Sarai Keestra

Vedrana Högqvist Tabor

Alexandra Alvergne
email: alexandra.alvergne@umontpellier.fr

Reinterpreting Patterns of Variation in Human Thyroid Function: An Evolutionary Perspective

Keywords: evolutionary medicine, thyroid hormones, hypothyroidism, hyperthyroidism, autoimmune thyroid diseases, evolutionary ecology .manuscriptcentral.com/emph

Two hundred million people worldwide experience some form of thyroid disorder, with women being especially at risk. However, why human thyroid function varies between populations, individuals and across the lifespan has attracted little research to date. This limits our ability to evaluate the conditions under which patterns of variation in thyroid function are best understood as 'normal' or 'pathological'. In this review, we aim to spark interest in research aimed at understanding the causes of variation in thyroid phenotypes. We start by assessing the biomedical literature on thyroid imbalance to discuss the validity of existing reference intervals for diagnosis and treatment across individuals and populations. We then propose an evolutionary ecological framework for understanding the phylogenetic, genetic, ecological, developmental and physiological causes of normal variation in thyroid function. We build on this approach to suggest testable predictions for how environmental challenges interact with individual circumstances to influence the onset of thyroid disorders. We propose that dietary changes, ecological disruptions of co-evolutionary processes during pregnancy and with pathogens, emerging infections and exacerbated stress responses can contribute to explaining the onset of thyroid diseases. For patients to receive the best personalised care, research into the causes of thyroid variation at multiple levels is needed.

INTRODUCTION

Thyroid dysfunction affects 200 million people worldwide [START_REF] Kuyl | The evolution of thyroid function tests[END_REF]. Although most research is conducted in Westernised, relatively wealthy societies, thyroid diseases are surprisingly common in all populations studied [START_REF] Taylor | Global epidemiology of hyperthyroidism and hypothyroidism[END_REF]. Thyroid function abnormalities have significant ramifications for body temperature regulation [START_REF] Weibel | The circadian thyrotropin rhythm is delayed in regular night workers[END_REF], metabolism (4), cardiac function and blood pressure [START_REF] Surks | Subclinical Thyroid Disease[END_REF], fertility [START_REF] Vivo | Thyroid Function in Women Found to Have Early Pregnancy Loss[END_REF], foetal neurological development [START_REF] Williams | Neurodevelopmental and neurophysiological actions of thyroid hormone[END_REF], intellectual performance of school-aged children [START_REF] Bleichrodt | A meta-analysis of research on iodine and its relationship to cognitive development[END_REF], mental health [START_REF] Bauer | The thyroid-brain interaction in thyroid disorders and mood disorders[END_REF] and overall quality of life [START_REF] Chakera | Treatment for primary hypothyroidism: Current approaches and future possibilities[END_REF]. Even at subclinical levels, thyroid dysfunction is associated with stroke risk [START_REF] Chaker | Subclinical hypothyroidism and the risk of stroke events and fatal stroke: An individual participant data analysis[END_REF], cardiac dysfunction [START_REF] Surks | Subclinical Thyroid Disease[END_REF], and neuro-psychiatric disorders, including anxiety and depression [START_REF] Gulseren | Depression , Anxiety , Health-Related Quality of Life , and Disability in Patients with Overt and Subclinical[END_REF][START_REF] Santos | Subclinical thyroid dysfunction and psychiatric disorders : cross-sectional results from the Brazilian Study of Adult[END_REF]. Understanding the causes underpinning thyroid dysfunction is therefore critical to improve global health.

This paper provides a holistic framework for rethinking the causes of variation in thyroid function at multiple levels (i.e. between species, populations, individuals, and across the lifespan). We aim to spark interest in reconsidering what counts as 'normal' and 'pathological' in thyroid phenotypes. While health is commonly defined as "a state of complete physical, social and mental wellbeing" [START_REF] Who | Constitution of the World Health Organisation[END_REF], from an evolutionary perspective, health is a means to the end of reproduction. In this latter framework, health is better conceptualized as the ability to adapt to changing environments [START_REF] Sterling | A model of predictive regulation[END_REF]. As a result, patterns of variation in thyroid function are expected to be constrained by phylogeny, genetic polymorphism, variation in early environments and current ecological stresses, which renders the task of differentiating between 'normal' and 'pathological' states difficult. To shed new light on patterns of variation, we first outline the biomedical literature on imbalances in the hypothalamic-pituitary-thyroidal (HPT) axis (Box 1), arguing that the use of reference intervals based on large population samples obscures natural intra-individual variation in thyroid function. Second, we review the ultimate (i.e. evolutionary) causes of variation in thyroid function, including phylogenetic and genetic influences, to show how the thyroid system accumulated multiple roles that are both common to eukaryotes and specific to taxa, species, and human populations. Third, we propose a life-history framework for understanding variation in thyroid function in response to environmental stressors experienced at various life stages. Fourth, we apply this multi-level framework to pathological patterns of thyroid function variation, focusing on four case studies (i) mismatches in diet composition and lifestyle, (ii), coevolutionary processes around pregnancy, (iii) microbial exposure and emerging infections and (iv) exacerbated stress responses. We contend 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. We conclude that field studies in different ecological contexts are needed to elucidate natural variation of human thyroid function, which is crucial for devising appropriate reference intervals.

[ENTER BOX 1 HERE]

Biomedical approaches to thyroid function Thyroid diseases: causes and treatment

From a biomedical perspective, the main causes of thyroid dysfunction are thyroid cancer, autoimmune thyroid diseases (AITD), and deficiencies in iodine and other micronutrients. Thyroid cancers are the most prevalent endocrine tumour [START_REF] Kim | Current trends in the features of male thyroid cancer: Retrospective evaluation of their prognostic value[END_REF] and despite being classified as non-reproductive cancers, thyroid neoplasms occur more often in women than men (122) and are the most commonly diagnosed cancer during pregnancy after breast cancer (123). AITD affects women nine times more than men [START_REF] Lockshin | Sex differences in autoimmune disease[END_REF], and autoimmunity leading to underactive thyroid function (hypothyroidism) is the most common of all autoimmune and endocrine disorders [START_REF] Caturegli | Hashimoto thyroiditis: Clinical and diagnostic criteria[END_REF]. Hashimoto's thyroiditis, a condition characterised by chronic inflammation and the presence of thyroperoxidase (TPO) and thyroglobulin (TG) autoantibodies, causes the destruction of the thyroid gland and hypothyroidism [START_REF] Santos | Hashimoto's Thyroiditis in Adolescents[END_REF]. In Graves' disease, a mix of stimulating and blocking autoantibodies against the TSH receptor overstimulates thyroid growth and hormone production, leading to hyperthyroidism, and in rare cases, hypothyroid or euthyroid Graves' disease [START_REF] Luck | The thyroid gland[END_REF][START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF][START_REF] Struja | Is Graves' disease a primary immunodeficiency? New immunological perspectives on an endocrine disease[END_REF]. Worldwide, more than one in twenty individuals has a subclinical underactive thyroid [START_REF] Wiersinga | Subclinical hypothyroidism and hyperthyroidism. I. Prevalence and clinical relevance[END_REF], and two billion people are at risk of suffering from the health consequences of deficiencies in iodine [START_REF] De Benoist | Iodine deficiency in 2007: Global progress since 2003[END_REF], a micronutrient needed for the synthesis of thyroid hormones. Iodine deficiency disorders commonly manifest themselves through hypothyroidism and endemic goitre, but can also cause wide-ranging deficits in cognition, growth, and fertility, due to thyroid hormones' vital importance for normal development, especially of the brain [START_REF] Chen | Cretinism revisited[END_REF]. In severe iodine deficient regions, endemic cretinism persists until the present day, manifesting itself as a neurological disorder with brain damage, mental https://mc.manuscriptcentral.com/emph retardation and deaf mutism due maternal hypothyroxinemia, often caused by iodine deficiency, during gestation. Neurological cretinism occurs alongside myxedematous cretinism, which results from severe hypothyroidism as a consequence of athyreosis or an underdevelopment of the thyroid at birth, causing dwarfism and impaired neurodevelopment if not diagnosed and corrected early using thyroid hormone replacement therapy [START_REF] Chen | Cretinism revisited[END_REF][START_REF] Stenzel | Role of maternal thyroid hormones in the developing neocortex and during human evolution[END_REF][START_REF] Dobson | The iodine factor in health and evolution[END_REF][START_REF] Gaitan | Epidemiology of iodine deficiency[END_REF].

