Establishing the sperm and seminal plasma mechanisms of paternal programming

我们成年后的健康会受到我们在子宫中发育情况的影响。怀孕期间糟糕的母亲饮食会增加她的后代超重、成年后患有2型糖尿病和心脏病的风险。虽然良好的母亲饮食的重要性是众所周知的，但父亲的饮食的重要性却被忽视了。然而，对人类和动物的研究表明，如果父亲在受孕时饮食质量不佳(过多或过少)，这不仅会影响他的精子质量，还会影响其后代长期的心血管和新陈代谢健康。动物研究在帮助我们了解父母的饮食可能如何影响后代健康方面发挥了重要作用。在这里，老鼠被证明是特别有信息量的，因为它们的繁殖和发育与人类相似。我们已经证明，无论是低蛋白饮食(LPD，营养不良)还是高脂肪饮食(HFD，营养过度)，喂养雄性小鼠都会影响它们睾丸内数百个基因的表达，加快它们胚胎发育的速度，并在怀孕期间增加后代的大小。重要的是，所有这些因素都与成年后肥胖、2型糖尿病和心脏病风险的增加有关。事实上，我们已经证明，喂食低密度脂蛋白的雄性小鼠的成年后代会超重，并出现心脏病和2型糖尿病的症状。有趣的是，我们观察到精子及其携带的液体(精浆)都能导致后代健康不佳。这些观察表明，父亲可以通过两种不同的方式影响子女的健康；第一种是通过精子中携带的信息，第二种是通过精浆。我们将在本项目中详细探索这两条路径。我们处于独特的地位，可以使用我们建立的小鼠LPD和HFD模型来定义父亲的饮食与其后代发育之间的联系机制。在这项建议下，我们将首先确定父亲的饮食如何影响其精子中传递的遗传信息。具体地说，我们将定义精子的RNA含量，即已知在受精后不久影响胚胎内基因表达的分子。我们还将研究当精子在睾丸中发育和成熟时，这些RNA分子是如何包装到精子中的。作为对这些研究的补充，我们将探索睾丸的细胞结构，以确定劣质饮食如何影响他们产生精子的方式。我们的第二个目标将研究精浆的组成以及它如何与精子和母体生殖道相互作用。这些相互作用很重要，因为精浆在精子离开睾丸后向精子添加额外的RNA分子，为精子受精做好准备。此外，精浆在子宫内启动一系列免疫和炎症反应，为胚胎植入做好准备。因此，我们将研究精浆如何修饰精子的RNA货物，以及它如何影响子宫内的蛋白质、免疫细胞和血管。接下来，我们将描述子宫和胚胎之间的相互作用，看看父亲糟糕的饮食是否会扰乱它们的正常沟通。最后，我们想要了解，一旦LPD和HFD男性接受控制饮食，精子和精浆恢复正常的速度有多快。这些研究对于告知劣质饮食对男性生殖健康的持久影响将是重要的。这项研究在关注父亲饮食的作用方面是及时的。此外，我们对精浆和精子的作用的关注意味着我们的研究也是新颖的。我们认为，低估父亲如何影响子女的健康，对于告诉男性如何提高成为父亲的机会以及对孩子健康的好处都是至关重要的。

Our health as an adult can be influenced by how we develop in the womb. Poor maternal diet during pregnancy can increase the risk her offspring will become overweight, have type 2 diabetes and heart disease as adults. While the importance of a good maternal diet is well understood, the importance of the father's diet has been overlooked. However, studies in humans and animals indicate that if the father eats a poor quality diet (too much or too little) at the time of conception, this not only affects the quality of his sperm, but can also affect the long-term cardiovascular and metabolic health of his offspring.Animal studies have played a significant role in helping us understand how parental diet may affect offspring health. Here, mice have proved especially informative as their reproduction and development are similar to humans. We have shown that feeding male mice either a low protein diet (LPD, under-nourished) or high fat diet (HFD, over-nourished) affects the expression of hundreds of genes within their testes, accelerates the rate their embryos develop and increases the size of their offspring during pregnancy. Importantly, all of these factors have been associated with increased risk of obesity, type 2 diabetes and heart disease in adult life. Indeed, we have shown that adult offspring from male mice fed LPD become over weight and developed symptoms of heart disease and type-2 diabetes. Interestingly, we observed that both the sperm and the fluid they are carried in (seminal plasma) were able to drive offspring ill-health. These observations suggest that a father can affect the health of his offspring in two separate ways; first through information carried in the sperm and second through the seminal plasma. It is these two pathways that we will explore in detail in this project. We are uniquely positioned to use our established mouse LPD and HFD models to define the mechanisms linking a father's diet with the development of his offspring.Under this proposal, we will first determine how a father's diet affects the genetic information passed on in his sperm. Specifically, we will define the sperm's RNA content, molecules known to influence gene expression within the embryo shortly after fertilisation. We will also study how these RNA molecules are packaged into the sperm as they develop and mature in the testis. Complementing these studies we will explore the cellular structure of the testes to determine how a poor quality diet affects the way they make sperm. Our second objective will study the composition of the seminal plasma and how it interacts with the sperm and the maternal reproductive tract. These interactions are important as the seminal plasma adds additional RNA molecules to the sperm after they leave the testes, preparing the sperm for fertilisation. Additionally, the seminal plasma initiates a range of immune and inflammatory responses within the uterus that prepares it ahead of embryo implantation. Therefore we will study how the seminal plasma modifies the RNA cargo of the sperm and how it affects the proteins, immune cells and blood vessels within the uterus. Following this, we will characterise the interaction between the uterus and the embryo to see if their normal communication is disrupted by poor paternal diet. Finally, we want to understand how quickly the sperm and seminal plasma can return to normal once the LPD and HFD males have been placed onto a control diet. These studies will be important for informing how permanent the effects of a poor quality diet might be for male reproductive health.This work is timely in its focus on the role of a father's diet. In addition, our focus on the role of the seminal plasma as well as the sperm means our study is also novel. We believe that understating how a father can affect the health of his offspring is critical for both informing men on how improve their chances of becoming a father and on the benefits for the health of their children.