Early psychosocial environment, biological and epigenetic printing and health status during adulthood – IBISS: Incorporation Biologique et Inéga

An integrative approach between different disciplines has been developed (including epidemiologists, statisticians, psychologists, neurobiologists, endocrinologist, epigeneticists, bioethicists and philosophers) distributed in 5 working groups (WG): WG1 defines and specifies the early psychosocial exposures likely to have an impact on long-term health in humans by involving psychologists, child psychiatrists, specialists in lifecourse epidemiology, neuroscientists; WG2 analyzes the biological effects of psychosocial (maternal separation) and nutritional (mother’s pregnancy obesity) stress on long-term health (cancer development, metabolic and behavioral disorders), including the analysis of epigenetic modifications; WG3 investigates statistical issues around the study of causal chains linking early exposure and adult health over the lifecourse; WG4 explores the societal and ethical issues in terms of public policies raised by the demonstration of a social to biological transition and how this knowledge can emerge in the public debate; WG5 incorporates some of the results produced by the other WGs to study the links between early social environment, biological functioning and adult health status in humans, using cohort data.

The main results of this project fall into different categories:
-Early psychosocial stress and the maternal nutrition during pregnancy are linked to biological (metabolic, epigenetic) and behavioral changes which may potentially have long-term impact (metabolic diseases, cancer) in animals and humans. This has been emphasized in mice in which maternal separation and maternal obesity have a long-term impact on metabolism, corticotropic axis, motivation for palatable food, and emotional behaviors in offsprings. These changes are associated with a modification of the gene expression profile specifically in the nucleus accumbens whici is a cerebral key region of the reward circuit, with differences depending on the type of stress and gender. These two early exposures also accelerate the kinetics of pancreatic carcinogenesis. These findings were also found in humans: analyzes from human cohorts found an influence of adversity during childhood and maternal BMI before pregnancy on biological functioning (overall physiological wear and tear, metabolic syndrome).
- An analysis of the ethical and societal impacts of this research and in particular an analysis of consequences that such results could produce both at the individual level (for future patients) as at the collective level (public health policies) including their dissemination in the society
- The production of a general theoretical model of biological embedding of the environment
- The production of a method to guide and produce interdisciplinary work

The results from IBISS have been the subject of numerous scientific publications as well as multiple presentations at national and international conferences. The results have been detailed in the deliverables scheduled in the original protocol. Societal and ethical debate has also been the focus of a particular effort, notably through the participation of several partners in meetings and discussions with policy makers.
The exploitation of the results is also reflected in the willingness of the «IBISS consortium«, involving all partners, to continue to explore this issue together. We propose to explore the new challenges highlighted in IBISS in the framework of a new ANR project, entiltled «GENESE». This project has been submitted as part of the AAPG ANR 2017.

This project has helped to establish a culture of «exchange« between social, biological and societal phenomena, which tend to still be investigated separately. Scientific production is important and includes mono and multi-partner scientific papers, reports as oral communications and posters in national and international conferences. Societal and ethical debate has also been the focus of a particular effort, notably through the participation of several partners in meetings and discussions with policy makers.

This project aims to determine how early life psychosocial exposures modify biological, in particular epigenetic processes leading to pathologies later in life. Such exposures, socially differentiated may explain some of the observed health inequalities. To achieve the project aim, six work-packages (WP) have been defined:
The aim of WP1 will be to specify what is meant by “early life psychosocial environment” and which psychosocial exposures occurring in early life have a long term impact on health status. Understanding of the timing, periods during early development, especially brain development, will be a main point. This work will also serve to elucidate which factors are necessary for optimal development in childhood. WP1 will develop pre-existing standardised tools for identifying the important exposures or mechanisms to carrying out research on future or current epidemiological studies.
WP2 aims to examine the biological processes involved in what ?. Animal models remain a vital tool for studying the influence of early events on adult health, by testing causality and having access to tissues that are inaccessible in humans. How the plasticity of the epigenome links early life psychosocial and nutritional exposures in early development and adult pathologies is a challenging issue. Allostatic load uses a number of so far traditional markers to measure the consequence of general adaption to the environment over time, on health status. This cannot be not limited to a few tissues and a few genes; however it necessarily results in a broad genome-wide and system-wide change in the epigenetic landscapes. Thus multiple functional gene networks remain to be elucidated at the genome-wide level, in a sex-specific manner. Most epigenetic marks supporting the memories of past environmental impacts are tissue-specific, generally not available in humans (prefrontal cortex, pancreas, liver). Recent data demonstrate that some changes may also affect WBC such as T-cells, tissue collected in human cohorts. WP2 will use three mouse models combined to next generation sequencing, MeDIP-seq and transcriptomic approaches. This genome-wide analysis of differential DNA methylation together with expression analysis will highlight specific causal mechanisms through the identification of genes, the methylation and the expression of which are altered. A short list of candidate sequences will be transfer to human cohorts in a sex-specific approach
WP3 will focus on method and statistical issues raised by the analysis of early life exposures in relation to later health outcomes. These issues include how to select appropriate variables and statistical models that take into account the complexity of lifecourse trajectories and the direction of causal pathways over time (mediation).
WP4 will focus on major ethical issues, on the way in which links between social and biological factors ought to be dealt as public health and gender issues. Also, how to disseminate these findings and bring about an appropriate public debate on results of the research are important issues to consider.
WP5 will synthesise the results from the aforementioned WP to translate the findings into epidemiological research on human populations. This WP will aim to use data available from cohort studies to test hypotheses generated on the links between the early psychosocial environment and adult health.
This innovative project explores the underlying mechanisms in the production of health inequalities using integrative approach (epidemiology, psychology, neuroscience, epigenetics, ethics, statistics) which produce knowledge useful for public health interventions to tackle social health inequalities.