Treatment for thyroid dysfunction does not always produce the expected outcomes.

For hyperthyroid individuals, surgery, antithyroid drugs, or radioiodine treatment are used to bring thyroid hormone production back into the strictly defined reference range [START_REF] Surks | Subclinical Thyroid Disease[END_REF][START_REF] Garber | Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of clinical endocrinologists and the American Thyroid Association[END_REF][START_REF] Jonklaas | Reference intervals in the diagnosis of thyroid dysfunction: treating patients not numbers[END_REF]. However, often, too much of the thyroid is inactivated, which is why 80% of hyperthyroid patients become hypothyroid after treatment [START_REF] Burch | Management of Graves Disease A Review[END_REF]. Furthermore, many individuals receiving lifelong T4 replacement therapy (levothyroxine) to correct underactive thyroid function continue being hypothyroid or become hyperthyroid due to overmedication [START_REF] Wiersinga | Subclinical hypothyroidism and hyperthyroidism. I. Prevalence and clinical relevance[END_REF]. A third of patients taking levothyroxine have abnormally high free thyroxine (T4) compared to free triiodothyronine (T3) ratios and up to 10% of patients experience depression, anxiety, or other manifestations of impaired psychological well-being despite normal TSH levels [START_REF] Wiersinga | Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism[END_REF]. Many patients therefore continue to experience a decreased quality of life even after thyroid function tests are in the right range according to reference values [START_REF] Watt | Quality of life in patients with benign thyroid disorders. A review[END_REF]. This raises the question of how reference intervals, the decision support tool for the interpretation of biomarkers, are developed.

Reference intervals: what is the 'normal' range?

The idea of a "normal range" for thyroid biomarkers is debatable on both methodological and biological grounds. Despite recent attempts starting in 2015 to harmonise TSH reference intervals across laboratories and countries [START_REF] Thienpont | Harmonization of serum thyroid-stimulating hormone measurements paves the way for the adoption of a more uniform reference interval[END_REF], there is still significant variation in assay sensitivity across manufacturers [START_REF] Stockigt | Assessment of thyroid function: towards an integrated laboratoryclinical approach[END_REF], differences in protocols for thyroid biomarkers analysis between laboratories [START_REF] Springer | Reference intervals for thyroid markers in early pregnancy determined by 7 different analytical systems[END_REF], disagreement over the appropriate statistical methods to establish reference intervals, and disparities in manufacturers' proposed reference intervals [START_REF] Jonklaas | Reference intervals in the diagnosis of thyroid dysfunction: treating patients not numbers[END_REF]. Furthermore, the halflives of TSH and T4 differ (one hour vs. one week in the circulation (36)), thus assessing the thyroid status of individuals currently experiencing changes in energy balance relying on these biomarkers alone is particularly challenging [START_REF] Joseph-Bravo | TRH, the first hypophysiotropic releasing hormone isolated: Control of the pituitary-thyroid axis[END_REF]. Finally, reference intervals vary depending on the population and assay manufacturer used to construct them (Figure 1, Table S1) [START_REF] Thienpont | Harmonization of serum thyroid-stimulating hormone measurements paves the way for the adoption of a more uniform reference interval[END_REF].

From a biological perspective, reference intervals should account for the significant inter and intra-individual variation in thyroid function. Although it is known that thyroid function varies widely with age [START_REF] Ehrenkranz | Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex[END_REF][START_REF] Aggarwal | Thyroid Function in Healthy Ageing and Longevity[END_REF], sex [START_REF] Sheikh | TSH Should not be used as a Single Marker of Thyroid Function[END_REF], ethnicity [START_REF] Surks | Age-and race-based serum thyrotropin reference limits[END_REF], season [START_REF] Grande | Using "big data" to describe the effect of seasonal variation in thyroid-stimulating hormone[END_REF], time of the day [START_REF] Ikegami | Interconnection between circadian clocks and thyroid function[END_REF][START_REF] Jensen | Sampling time is important but may be overlooked in establishment and use of thyroid-stimulating hormone reference intervals [1[END_REF], iodine sufficiency of the region [START_REF] Taylor | Global epidemiology of hyperthyroidism and hypothyroidism[END_REF][START_REF] Ittermann | Shift of the TSH reference range with improved iodine supply in Northeast Germany[END_REF], socioeconomic status [START_REF] Levy | Seasonal and Socioeconomic Influences on Thyroid Function Among the Yakut (Sakha) of Eastern Siberia[END_REF], stress levels [START_REF] Stratakasis | Neuroendocrinology and Pathophysiology of the Stress System[END_REF], body mass index (BMI) [START_REF] Reinehr | Obesity and thyroid function[END_REF], white blood cell count [START_REF] Kratzsch | Reference intervals for TSH and thyroid hormones are mainly affected by age, body mass index and number of blood leucocytes, but hardly by gender and thyroid autoantibodies during the first decades of life[END_REF], menstrual cycle phase [START_REF] Benvenga | Serum Thyrotropin and Phase of the Menstrual Cycle[END_REF], overall health status [START_REF] Klein | The immune system as a regulator of thyroid hormone activity[END_REF], and is released in a pulsatile fashion [START_REF] Crockford | Thyroid rhythm phenotypes and hominid evolution: A new paradigm implicates pulsatile hormone secretion in speciation and adaptation changes[END_REF], these factors are not typically taken into account by clinicians in the diagnosis of thyroid disorders, nor is the treatment adjusted accordingly [START_REF] Duntas | Levothyroxine Dose Adjustment to Optimise Therapy Throughout a Patient's Lifetime[END_REF]. Rather, a single blood test needs to be adjusted by +/-25% for thyroid hormones and +/-50% for TSH, as repeated testing of healthy subjects reveals significant intra-individual variation around a unique, personal thyroid function [START_REF] Andersen | Narrow individual variations in serum T4 and T3 in normal subjects: A clue to the understanding of subclinical thyroid disease[END_REF]. While thyroid function tests might sometimes fall outside of the reference interval, in the absence of symptoms, it might not always indicate that medication is necessary [START_REF] Jonklaas | Reference intervals in the diagnosis of thyroid dysfunction: treating patients not numbers[END_REF]. Conversely, small variations in thyroid function can be experienced as significant to the individual, but reference ranges relying on population level variation obscure this variation [START_REF] Andersen | Narrow individual variations in serum T4 and T3 in normal subjects: A clue to the understanding of subclinical thyroid disease[END_REF][START_REF] Leow | The homeostatic set point of the hypothalamuspituitary-thyroid axis -Maximum curvature theory for personalized euthyroid targets[END_REF][START_REF] Goede | Hypothalamus-Pituitary-Thyroid Feedback Control: Implications of Mathematical Modeling and Consequences for Thyrotropin (TSH) and Free Thyroxine (FT4) Reference Ranges[END_REF].

