎的代谢，胚胎发育的速度，并观察胚胎表达的蛋白质。这是因为我们知道早期胚胎发育的变化会影响胎儿的生长和后代成年后的健康。我的第二个目标是确定后代的生长是否受到胎盘功能的影响。在这里，我将测量关键营养物质从母亲到胎儿的运输，并将其与胎盘中表达的所有基因联系起来。这些研究将揭示父亲是否“劫持”了胎盘，对其进行编程，以促进后代的生长。第三个目标是将父亲的饮食与其后代骨骼的发育联系起来。在这里，我将使用最先进的成像技术来测量后代骨骼是如何构建、组织和结构的，从而对他们晚年的骨骼强度有重要的了解。最后，我将描述父亲的饮食如何影响他精子的发育，以及遗传信息是如何代代相传的。这项工作很及时地关注了父亲的饮食对后代的成长和健康的作用。这项研究的结果将帮助那些希望成为父亲的男性改善他们的饮食和生活方式，以有利于孩子的健康。

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.