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Defining the impact of paternal nutrition on fetal growth regulation

Reference	BB/R003556/1
Principal Investigator / Supervisor	Dr Adam Watkins
Co-Investigators / Co-Supervisors
Institution	University of Nottingham
Department	School of Medicine
Funding type	Research
Value (£)	506,484
Status	Completed
Type	Research Grant
Start date	01/04/2018
End date	31/12/2021
Duration	45 months

Abstract

Our health as an adult can be shaped by our development prior to birth. The link between maternal nutrition, fetal growth and adult health is well established. However, the impact a father's diet has on the health of his offspring remains largely unknown. I have shown that offspring from male mice fed a sub-optimal low protein diet (LPD) were born heavier, had increased adiposity, cardiovascular dysfunction and glucose intolerance. These effects were associated with significant reductions in embryonic gene expression, increased fetal growth, decreased placental size and reduced paternal sperm epigenetic status. These data establish for the first time a new link between paternal diet, sperm quality, fetal development and adult offspring health. However, the underlying mechanisms remain poorly defined. This proposal will elucidate the molecular mechanisms underlying paternal programming of offspring development. Male mice will be fed either a control diet, LPD (under-nutrition), high fat diet (HFD; over-nutrition) or methyl-donor supplemented LPD or HFD as a dietary intervention to preserve paternal epigenetic status. Using these males, I will first define embryonic development, metabolism and transcription profiles, relating patterns of early development with late gestation tissue status. Second, I will quantify placental global transcription profiles by RNA-Seq and the in vivo trans-placental maternal-fetal transfer of nutrients. Following this, I will characterise offspring mesenchymal stem cell differentiation capacity in addition to imaging analyses of offspring bone development. Finally, I will establish the impact of diet on paternal methyl-donor metabolism, sperm DNA methylation, histone modifications and miRNA content. This proposal represents a paradigm shift in developmental programming and the amelioration of such mechanisms. Findings from this proposal will have translational relevance for human health, being of significance to intending fathers.

Summary

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.

Impact Summary

Enhancing public awareness of current societal issues: While the concept that an expectant mother should consume a healthy, balanced diet during pregnancy is well accepted, no such advice is given to the father. Findings from this proposal will reveal the significance of a poor paternal diet for the development of his offspring and the effectiveness of a simple dietary supplementation. Therefore, we anticipate the general public will be very interested in the findings of our study. As such, dissemination of our results to the public will be a core, managed component of this project. To achieve this, the PI, PDRA and Collaborators will engage with institutional facilitators, popular science outlets (e.g. the Conversation https://theconversation.com/profiles/adam-watkins-309540), professional society activities (SRF, COST), social media and University open days. Public health: The long-term goal of this study is the implementation of its findings, through the public and private sector, to benefit public health and well-being. The focus of this proposal on both under- and over-nutritional regimens will have significant benefit for developing- as well as developed-nations and the health systems that support them. The investigation into the impact of simple dietary supplementation on paternal reproductive epigenetic status, offspring development and health could result in new Public Health policies concerning advice to prospective parents. The analysis of changes in paternal epigenetic status could be developed also into a new non-invasive tools for analysis of paternal reproductive fitness. Commercialisation: While it is not the focus of our study to develop specific commercial products or industrial stakeholder partnerships, the use of a mouse model allows for un-paralleled analysis of the genetic, epigenetic and molecular mechanisms underlying the programming of offspring health in response to parental diet. Identification of essential nutrients and dietary intervention strategies, as well as markers of paternal epigenetic status that link reproductive fitness with offspring development, would have clear translational impact and be of commercial interest (See attached letter of support from Ostara Biomedical). Defining the mechanisms underlying development, health and well-being: This novel mechanistic investigation will define new associations between paternal nutrition, reproductive epigenetic status and post-fertilisation development. While this study is focused fundamentally on the underlying mechanisms in a mouse model, we believe findings from this proposal will be of benefit to relevant clinical and industrial stakeholders. Non-academic beneficiaries: Findings from this proposal will be of benefit to health-care professionals offering dietary advice to intending parents, clinicians involved in assisted reproduction and fertility treatment, paediatricians, policy makers concerned with diet, adult health, fertility and pregnancy management and prospective parents. Enhancing the knowledge base: Wider developmental and biomedical research communities will benefit through the deposition of novel RNA-Seq data sets within online repositories and the development of new software pipelines for transcript profile analysis. Collaborations established within this proposal will allow for the transfer of knowledge and skills between the Collaborator institutions and Aston University. Added value and impact for the PI and PDRA: The appointment of a PDRA to the laboratory of Dr Watkins will add significantly to the output, impact and career development of Dr Watkins. In addition, significant training and career development opportunities will be given to the PDRA. New collaborations with Dr Glazier and Dr Dunn, as well as continued collaboration with Professor Emes and Professor Addison, will be key for increasing the skill base, career development and collaborative capacity of both Dr Watkins and the PDRA.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Ageing, Diet and Health
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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