[ENTER FIGURE 1 HERE] By not taking into account the possibility that variation in thyroid hormones is the manifestation of an evolved response to individual environmental contexts, biomedicine runs the risk of treating the symptoms of the problem instead of addressing the underlying causes of thyroid ill-health. In the remainder of the paper, we draw on an evolutionary ecological framework to shed new light on the causes of variation in thyroid function. In this framework, variability is the norm "rather than an aberration" [START_REF] Vitzthum | The ecology and evolutionary endocrinology of reproduction in the human female[END_REF] and various interconnected levels of causality must be considered for understanding both normal and pathological patterns of variation, including evolutionary, ecological, developmental and physiological factors [START_REF] Nesse | Tinbergen's four questions, organized[END_REF].

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The evolutionary history of thyroid function

Normal patterns of variation in thyroid function are constrained by the evolutionary history of the thyroid system. Whilst the initial use of thyroid hormone precursors most likely evolved to counteract oxidative stress in unicellular organisms, the capacity of thyroid hormones to regulate metabolism has since been co-opted multiple times (Figure 2), e.g. to coordinate development in chordates and facilitate the evolution of endothermy in birds and mammals. In humans, there is some evidence for genetic polymorphisms evolved in response to cold and iodine-deficient ecologies (Box 2).

Thyroid hormones have acquired a wide range of functions during their evolutionary history through exaptation (Figure 2). The cellular use of iodine and its hydrated derivatives, iodides, predates eukaryotic life itself and may have been present in prokaryote oxygen-producing cyanobacteria living three billion years ago [START_REF] Venturi | Environmental Iodine Deficiency: A Challenge to the Evolution of Terrestrial Life?[END_REF][START_REF] Crockford | Evolutionary roots of iodine and thyroid hormones in cellcell signaling[END_REF]. Iodinated compounds, abundant in the primordial sea, probably served as antioxidants against the damaging effects of radical oxygen species, which in the form of oxidative stress can interfere with normal cellular signalling, growth, differentiation, and metabolism [START_REF] Venturi | Evolution of Dietary Antioxidants: Role of Iodine[END_REF]. Because these cyanobacteria were later incorporated in eukaryotic cells as mitochondria, iodinated tyrosines, the evolutionary and biochemical precursors of thyroid hormones, have important regulatory roles in cellular metabolism [START_REF] Crockford | Evolutionary roots of iodine and thyroid hormones in cellcell signaling[END_REF]. Algae, one of the most ancient forms of multicellular eukaryote life, accumulate large quantities of iodine from sea water, and various other invertebrates store iodinated tyrosines [START_REF] Heyland | Cross-kingdom hormonal signaling: An insight from thyroid hormone functions in marine larvae[END_REF]. As iodinated tyrosines easily pass through cell membranes, they were potentially involved in the earliest forms of cell-tocell signaling and the evolution of multicellular life. Iodine additionally plays a role in the most primitive features of the immune system, by increasing inflammation and enhancing phagocytosis [START_REF] Stone | The role of the primitive sea in the natural selection of iodides as a regulating factor in inflammation[END_REF]. Some non-genomic functions of iodinated compounds therefore precede thyroid hormones and are shared with invertebrates and vertebrates alike [START_REF] Heyland | Cross-kingdom hormonal signaling: An insight from thyroid hormone functions in marine larvae[END_REF][START_REF] Opitz | Editorial: Get inspired -Lessons learned from evolution of thyroid hormone signaling in developmental processes[END_REF]. For example, already in the common ancestor of invertebrates and vertebrates the presence of iodotyrosines may have served as an energy-related plasticity cue [START_REF] Crockford | Evolutionary roots of iodine and thyroid hormones in cellcell signaling[END_REF][START_REF] Portulano | The Na+/I-Symporter (NIS): Mechanism and medical impact[END_REF].

Thyroid hormones later developed novel, genomic functions in the coordination of development [START_REF] Heyland | Cross-kingdom hormonal signaling: An insight from thyroid hormone functions in marine larvae[END_REF][START_REF] Laudet | The origins and evolution of vertebrate metamorphosis[END_REF]. Although non-vertebrates use exogenous thyroid hormones derived from food (e.g. ingested algae) as a developmental cue of energetic conditions to initiate metamorphic transformation, in vertebrates these thyroid hormones are produced endogenously for the first time [START_REF] Crockford | Evolutionary roots of iodine and thyroid hormones in cellcell signaling[END_REF][START_REF] Portulano | The Na+/I-Symporter (NIS): Mechanism and medical impact[END_REF]. Experiments in the early twentieth century established the important role of the thyroid in the timing of metamorphosis of tadpoles into frogs [START_REF] Gudernatsch | Feeding experiments on tadpoles. II. A further contribution to the knowledge of organs with internal secretion[END_REF]. Further research has shown that thyroid hormone signalling coordinates the timing of tissue differentiation programmes across different chordate species, including human neurodevelopment during gestation [START_REF] Williams | Neurodevelopmental and neurophysiological actions of thyroid hormone[END_REF]. Crockford [START_REF] Crockford | Thyroid rhythm phenotypes and hominid evolution: A new paradigm implicates pulsatile hormone secretion in speciation and adaptation changes[END_REF][START_REF] Crockford | Evolutionary roots of iodine and thyroid hormones in cellcell signaling[END_REF] and others have argued that due to their central regulatory role and pleiotropic actions in growth, development, reproduction, and stress, alterations in thyroid phenotypes may subsequently underlie rapid speciation and the gradual adaptation of populations to new habitats.

