Epigenetic stability in a stressful environment and its effects on reproductive function

Lead Research Organisation: Durham University
Department Name: Anthropology

Abstract

Why do behaviour and health vary among individuals? Social scientists are interested in finding out how the environment influences our lives. Similarly, many biologists study DNA - the genetic material in our cells - to understand how we develop. Until recently it was thought that small differences in our DNA could largely explain the way we are. "It's all in the genes" was the assumption. We now know that the DNA sequence of an individual does not tell the whole story. The way DNA is stored in cells plays a key role in how genes are turned on and off. Such gene 'regulation' - termed epigenetics - includes a variety of mechanisms, such as the addition or removal of a methyl-group to one of the building blocks of DNA -- a dynamic process across life. Importantly, biologists have recently realised that environmental stimuli and stresses can influence gene regulation during certain stages of development. Understanding how genes become regulated would greatly improve our knowledge of why individuals differ. To answer some of these questions, we have established a network of researchers in epigenetics and social science to explore how early life stress influences reproductive health in females. We will focus on groups of Bangladeshi migrants that have been shown in prior studies to have different levels of reproductive function depending on where they lived when they were young. Those who grew up in Bangladesh (with greater exposure to infectious diseases) have consistently lower biomarkers of reproductive function, including hormone levels such as progesterone. We will use migrant Bangladeshis as a human case study to assess possible epigenetic mechanisms that might explain this lower reproductive function. Rates of epigenetic ageing will be compared between groups through analyses of DNA methylation patterns to assess whether early life stress has altered the epigenetic clock in these groups. In addition, we will evaluate the epigenetic stability of methylation patterns in one of the genes which is key player operating within the reproductive system, namely the luteinising hormone receptor gene (LHR). We will compare methylation patterns of the LHR across Bangladeshi groups to assess whether epigenetic mechanisms can help to explain differences in progesterone levels. We will also study epigenetic regulation of genes and hormones that control the processes of reproduction in mice that are exposed to different environments when they are young. We hypothesise that the treated mice will have a delayed onset of puberty and also lower levels of progesterone. We will look for changes in epigenetic packaging and modification of the DNA around the LH, LHR and other key genes between the two groups of mice that might explain any changes in hormone levels. We will also compare epigenetic signatures following treatment in different mouse tissues, such as ovarian and buccal (cheek) tissue. If these two tissues are similarly altered, this will indicate that buccal tissue (non-invasive) can be used as a source for future epigenetic studies in humans as well. The mouse buccal tissue will be compared to human buccal tissue from 24 Bangladeshi volunteers, 12 each from first- and second-generation groups. The research could inform us about presently unknown epigenetic mechanisms affecting reproductive variability that results from stress during early life development, as well as the utility of a mouse model for these kinds of studies. It will also highlight the possibility of using different tissue types to detect some of these epigenetic modifications. The study will present opportunities to train new generations of multi-disciplinary researchers. Finally, it will demonstrate the potential of targeted, cross-sectional studies in migrant groups to answer questions of interest to epigeneticists and social scientists, particularly about the importance of early life in influencing individual health and wellbeing during adulthood.

Planned Impact

Academics across the divide of biological and social sciences will benefit from the research because it forges a new, cross-disciplinary and international collaboration between biologists/epigeneticists (working on animal models, cell lines and theory) to social scientists working with humans. This means that results from the proposed study will be directly applicable to human health and wellbeing. At present, much research is emerging from epigeneticists that is not being applied to our own species, while on the other side, many social scientists make assumptions about potential epigenetic effects without having data to uphold these assumptions. There is a great interest among researchers from both areas in how early life stress and plasticity contribute to the phenotype in later life, and the research proposed here directly speaks to these issues. The data generated can thus inform future study designs by other researchers that aim to explore cross-cultural studies in humans in relation to environmentally-induced epigenetic change. Improved study design, based on solid data sets, ensures cost-efficient, high-impact research through public investment.
Global migration, international mobility and migrant integration are highly relevant issues for public policy and capture the public attention. This interest provides an excellent opportunity to engage with the community and the general public about issues relevant to migrant health. They will therefore benefit from our contribution to the understanding of processes involved in immigration, environmental stresses and basic biology. More specifically, the ethnic minority of Bangladeshis will directly benefit because they are providing the migrant model for the human part of this study. Any measures that promote improved understanding of migrant wellbeing will provide benefit to our society with respect to quality of life, health, creative output and economy. Policy makers appreciate the connection between immigration, health and economic success. Thus, in the longer term, our research has the potential to impact on areas of health and wealth.
We act in the strong belief that competitive academic research cannot and should not be separated from teaching. We will therefore integrate concepts and approaches of this research into our university-taught lectures and seminars that reach a broad audience of students across under-graduate and postgraduate levels. We will also train young professionals (both postdoctoral associates and students) in the course of our project in order to broaden their disciplinary horizons and skill-sets, attributes that they will then transmit to future generations of scholars.
Furthermore, the proposed work has the potential to identify novel diagnostic tools (biomarkers) that may be used to monitor or predict reproductive function and that could be patentable in the long-term future. This would be of immense value to women in many different contexts and could contribute to reproductive health. Any such patents and products would contribute to the economic health of the UK and its bio-industries.
 
