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Periconceptional Programming of Health Training Network

Periodic Reporting for period 1 - DohART-NET (Periconceptional Programming of Health Training Network)

Reporting period: 2019-07-01 to 2021-06-30

Altered conditions during the periconceptional (PC) period of gamete maturation and early embryonic development have long lasting effects on the health of the progeny, including the childhood, adolescent and adult-life onset of cardiovascular, metabolic and neurological diseases (‘Developmental Origins of Health and Disease (DOHaD) concept). Increasing evidence from epidemiological and animal model studies shows that children worldwide exhibit conditions and disease risks associated with the exposures of their parents, including chemical stressors before and during pregnancy, reproductive failure, adverse pregnancy outcome, diabetes, obesity and nutritional compromise. Babies born following human Assisted Reproductive Technology (ART, “test-tube”) interventions render this population (over 8 million world-wide) one of the largest well-defined clinical cohorts to be studied for a better understanding of the future risk of disease for current and succeeding generations in Europe. The DohART-NET project focuses on the integration of pre-clinical (animal and stem cell-models) and clinical studies and applies data linkage, bioinformatics and network science for the identification and validation of mechanisms of diseases common in early development. We will exploit our new understanding to promote efficient disease prevention and potential personalised therapeutic interventions in both the general and ART populations to overcome adverse disease pathways.
The DohART-NET project scientific activities have efficiently started, and all ESRs have their own scientific projects as planned, with well-defined roles and responsibilities, received the planned consortium wide trainings and they are also highly involved in the discussions of the consortium aims and progress. The scientific progress was slightly delayed by the COVID epidemy related restrictions, temporary laboratory closures and travel restrictions, but overall the project work tasks are well underway, and the very important dry data projects experienced only minor delays. The ESRs using all electronic communication means completed several literature reviews resulting in collaborative manuscripts for a journal special issue closely related to the topic https://doi.org/10.3390/genes12101564. A high-quality paper with ESR3 as second-author have been published in Nature Genetics (https://doi.org/10.1038/s41588-021-00898-9). The ESRs contributed to promote the project results with dissemination and outreach activities very efficiently.
In the frame of DohART-NET project the consortium members are efficiently contributing to find new evidences using different models and datasets to prove that children physiological well-being and future disease risks are associated with the exposures of their parents. However, the exact mechanism and possibilities for prevention remain poorly understood. Because the oldest ART children are only just entering adulthood, there is an urgent need to improve the current very limited epidemiology-based risk assessment and ultimately modifying high risk ART factors to improve long term health of ART children. DohART-NET is going significantly beyond the current state-of-the-art by addressing the issues described above with an unprecedented in depth-analysis, using access to the UK National ART cohort which is the largest and oldest available and will provide access for the first time to data on ART children into adulthood, and by combining detailed clinical cohorts of ART and normal pregnancies. Furthermore, the in-depth integration of rodent and large-animal models, clinical datasets with biomarker discovery and the appropriate human stem cell models and network science applied to such datasets has never been previously attempted. The expected outcome of the project is also beyond the state-of-the-art by aiming at active interventions to correct adverse effects of ART and paternal exposures, which would be a paradigm change for the medical field.
Significant progress beyond the current state-of-the-art have been made in all aspects of the project. Work package activities include human participants, mouse and pig in vivo models as well as human in vitro models, human birth cohorts and other databases, and in silico methods, including network science methods to analyse correlations among contributing factors and health outcomes. Furthermore, studies cover 3D measurements and mHealth data base analysis in the Smarter Pregnancy human cohort. Specifically, the individual projects of the students enhancing the knowledge of the scientific community and the public on DOHaD, for example ESR4 completed a full literature review of the impact of human ART on birthweight and child growth and started to analyse existing databases, including the impact of ART exposure on growth of twins from the Scottish linkage cohort. ESR5 has conducted a molecular level analysis of possible mechanisms underlying this effect, which is also being prepared for publication in a high-quality journal and has also been chosen for an oral presentation at Fertility 2022. ESR7 results provide essential information on the impact of maternal lifestyle factors on foetal development, in hope to better understand intrauterine developmental mechanisms and ultimately help clinicians to improve pregnancy care. The generation of a new cohort of maternal high fat diet mice has taken place. Preliminary results are gathered on metabolic and cognitive behaviours, as well as tissues from adult offspring for later analysis. Cohorts of diabetic pig model is also underway with generation of data and tissues. Neuronal and cardiac differentiation of human induced pluripotent stem cells allows measurement of the effect of different stressors during early differentiation events and tissue lineage commitment (ESR1 and ESR2, respectively).
Expected results of the projects include:
Report on impact of periconceptional maternal obesity severity, related dietary patterns on embryonic, foetal and infant human health and on 1-C pathway and other biomarker networks.
Report on effect of mouse HFD on maternal uterine fluid composition, serum metabolites and adult brain.
Report on effects of maternal diabetes on physiological parameters and OMICs profiles in pig neonates, generation of a biobank of body fluids and tissues.
Report on the effect of nutritional exposures on the neuronal and cardiac differentiation of human pluripotent stem cells.
Identification of the risk for pregnancy complications and outcome in obese women during the periconception period based on oxidative stress markers routinely used in clinical practice.
The use of eHealth application „Smarter Pregnancy” tailored to lifestyle coaching platform for obese women to reach a healthier state of pregnancy.

The long-term impact of the project can have a major impact on European society which is ageing and suffering from a dramatic increase in metabolic syndrome diseases. DohART-NET provides major added value by focusing on long-term consequences of periconceptional events and ART technologies on human health. Importantly, DohART-NET is also an excellent training programme for 13 talented early stage researchers who joined the consortium from different parts of the world with the aim of reaching the project goals and help society in Europe and beyond during their future scientific carriers.
ESR13 presents on ESHRE