The evolution of the thyroid gland may have enabled the evolution of terrestrial life by storing a pool of releasable thyroid hormone precursors in order to compensate for the unpredictable access to iodine on land [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF][START_REF] Crockford | Evolutionary roots of iodine and thyroid hormones in cellcell signaling[END_REF][START_REF] Krude | Evolution, child development and the thyroid: A phylogenetic and ontogenetic introduction to normal thyroid function[END_REF][START_REF] Venturi | Evolutionary significance of Iodine[END_REF], otherwise found in dark green leafy vegetables, eggs, and seeds (see also section 4). Originally, thyroidhormone producing cells, organised in follicles, where scattered throughout the body https://mc.manuscriptcentral.com/emph until the emergence of the precursor of the thyroid gland, the endostyle, which developed from the primitive gut of chordates, and evolving the enzymatic machinery found in all vertebrate thyroids today [START_REF] Barrett | The Evolutionary Significance of the Thyroid Gland[END_REF][START_REF] Kluge | Anatomical and molecular reinvestigation of lamprey endostyle development provides new insight into thyroid gland evolution[END_REF][START_REF] Krude | Evolution, child development and the thyroid: A phylogenetic and ontogenetic introduction to normal thyroid function[END_REF]. The evolutionary origin of the gland from the foregut can be witnessed in the human embryology of the thyroid, as the thyroid develops from the endodermal cells at the base of the tongue descending downwards to its position in the neck [START_REF] Policeni | Anatomy and Embryology of the Thyroid and Parathyroid Glands[END_REF].In contrast to many other hormonal systems, all vertebrate species essentially share the same chemical structure for thyroid hormones and their active derivatives [START_REF] Opitz | Editorial: Get inspired -Lessons learned from evolution of thyroid hormone signaling in developmental processes[END_REF]. The evolution of the follicular thyroid in vertebrates might have been critical to allow for life to move from saltwater to iodine-depleted freshwater to land. Such transition was facilitated by both the biochemical evolution of cell surface iodine transporters, driving iodine against its concentration gradient, and the appearance of the TPO enzymatic machinery, which allowed the iodine to be stored as thyroglobulin complexes, an intermediary product of thyroid hormones [START_REF] Venturi | Environmental Iodine Deficiency: A Challenge to the Evolution of Terrestrial Life?[END_REF][START_REF] Crockford | Evolutionary roots of iodine and thyroid hormones in cellcell signaling[END_REF][START_REF] Barrett | The Evolutionary Significance of the Thyroid Gland[END_REF]. By binding most of these hydrophobic thyroid hormones to hydrophilic carrier proteins such as thyroid-binding globulin, albumin, and transthyretin, thyroid hormones can be easily transported in the circulation, prolonging the half-life and turnover of thyroid hormones. Even small polymorphisms in genes related to thyroid hormone production and metabolism can lead to significant interspecies variation in thyroid rhythm phenotypes [START_REF] Crockford | Thyroid rhythm phenotypes and hominid evolution: A new paradigm implicates pulsatile hormone secretion in speciation and adaptation changes[END_REF]: humans have higher total T4 and T3 levels and increased free T4 levels than other great ape genera [START_REF] Aliesky | Thyroid autoantibodies are rare in nonhuman great apes and hypothyroidism cannot be attributed to thyroid autoimmunity[END_REF], which may be due to lower transthyretin levels in humans [START_REF] Gagneux | Proteomic comparison of human and great ape blood plasma reveals conserved glycosylation and differences in thyroid hormone metabolism[END_REF].

Mammals and birds subsequently developed endothermy through convergent evolution enhancing thyroid-driven metabolism, allowing them to adjust to colder terrestrial environments [START_REF] Crockford | Thyroid rhythm phenotypes and hominid evolution: A new paradigm implicates pulsatile hormone secretion in speciation and adaptation changes[END_REF][START_REF] Barrett | The Evolutionary Significance of the Thyroid Gland[END_REF][START_REF] Farmer | Parental care: The key to understanding endothermy and other convergent features in birds and mammals[END_REF]. Intensified selection on thyroid function and https://mc.manuscriptcentral.com/emph resting metabolic rate may have continued throughout human evolution for example due to the sustained exertion involved in early hunter-gathering activities and the challenges posed by colder climates during human expansions out of Africa [START_REF] Barrett | The Evolutionary Significance of the Thyroid Gland[END_REF][START_REF] Sellayah | On the evolutionary origins of obesity: A new hypothesis[END_REF][START_REF] Leonard | Metabolic Adaptation in Indigenous Siberian Populations[END_REF]. It has even been speculated that in Neanderthals, selection towards a distinct cold-tolerant thyroid hormone phenotype and its downstream effects on developmental programs resulted in significant differences in Neanderthal post-natal growth rates and morphology compared to Homo sapiens, despite their closeness in genetic ancestry [START_REF] Crockford | Thyroid rhythm phenotypes and hominid evolution: A new paradigm implicates pulsatile hormone secretion in speciation and adaptation changes[END_REF].

Climatic changes altered the ecological niche and thereby the dietary intake of iodine and exogenous thyroid hormones ingestion throughout human evolutionary history, which may have played an important role in speciation events in the human lineage [START_REF] Crockford | Thyroid rhythm phenotypes and hominid evolution: A new paradigm implicates pulsatile hormone secretion in speciation and adaptation changes[END_REF]. Given the importance of thyroid hormones for cognitive development and function [START_REF] Williams | Neurodevelopmental and neurophysiological actions of thyroid hormone[END_REF], some authors propose that enhanced access to iodine rich foods due to increased meat consumption or a shore-based diet may have freed human brain development from the nutritional constraints on thyroid function experienced by other primates [START_REF] Dobson | The iodine factor in health and evolution[END_REF][START_REF] Cunnane | Energetic and nutritional constraints on infant brain development: Implications for brain expansion during human evolution[END_REF][START_REF] Broadhurst | Brain-specific lipids from marine, lacustrine, or terrestrial food resources: Potential impact on early African Homo sapiens[END_REF][START_REF] Previc | Thyroid Hormone Production in Chimpanzees and Humans : Implications for the Origins of Human Intelligence[END_REF]. For example, the shift from scavenging towards hunting in an open savannah-type environment that accompanied the emergence of Homo erectus would have increased thyroid gland consumption by hominins and thereby exogenous thyroid, potentially causing heterochronic changes in both body proportions and brain size through altering the timing of developmental programmes [START_REF] Crockford | Thyroid rhythm phenotypes and hominid evolution: A new paradigm implicates pulsatile hormone secretion in speciation and adaptation changes[END_REF]. Due to the importance of thyroid function in brain development and their ability to enhance the synthesis of the precursor of the neurotransmitter dopamine, it has even been hypothesised that increasing thyroid hormone levels throughout our https://mc.manuscriptcentral.com/emph evolutionary history has contributed to the evolution of intelligence and increased cognitive capacity in modern day humans compared to our ancestors [START_REF] Previc | Thyroid Hormone Production in Chimpanzees and Humans : Implications for the Origins of Human Intelligence[END_REF].