Description 1) We met and exceeded expectations raised in our grant. From our earlier studies, we knew that early life stress, such as challenges from infectious diseases, leads to modified reproductive function in adult migrant Bangladeshi women. In this study, we used a rodent model (in mice) that largely mirrors this finding in humans and which can be used to uncover molecular (cellular) and epigenetic mechanisms responsible. Specifically, we have shown that environmental stressors, such as disease loads experienced during early life, delayed puberty and altered reproduction function in both mice and humans, reflecting a shorter reproductive life span. Transcriptome analysis of ovaries from treated (stressed) mice revealed up-regulation of genes that induce follicle growth in the ovary, and repression of genes that promote cell death. This included repression of the Srd5a1 gene, the down-regulation of which matched findings from Bangladeshi migrants obtained using cheek swabs and that revealed an increase in its methylation. In mice, expression of Srd5a1 was also significantly reduced in the hypothalamus, a region of the brain where neurosteroids direct central activation of both the reproductive (hypothalamic-pituitary-gonadal - HPG) and stress (hypothalamic-pituitary-adrenal - HPA) axes through binding and activating specific neuronal (GABA) receptors.
While the HPG axis is activated during puberty in both mice and humans, the HPA axis is activated during adrenarche in humans - a unique, pre-pubertal stage of development, usually completed by the age of 8 years. Adrenarche is associated with the development of secondary sexual characteristics (such as specific sweat glands), and linked to neurological maturation that signals the onset of what is called middle childhood. Crucially, from prior studies, an important threshold for altered reproductive function in Bangladeshi migrant women and men was also age 8. Furthermore, previous findings showed that Bangladeshi children who moved at very early ages to the UK had a significantly earlier age at adrenarche. Our studies therefore link central changes in activation and functioning of the adrenal axis with possible epigenetic regulation of Srd5a1 expression during a crucial developmental window. Changes in the activation of hypothalamic control-centres via reduced 5a-reductase activity, could provide a possible mechanism for alteration in age of both puberty and adrenarche, as well as modified function of these axes in adulthood.
Our findings reveal that epigenetic modifications comprise a flexible, regulatory mechanism in response to environmental perturbations that can mediate phenotypic changes through altering gene expression.
2) By combining observations and measurements obtained from well-controlled human populations with a mouse model which enables dissection of tissues inaccessible in human populations, our interdisciplinary research has begun to reveal the epigenetic basis for altered reproductive function in response to stressful childhood environments, and could have future applications for improving human health. We would like to take our findings further by applying for more funding from RCUK and/or elsewhere.
3) We have successfully established and maintained a new international network across biological and social sciences to address questions of interest to both disciplines.
4) We have demonstrated the value of taking cross-sectional approaches to data.
Exploitation Route We are beginning to uncover mechanisms to explain observed inter-individual and inter-group differences in ovarian function that appear to be influenced by early life developmental factors and that can alter fecundity and the reproductive lifespan. It is possible that a greater understanding of these mechanisms could translate into potential methods to improve fertility and health in women in the future, but much more work needs to be undertaken in this area.
Sectors Environment,Healthcare,Pharmaceuticals and Medical Biotechnology,Other

 
Description We are in the process of completing our publications and expect to submit our first paper within the next few weeks. At that point, we may be able to report more impact. We will update this narrative as matters develop.
 
Description BIRAX Conference presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation about how our study has bearings on reproductive ageing and illuminating the benefits of international collaboration to the British Council Israel and the UK Science and Innovation Network (SIN).
Year(s) Of Engagement Activity 2018
URL http://www.biraxageing.org/
 
Description Presentation at conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Giving a talk at the Genome Science 2018 meeting at Nottingham University
Year(s) Of Engagement Activity 2018
URL https://www.nottingham.ac.uk/conference/fac-mhs/lifesciences/genome-science-2018