B3905 - Developmental origins of thyroid function regulation in the Avon Longitudinal Study of Parents and Children ALSPAC birth cohor - 10/12/2021

B number: 
Principal applicant name: 
Alexandra Alvergne | CNRS (French National Centre for Research) (France)
Ms. Sarai Keestra, Mr. Austin Argentieri , Prof. T. J. Roseboom, Dr Martijn Finken, Dr Vedrana Högqvist Tabor
Title of project: 
Developmental origins of thyroid function regulation in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohor
Proposal summary: 

Thyroid dysfunction due to hypo- or hyperthyroidism affects 200 million people worldwide and is a major health burden. Thyroid hormones are vital for healthy metabolism, tissue differentiation, neurodevelopment, growth, immune function, reproduction, and ageing, yet the relative contribution of environmental exposures (e.g. nutrition, psycho-socio-economic adversity, etc.) in shaping thyroid function regulation remains unknown. The thyroid axis is especially important for the health of (pregnant) women and their children , but currently there is a lack of intergenerational data that can help understand the complex interplay between environment and genetics in thyroid function regulation. We aim to fill that gap by analysing thyroid function related variables in the ALSPAC data. Specifically, we will (1) investigate critical periods in which environmental and life-history influence thyroid function regulation, (2) analyse the impact of thyroid function on reproductive health outcomes, and (3) explore the epigenetic pathways by which thyroid function affects health outcomes in mothers and children. Within these analyses we will look at both natural variation in thyroid function parameters as well as pathological variation due to thyroid dysfunction. Identifying critical periods of thyroid function plasticity may have significant implications for the optimal timing of comprehensive public health interventions that can decrease the burden of thyroid dysfunction and its health consequences over the life course.

Impact of research: 
Thyroid dysfunction affects 200 million people worldwide and is major health burden (Kuyl, 2015). Few studies have considered the comprehensive impact of environmental exposures on the thyroid function and reproductive health outcomes of mothers and their offspring, and none take a longitudinal life course approach. Identifying environmental risk factors for developing thyroid dysfunction can inform efforts at prevention and early identification of thyroid disease. Since thyroid hormones can play fundamental roles in the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes, understanding plasticity in healthy thyroid function also has the potential to help better understand natural variation in these neuroendocrine axes in face of adversity and its effects on reproductive health outcomes. Ultimately, we seek to determine the critical periods throughout the life course in which thyroid function is most flexible and plastic, which will help inform optimal timing for comprehensive public health interventions that address thyroid dysfunction and its health consequences. Using an evolutionary ecology framework we suggest that by understanding the role of thyroid function in regulating the energetic trade-offs between the functions of reproduction, growth, and somatic maintenance, an evolutionary medicine approach can contribute to clinical medicine by reinterpreting natural variation in thyroid function within an ecological context (Keestra et al., 2020). By investigating the effect of normal thyroid function variation during the life span on timing of maturation, we can enhance our understanding regarding the role of thyroid function in translating early life environmental exposures into differential developmental tempos. In this context, we also consider how variation in thyroid hormone levels in pregnant women affect incidence of pregnancy disorders and influence obstetric and neonatal health outcomes. Finally, we aim to develop a novel approach to understanding healthy thyroid function in later life by characterising the interactions between women’s reproductive history, thyroid function, and epigenetic markers of cellular ageing. By taking an experimental approach as outlined in this proposal, we seek to stimulate a new research programme that reconsiders thyroid function as an important pathway by which energy investments over the life course are regulated, utilising thyroid evolutionary ecology as a new predictive framework. Thyroid dysfunction has significant ramifications for the regulation of body temperature, metabolism, fertility, foetal neurological development, intellectual performance of school-aged children, adult mental health, and overall quality of life (Keestra et al., 2020). Even at subclinical levels, thyroid hormone imbalances are associated with psychiatric disorders, stroke risk, and altered cardiac function, and are thereby a significant source of ill health worldwide. Identifying environmental risk factors and biomarkers that associate with development of thyroid dysfunction can inform prevention efforts and enable early identification of thyroid disease. To reduce the disease burden of thyroid dysfunction and its associated comorbidities, chronic disease prevention must start at the earliest beginning (Klimek et al., 2014). Appreciating the way genetics, environment, and early life experiences give shape to organisms throughout their life span opens up new avenues towards personalised medicine in the prevention, diagnosis, and treatment of disease (Wells et al., 2017). By utilising the birth cohort’s longitudinal and diverse datasets, it is possible to study human beings in all their bio-psycho-social complexity, whilst bridging the gap between epidemiological studies and animal model research to elucidate the epigenetic mechanisms underlying environmental exposures and chronic disease risk (Thalabard et al., 1996). It is at these interfaces that interdisciplinary teams such as ours, consisting of medical anthropologists, evolutionary biologists, epigeneticists, and clinicians, can make the greatest contribution towards science and our understanding variation in health and disease across different contexts.
Date proposal received: 
Friday, 10 December, 2021
Date proposal approved: 
Friday, 10 December, 2021
Endocrinology, Thyroid disease, Statistical methods, Hormones - cortisol, IGF, thyroid