[ENTER FIGURE 2 HERE]

The evolutionary literature therefore shows that since the first use of iodides in cyanobacteria, the thyroid system adopted a wide range of functions, from the regulation of cellular metabolism and body temperature to the coordination of tissue differentiation during development. Acknowledging that the thyroid system serves multiple functions evolved in response to various species-specific environmental challenges can help draw a holistic framework in which evolutionary and ecological factors are integrated together to explain patterns of variation.

The ecology of thyroid function Thyroid function, plasticity and life-history theory

Natural diversity in thyroid hormone levels may result from phenotypic plasticity, i.e. the evolved capacity of an organism to adjust its physiology, development and behaviour to variable environments in a way that maximizes its overall fitness (81).

To understand how organisms "adjust" their phenotype to their environments, evolutionary biologists use life-history theory [START_REF] Stearns | The Evolution of Life Histories[END_REF][START_REF] Roff | Life History Evolution[END_REF]. This framework posits that when resources are limited, organisms face trade-offs between the fitness functions of growth, reproduction, and somatic maintenance (Box 3). Natural selection is expected to favour organisms that make optimal allocation 'decisions' in growth, reproduction and immunity, given each life stage (e.g. infancy, childhood, adolescence, adulthood) and ecological conditions (i.e. mortality risk, resource availability).

Allocation decisions across the lifespan lead to various life-history trajectories with regards to growth, reproductive development and immune function. At the physiological level, such allocation 'decisions' are regulated through the action of hormones which modify cellular functions across different organs and tissues in response to endogenous as well as exogenous environmental stressors [START_REF] Wells | Evolutionary public health 1 Evolutionary public health: introducing the concept[END_REF]. Given that thyroid hormones play a critical role in modulating energy expenditure and the timing of life-history transitions (e.g. metamorphosis), using a life-history framework for understanding how environmental diversity mediates variation in thyroid function appears relevant.

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Developmental Plasticity

Developmental plasticity is a form of phenotypic plasticity, which indicates the ability of an organism to adjust its phenotype to the conditions encountered early in life. In this way, variation in thyroid function might correlate with conditions encountered early in life, where environments characterized by high mortality risk promote an accelerated development and metabolism through the upregulation of the thyroid, while early energetic deprivation promote the downregulation of thyroid hormones to slow down maturation and preserve energy for later reproduction (Box 4).

Life-expectancy at birth. When environments are characterized by a high extrinsic risk of mortality (i.e. mortality due to external stressors rather than the phenotype), organisms are expected to display accelerated reproductive development [START_REF] Stearns | The Evolution of Life Histories[END_REF][START_REF] Roff | Life History Evolution[END_REF], with faster transitions between life stages and the prioritisation of reproductive function at the expense of other fitness functions (growth, somatic maintenance). In this line, children growing up in the U.K. and the U.S. in socioeconomically deprived circumstances associated with a shorter life expectancy undergo reproductive maturation earlier, have their first child at a younger age, and experience poorer quality of health [START_REF] Hartman | External-environmental and internal-health early life predictors of adolescent development[END_REF][START_REF] Nettle | Dying young and living fast: Variation in life history across English neighborhoods[END_REF][START_REF] Ellis | The hypothalamic -pituitary -gonadal axis : A switch-controlled , condition-sensitive system in the regulation of life history strategies[END_REF]. Individuals living under difficult circumstances might thus be expected to display elevated thyroid hormone levels, an accelerated metabolism and a shorter lifespan. A Brazilian cohort study found that an underactive thyroid is less prevalent in lower income classes and in those with less years of education [START_REF] Olmos | Gender, race and socioeconomic influence on diagnosis and treatment of thyroid disorders in the Brazilian longitudinal study of adult health (ELSA-Brasil)[END_REF]. In elderly UK people, it was similarly found that subclinical hyperthyroidism was significantly associated with socioeconomic deprivation [START_REF] Wilson | Prevalence of Subclinical Thyroid Dysfunction and Its Relation to Socioeconomic Deprivation in the Elderly : A Community-Based Cross-Sectional Survey[END_REF].

Energetic stress early in life.

Assuming equal risks of extrinsic mortality, energetic stress may lead to decreased thyroid hormone levels. Decades of research on the ecology of human reproductive function have shown that differences in gestational and childhood environments alter the hypothalamic-pituitary-gonadal axis regulation and associated metabolic processes, as immunologically, nutritionally, or otherwise energetically stressed populations exhibit chronically lower ovarian steroid levels than more affluent population [START_REF] Jasienska | Human reproduction and health: an evolutionary perspective[END_REF]. Similar processes might be at play in shaping diversity in thyroid function over the life course. For instance, T3 levels are lower in babies born to anaemic and malnourished mothers [START_REF] Mahajan | Thyroid Hormone Dysregulation in Intrauterine Growth Retardation Associated with Maternal Malnutrition and / or Anemia[END_REF], and women with low birth weight and smaller size at birth have an increased risk of developing an underactive thyroid in adulthood [START_REF] Kajantie | Spontaneous Hypothyroidism in Adult Women Is Predicted by Small Body Size at Birth and during[END_REF]. Lower T4 levels were recorded in 61-70 year old British women bottle-fed or weaned early as compared to those who were breast-fed beyond their first year of life, suggesting an important role of infant nutrition and maternal thyroid hormones in breast milk for adulthood HPT axis regulation [START_REF] Phillips | Infant feeding, fetal growth and adult thyroid function[END_REF].

Another British cohort study found that among women aged 60-64 years, childhood weight gain from birth to puberty independently of height gain is positively associated with the presence of anti-TPO antibodies and T4 use, which were used as indicators of thyroid dysfunction, whereas being overweight or obese at 14 also correlated with positive anti-TPO antibodies [START_REF] Ong | Childhood weight gain and thyroid autoimmunity at age 60-64 years: The 1946 British birth cohort study[END_REF]. Hypothyroidism furthermore clusters with other metabolic-endocrine disorders, such as cardiovascular disease, obesity, and polycystic ovary syndrome, which have all previously been linked to prenatal undernutrition and small gestational size followed by improved nutritional conditions during childhood [START_REF] Kuzawa | Evolution, developmental plasticity, and metabolic disease[END_REF][START_REF] Gaberšček | Thyroid and polycystic ovary syndrome[END_REF]. Further investigation is needed regarding the relationship between nutritional status in early life and adult thyroid function, as well as the role of epigenetic mechanisms in mediating these effects.

