Establishing the sperm and seminal plasma mechanisms of paternal programming

建立父系编程的精子和精浆机制

• 批准号: BB/V006711/1
• 负责人: Adam Watkins
• 金额: $ 108.29万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV006711%2F1
• 关键词: Establishing; sperm; seminal; plasma; mechanisms

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.

我们作为成年人的健康可能会受到我们在子宫中发展的方式的影响。怀孕期间的孕产妇饮食不佳会增加她的后代超重，成年后患有2型糖尿病和心脏病。虽然良好的孕产妇饮食的重要性是充分理解的，但父亲饮食的重要性被忽略了。但是，对人类和动物的研究表明，如果父亲在受孕时吃质量较差（太少或太少），那么这不仅会影响他的精子质量，而且还会影响长期的心血管和代谢健康的后代健康。在他的后代研究中，动物研究在帮助我们了解养育饮食的影响方面发挥了重要作用。在这里，小鼠的繁殖和发育与人类相似，因此事实证明了小鼠的信息特别丰富。我们已经表明，喂养雄性小鼠低蛋白质饮食（LPD，营养不良）或高脂肪饮食（HFD，过度营养）会影响其睾丸中数百个基因的表达，从而加速其胚胎在怀孕期间的胚胎发展并增加其后代的大小。重要的是，所有这些因素都与成人生活中肥胖，2型糖尿病和心脏病的风险增加有关。确实，我们已经表明，喂食LPD的雄性小鼠的成年后代变得过重，并出现了心脏病和2型糖尿病的症状。有趣的是，我们观察到，精子和液体都被带入（精确等离子体）都能够使后代不良健康。这些观察结果表明，父亲可以以两种不同的方式影响他的后代的健康。首先，通过精子中的信息，然后通过精确等离子体进行。我们将在这个项目中详细探讨这两种途径。我们有独特的位置，可以利用我们已建立的小鼠LPD和HFD模型来定义将父亲饮食与他的后代发展联系起来的机制。在这一提议下，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。具体而言，我们将定义精子的RNA含量，即受精后不久会影响胚胎中基因表达的分子。我们还将研究这些RNA分子在睾丸中形成和成熟时如何包装到精子中。与这些研究相辅相成，我们将探索睾丸的细胞结构，以确定质量较差的饮食如何影响精子的方式。我们的第二个目标将研究精确血浆的组成及其与精子和孕产妇生殖道相互作用的组成。这些相互作用很重要，因为精液离开睾丸后为精子增加了其他RNA分子，为精子做准备以施肥。此外，精确的血浆在子宫内启动一系列免疫和炎症反应，使其在胚胎植入之前进行准备。因此，我们将研究精液如何修饰精子的RNA货物以及它如何影响子宫内的蛋白质，免疫细胞和血管。之后，我们将表征子宫与胚胎之间的相互作用，以查看其正常交​​流是否因父亲饮食不良而破坏。最后，我们想了解一旦将LPD和HFD雄性置于对照饮食中，精子和精液血浆可以恢复正常。这些研究对于告知质量不佳饮食对男性生殖健康的永久影响至关重要。这项工作及时关注父亲饮食的作用。此外，我们关注的血浆以及精子的作用意味着我们的研究也是新颖的。我们认为，低估父亲如何影响他后代的健康对于向男人告知他们成为父亲的机会以及对子女健康的好处的机会至关重要。

项目成果

Paternal low protein diet perturbs inter-generational metabolic homeostasis in a tissue-specific manner in mice.

• DOI: 10.1038/s42003-022-03914-8
• 发表时间: 2022-09-08
• 期刊: Communications biology
• 影响因子: 5.9

Parental Programming of Offspring Health: The Intricate Interplay between Diet, Environment, Reproduction and Development.

• DOI: 10.3390/biom12091289
• 发表时间: 2022-09-13
• 期刊: BIOMOLECULES
• 影响因子: 5.5
• 作者: Batra, Vipul;Norman, Emily;Morgan, Hannah L.;Watkins, Adam J.
• 通讯作者: Watkins, Adam J.

Characterisation of the Paternal Influence on Intergenerational Offspring Cardiac and Brain Lipid Homeostasis in Mice.

• DOI: 10.3390/ijms24031814
• 发表时间: 2023-01-17
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Furse, Samuel;Morgan, Hannah L.;Koulman, Albert;Watkins, Adam J.
• 通讯作者: Watkins, Adam J.