B4336 - Developmental origins of thyroid function regulation and its neurocognitive and reproductive consequences - 20/06/2023

B number: 
Principal applicant name: 
T.J. Roseboom | Amsterdam UMC, University of Amsterdam, the Netherlands. (The Netherlands)
Ms. Sarai Keestra , Dr. Martijn Finken , Dr. Marsh Königs , Prof. Jaap Oosterlaan , Prof. Velja Mijatovic , Dr. Nienke van Welie , Dr. Kim Dreyer , Dr. Alexandra Alvergne , Dr. Charlotte Faurie, Dr. Austin Argentieri
Title of project: 
Developmental origins of thyroid function regulation and its neurocognitive and reproductive consequences
Proposal summary: 

Thyroid dysfunction due to hypo- or hyperthyroidism affects 200 million people worldwide and is a major health burden, particularly in women who are 4-10 times more likely to suffer from hypothyroidism as a result of autoimmune disease. 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 women and their children, but currently there is a lack of intergenerational data that can help understand the complex interplay between iodine, environmental factors in early life and thyroid function regulation in the offspring. We aim to fill that gap by investigating (1) critical environmental exposures that impact thyroid function regulation, and their subsequent influence on (2) reproductive health and (3) neurocognitive outcomes. Within these analyses we will look at both natural variation in thyroid function parameters as well as pathological variation due to thyroid dysfunction. At the centre of this exploration is the complex interplay between mother and offspring around limited iodine resources and thyroid function regulation during pregnancy and its long-term consequences. 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 costs over the life course. This proposal has been adjusted from proposal B3905 submitted in 2021.

Impact of research: 
Thyroid dysfunction affects 200 million people worldwide and is major health burden. 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. 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. 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, Tabor and Alvergne, 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). 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: 
Thursday, 15 June, 2023
Date proposal approved: 
Tuesday, 20 June, 2023
Endocrinology, Thyroid disease, Neurocognitive impairement, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Biomarkers; Birth outcomes; BMI; Childood adversity; Growth; Hormones; Mothers; Nutrition; Puberty; Sex differences