Acclimatisation: short term adjustments in thyroid function

Thyroid hormones might enable organisms to adjust to current changes in their environment and associated energetic conditions. Research suggests that extreme temperatures, infections, resource scarcity, as well as psychological or social stresses, alter the thyroid function in humans and other animals. For example, thyroid hormones are upregulated in male California sea lions during the breeding season, enhancing energetic investment into costly reproductive behaviour [START_REF] Derango | Climate variability and life history impact stress, thyroid, and immune markers in California sea lions (Zalophus californianus) during El Niño conditions[END_REF], whereas by contrast, fasting reduces T4 levels in juvenile Northern Elephant Seals [START_REF] Jelincic | Variation in adrenal and thyroid hormones with life-history stage in juvenile northern elephant seals (Mirounga angustirostris)[END_REF]. Although the HPT axis is stimulated by some (anticipated) acute energy-demanding situations including cold or exercise, bodily states of overall negative energy balance such as chronic stress, inflammation, or fasting, suppress the HPT axis' activity [START_REF] Joseph-Bravo | TRH, the first hypophysiotropic releasing hormone isolated: Control of the pituitary-thyroid axis[END_REF][START_REF] Chatzitomaris | Thyroid allostasis-adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming[END_REF].

Rather than conserving a constant set point and feedback control within the HPT axis, as expected based on the concept of homeostasis under situations of strain and stress, the HPT axis acts as a flexible system that adjusts metabolism efficiently in anticipation of energetic challenges, which aligns with the model of adaptive allostasis [START_REF] Sterling | A model of predictive regulation[END_REF][START_REF] Chatzitomaris | Thyroid allostasis-adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming[END_REF]100). In this context, allostasis is a dynamic stress reaction that maintains stability in the internal milieu through change, complementing homeostatic processes [START_REF] Chatzitomaris | Thyroid allostasis-adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming[END_REF]. Across animal species, downregulated thyroid function might be an adaptive response to sustained energetic stress. Sea otters under resource stress experience T3 levels that are reduced by 12% on average (101). Further, the expression of the deiodinase enzymes, which mediates the peripheral conversion of T4 to T3, may be suppressed as a result of the activation of the stress response [START_REF] Stratakasis | Neuroendocrinology and Pathophysiology of the Stress System[END_REF]102). This effect is most likely mediated by glucocorticoids and inflammation [START_REF] Stratakasis | Neuroendocrinology and Pathophysiology of the Stress System[END_REF], changing the expression of these enzymes and creating a flexible system that can https://mc.manuscriptcentral.com/emph accommodate ecological challenges. In fasting juvenile Northern Elephant Seals for example, cortisol levels are inversely associated with free T3 levels [START_REF] Jelincic | Variation in adrenal and thyroid hormones with life-history stage in juvenile northern elephant seals (Mirounga angustirostris)[END_REF]. This suggests that lowered thyroid function preserves limited resources in the face of sustained energetic stress. By contrast, in situations where substantial increases in energy demands are anticipated, such as during pregnancy or in psychosocial stressful situations, active thyroid hormone production is upregulated [START_REF] Chatzitomaris | Thyroid allostasis-adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming[END_REF]. In this context, elevated T3 levels in patients with combat-related posttraumatic stress disorder (103) can be reinterpreted as an exacerbation of an otherwise adaptive response to an anticipated energy-demanding situation such as conflict. Although both homeostasis and allostasis are critical to thyroid function, allostatic adaptations in response to anticipated energetic stresses challenges the appropriateness of using reference intervals created based on the assumption of homeostatic regulation only [START_REF] Chatzitomaris | Thyroid allostasis-adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming[END_REF]. Such reference intervals may not be appropriate to accurately diagnose thyroid dysfunction in a physiological system that is in flux.

Although research in humans is limited, thyroid hormones appear to be key modulators of the optimal investment of energy into the competing physiological functions of growth, reproduction, and somatic maintenance in other animals (104).

Using an evolutionary framework, we suggest that energetic challenges resulting from ecological pressures such as pathogenic exposure or cold temperatures mobilise genetic, developmental, and short-term adaptations, which may lead to significant natural variation in thyroid hormone levels (Figure 3).

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Evolutionary perspectives on thyroid pathologies Evolutionary Approaches to Health and Diseases

The field of Evolutionary Medicine and Public Health (84,105-107) proposes a novel framework for disease aetiology that goes beyond understanding the proximate causes of illness only. Instead of narrowly considering the mechanisms responsible for thyroid disease, i.e. the immediate molecular, physiological, and anatomical causes, an evolutionary medicine approach considers the broader evolutionary, sociocultural, and developmental context from which these vulnerabilities to pathology emerged. Below we discuss the causes of thyroid disorders in light of this framework, focusing on four aetiologies of thyroid disease (i) mismatches in diet composition and lifestyle, (ii) maternal-foetal conflict and the female preponderance in thyroid disease, (iii) host-pathogen co-evolution and emerging infections, and (iv) exacerbated defence mechanisms.

Evolutionary mismatch and micronutrient deficiencies

Low levels of micronutrients are often implicated in the aetiology thyroid disorders, suggesting that diet is an important pre-disposing factor in the development of thyroid disease (109). A third of the world population lacks adequate iron intake, impairing the function of the haeme-dependent TPO-enzyme involved in thyroid hormone synthesis (110), 15% of the world population is deficient in selenium, an integral component of the deiodinase enzymes converting T4 into T3 (110), and two billion people are iodine deficient, including 50% of continental Europe (111). While seasonal and geographical variation in the availability of micronutrients, such as iodine, probably characterised the environment in which our species evolved (112), https://mc.manuscriptcentral.com/emph the widespread prevalence of iodine deficiency could be an evolutionary novel phenomenon [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF]113), resulting from the agricultural transition, the industrialisation of food production and the dietary shifts that accompanied these events [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF]113).

Although our physiology has evolved to be flexible and quickly adapt to new ecologies, cultural changes associated with the Neolithic agricultural transition and the more recent industrialisation and urbanisation happened so rapidly that our physiology struggles to catch up (114). Certain food items rich in iodine such as seaweed, sea food, dark green leafy vegetables, egg yolk, and seeds, were probably more common in our ancestral diets [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF]. In seemingly iodine depleted regions, such as the Congo basin, the consumption of iodine-rich aquatic plants has even been reported in non-human primates (184). However, an increased consumption of cereal grains, legumes, and tubers associated with the adoption of agriculture may have heightened our ingestion of substances that interfere with our body's ability to utilise dietary iodine effectively, also known as goitrogens (115). As a carbohydrate-rich diet increases T3 levels, Kopp (2004) has furthermore proposed that adopting a cereal based diet might contribute to an increase in iodine requirement in populations relying on agriculture (113). Increased flooding and soil erosion associated with intensified agriculture can deplete iodine in the soil, which causes the crops grown in such areas to be much lower in iodine content (111). Despite the important contributions of globalisation and iodised salt in decreasing iodine deficiency and its severe health consequences, as people move towards a more industrialised, Western diet, their intake of iodine decreases yet again due to the lack of iodised salt in processed and fast foods (116).

Sex disparities in thyroid disease and the maternal-offspring conflict

Although according to some research parity itself does not put women at risk of developing thyroid dysfunction later on (131), women are especially vulnerable to developing thyroid conditions around reproductive transitions such as pregnancy; in the US 15.5% of pregnant women are hypothyroid (124) and 5-8% of iodine-sufficient women experience transient thyroid dysfunction postpartum [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF]125). In this context reinterpreting the meaning of reproductive disease is necessary to move the women's health agenda beyond studying pathologies of reproductive organs alone (126).

https://mc.manuscriptcentral.com/emph There might have been significant selection pressure throughout human evolutionary history to adequately manage the maternal-offspring conflict over thyroid hormones and iodine access during gestation, which may predispose women to develop thyroid disease. Evolutionary biologists consider gestation as a period of both mutual and competing interests because of the dissimilar 'goals' of mother and foetus (107,127,128). Whereas the offspring seeks to maximise maternal investment into thyroid hormone production during pregnancy to enhance its own long-term fitness, the maternal body has evolved to optimise thyroid hormone allocation in a way that does not harm her health and future reproductive success (128). Pregnancy increases the mother's daily iodine requirement due to enhanced renal excretion whilst thyroid hormone synthesis increases by 50-75% [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF]. Although the thyroid is the first endocrine gland developing in the offspring, it only becomes active after the 12 th week of gestation and the progeny continues to rely on maternal thyroid hormone throughout pregnancy and lactation to gain access to iodine [START_REF] Chatzitomaris | Thyroid allostasis-adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming[END_REF]129).

Therefore, the embryo depends on the mother's thyroid hormone production during this critical early period of neural tissues differentiation [START_REF] Williams | Neurodevelopmental and neurophysiological actions of thyroid hormone[END_REF]128), thereby inevitably also relying on the mother's iodine status as a result of her diet. Iodine deficiency during pregnancy may cause miscarriage or brain damage in the offspring [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF], whereas iodine-deficient mothers risk developing a goitre leading to thyroid dysfunction and even infertility later on (107,128). Understanding changes in thyroid function regulation during pregnancy may also shed new light on the aetiology of thyroid disease in women.

It has been suggested that a maternal-offspring conflict may take place over thyroid hormones and iodine access during pregnancy, resulting in a physiological tug-of-war (128,132). [START_REF] Boddy | The impact of iron and selenium deficiencies on iodine and thyroid metabolism: Biochemistry and relevance to public health[END_REF] have proposed that foetal cells preferentially infiltrate maternal tissues important in resource allocation, manipulating them as part of their tug-of-war (132). In the context of the maternal-offspring conflict over iodine, we suggest that in addition to using enhanced thyroid metabolism as a means to upregulate maternal heat production postpartum, foetal cells may also enhance thyroid hormone production during pregnancy and lactation to enhance iodine access during gestation and iodine transfer in the mother's milk. However, recognition of foetal cells by the maternal immune system could cause autoimmune reaction against thyroidal tissue and the high prevalence of postpartum thyroiditis (107).

Accordingly, foetal microchimerisms are found more frequently in the thyroids of AITD-patients than in healthy volunteers or nulliparous women (133,134) and may also be preferentially located in thyroid neoplasms (135). Therefore microchimerisms may be one mechanism underlying the preponderance of thyroid disease in women.

Oestrogen is also closely linked to maternal thyroid function during gestation, as studies of combined oral contraceptive users show that using hormonal contraception, which in certain ways mimic pregnancy conditions, increases pituitary sensitivity towards thyrotropin-releasing hormone (TRH) and is associated with higher thyroid hormone levels [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF]. [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF], has suggested that due to antagonistic pleiotropy the adaptive connection between oestrogen and thyroid function during pregnancy may be deleterious when oestrogen levels fall during menopause, contributing to the sex disparity in thyroid disease [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF]. Yet, a large cohort study in oral contraception users suggests that oestrogen might actually be protective against developing thyroid disease (130). It therefore remains to be investigated what adaptations enabling the manipulation of the maternal thyroid https://mc.manuscriptcentral.com/emph during pregnancy might also be proximate mechanisms by which thyroid disease develops during other reproductive transitions such as menopause [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF].

Another proposed mechanism for the mother-offspring conflict over HPT axis regulation is based on the structural similarity between human Chorionic Gonadotropin (hCG), the 'pregnancy hormone' secreted by the embryo during the first few weeks of gestation, and TSH (136,137). Due to its chemical similarity to TSH, hCG is able to attach to TSH receptors on the thyroid, stimulating the growth of the gland and T4 and T3 production (128,138,139). The offspring in turn uses the placental deiodinase 3 enzyme to convert any excess of maternal thyroid hormone into its inactive forms, such as reverse T3 (rT3) (128). This process, in which hCG acts as a thyroid stimulator, has been viewed to serve embryonic interests at the cost of maternal interests under condition of iodine deficiency (128). Forbes (2014) argues that when iodine is plentiful, the correlates of surplus thyroid hormone production (e.g. rT3) might be proximate triggers for pregnancy sickness (128,140), although this remains to be tested. More generally, because the manipulation of the maternal thyroid during pregnancy is produced outside the maternal thyroid control circuit, thyroid function during pregnancy is prone to dysregulation. In the context of Flaxman & Sherman's seminal work on nausea and vomiting during pregnancy in relation to food aversions and cravings, it would also be relevant to see whether goitrogenic foods, which interfere with thyroid metabolism, are considered more aversive during early gestation in societies that are relatively iodine-depleted, whereas iodine-rich foods are being craved (185).

Old Friends, emerging infections, and AITD

https://mc.manuscriptcentral.com/emph Complex interactions exist between pathogen exposure and AITD risk. The Old Friend hypothesis proposes that some contemporary environments deprive humans of the input from microorganisms such as helminthic parasites that induce important regulatory pathways involved in immunotolerance during development (141). The involvement of 'Old Friends' in these pathways is the result of a symbiotic coevolution throughout mammalian evolutionary history. Helminths acquired the capacity to manipulate the host immune system for their own benefit by inducing a modified Th2-type response and regulatory T-and B-cells to down regulate the host's inflammatory responses (141,142). Some modern lifestyles, lacking this helminthinduced immunoregulation, might therefore predispose to disorders associated with excessive inflammation, including autoimmunity (141,143). In this line, a study in mice shows that prior infection with the helminth Schistosoma mansoni suppresses inflammatory Th1-type immune responses against the TSH-receptor, thereby preventing Graves' disease development (144). Reintroducing coevolved microbiota has been used as a treatment for some autoimmune diseases such as multiple sclerosis, where helminth therapy shows some beneficial effects, mostly by reducing inflammatory cytokine levels (142). However, in the context of Graves' disease in mice, helminth therapy is only effective before the aberrant immune response against the TSH-receptor has developed; later introduction of helminths was not effective (144). Further studies are necessary to confirm whether helminth therapy, in the form of helminth-derived immunomodulatory molecules rather than living parasites have a beneficial effect in preventing or treating AITDs in humans, as the safety of using live parasites is still under investigation (183).

Exacerbation of adaptive responses

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In some instances pathology may result from an exacerbation of a normally adaptive response (105,108). An example is the phenomenon of 'non-thyroidal illness syndrome' (NTIS), occurring in 60-70% of critically ill patients [START_REF] Haarburger | Thyroid disease: thyroid function tests and interpretation[END_REF], which is characterized by extremely low levels of thyroid hormones despite TSH being initially unaltered [START_REF] Jonklaas | Reference intervals in the diagnosis of thyroid dysfunction: treating patients not numbers[END_REF]. Patients admitted to the intensive care unit various acute illnesses have higher reverse T3 (rT3) levels due to the inactivation of T3 by deiodinase enzymes, and disease severity correlates with higher concentrations of rT3 (156), suggesting that deiodinase enzyme expression is altered [START_REF] Chatzitomaris | Thyroid allostasis-adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming[END_REF]. Patients with low T3 require longer ventilation and experience higher mortality rates [START_REF] Chatzitomaris | Thyroid allostasis-adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming[END_REF], and low serum T3 have also been recorded in 96% of hospitalised patients with SARS-CoV infection (147,157).

Despite several clinical trials attempting to correct abnormal thyroid function in NTIS using thyroid hormone replacement, there is not enough improvement in patient outcomes to justify the use of this therapy (158). The evolutionary ecology framework proposed here, with its focus on energy balance, suggests that improving energetic conditions rather than thyroid hormone supplementation would benefit patients with NTIS, which is a contribution from evolutionary medicine to clinical medicine. Indeed, a recent study shows that high caloric exposure can attenuate the decrease of T3, aiding patient recovery (159). NTIS can therefore be reinterpreted as an exacerbated adaptive response to illness in which thyroid function is downregulated to lower energetic requirements of non-vital functions in the face of chronic negative energy balance during illness [START_REF] Klein | The immune system as a regulator of thyroid hormone activity[END_REF]160). To shed light on the extreme ends of normal https://mc.manuscriptcentral.com/emph variation in thyroid function, characterising the role of different types of stress on thyroid function and T4 to T3 conversion by deiodinases is required.

CONCLUSION

This review sought to challenge the idea that all variation in thyroid function is best interpreted as pathological. We have advocated for an evolutionary perspective to shed new light on normal patterns of variation across populations, individuals and over the lifespan, framing diversity in thyroid function as an evolved response allowing organisms to adapt their metabolism to the energetic requirements of their ecology (Figure 4). The insight that the thyroid system evolved in response to various species-specific environmental challenges to serve multiple functions can help draw a holistic framework integrating multiple ecological factors to comprehend normal patterns of variation and helps identify a number of outstanding questions (Box 5). To that end, using big data and digital health apps might help us access untapped sources of variation to develop a deeper insight into the associations between an individual's life-history and ecology and changes in thyroid function and patients' symptomatology. By creating a better understanding of the natural variation in thyroid function, we can start providing the more personally adjusted care that patients deserve by giving greater attention to the underlying causes of thyroid dysfunction rather than focusing on treating patients within constructed reference values. When different species or taxa evolve a similar feature or function independently at different time points in their evolutionary history.

Endothermy

The ability to self-regulate body temperature. Exaptation A co-option of an anatomical structure, a certain behavioural trait or a physiological system during the evolutionary history of a species to serve a novel function.

Goitre

A swelling of the neck due to an enlarged thyroid gland.

Hyperthyroidism

An overactive thyroid characterised by high T4 levels and low TSH levels.

Hypothyroidism

An underactive thyroid characterised by low T4 levels and high TSH levels.

HPT axis

The hypothalamic-pituitary-thyroid axis (see Figure I).

Life-history theory

A framework in evolutionary biology aimed at understanding diversity in life-histories between species and individuals.

Maternal hypothyroxinaemia

Low T4 levels in the mother during gestation, which can cause cretinism in the offspring.

Microchimerisms

The bidirectional exchange of maternal and foetal cells during gestation. When these cells are not adequately cleared after parturition, they are a predisposing factor for the development of autoimmunity as they may cause the body to launch an immune response against the foreign invading cells. Some research suggest that foetal cells may preferentially travel to the maternal thyroid amongst other tissues.

Molecular mimicry

Pathogens have evolved the capacity to escape recognition by the host immune system by mimicking the host's own bodily molecules on their surface. However, this means that an immune response against these molecules may have a cross-over effect with the host's own tissues, which can result in the development of aberrant immune responses and autoimmune disease after the infection.

Myxedematous cretinism

Results from severe iodine deficiency in late pregnancy or the neonatal period, causing mental retardation, short stature, goiter, and hypothyroidism. Can be caused by the underdevelopment or atrophy of the thyroid in the offspring.

Neurologic cretinism

Results from maternal iodine deficiency or hypothyroidism during pregnancy, leading to intellectual disability, deaf mutism, spasticity and disturbances in gait in the offspring.

However, the offspring has adequate thyroid function postnatally.

Plasticity

The evolved capacity of an organism to adjust its physiology, development and behaviour to variable environments in a way that maximizes its overall fitness. T3

Triiodothyronine (T3) is the more metabolically active type of thyroid hormone which is taken up by cells. T4 Thyroxine (T4) is the less active variant of thyroid hormone but binds to thyroid hormone binding proteins with higher affinity, and therefore has a longer half-life in the circulation. Thyroglobulin (TGB)

Intermediate/precursor product of thyroid hormone synthesis. TPO(-enzyme) Thyroid hormones are synthesised through the iodination of the amino acid tyrosine by the enzyme thyroid peroxidase (TPO).

Box 1: The hypothalamic-pituitary-thyroid (HPT) axis and the diagnosis of thyroid dysfunction

Thyroid hormone production is under the regulation of the hypothalamic-pituitary-thyroid (HPT) axis, which starts with hypothalamic neurons secreting thyrotropin-releasing hormone (TRH), stimulating the release of thyroid stimulating hormone (TSH) from the pituitary. TSH binds to receptors on the thyroid, which produces two closely related thyroid hormones; thyroxine (T4), and triiodothyronine T3. These thyroid hormones are synthesised through the iodination of the amino acid by the enzyme thyroid peroxidase (TPO) and can consequently temporarily be stored as an intermediate thyroglobulin complex. The majority of the thyroid gland's output consists of T4, which is the less active variant of T3, but binds to thyroid hormone binding proteins with higher affinity, and therefore has a longer half-life in the circulation. Unbound, free thyroid hormone is taken up by cells where they have a wide range of genomic and non-genomic effects, including the enhancement of oxygen use in the mitochondria, increasing energy availability for muscular work or thermoregulation. Through differential expression of deiodinase enzymes, which convert the pro-hormone T4 to its active T3 form, tissues can adjust the concentration ratio of free thyroid hormones to local metabolic needs.

Thyroid dysfunction is commonly diagnosed by analysing serum thyroid stimulating hormone (TSH), and often other thyroid biomarkers are only tested if TSH is considered abnormal. TSH tests are then complemented by measurements of thyroid autoantibodies, free thyroxine (T4), and its more metabolically active form free triiodothyronine (T3). These biomarkers are compared with reference intervals for large populations without thyroid disease, using a 95% interval for T4 and T3 and the 2.5 th and 97.5 th percentiles to determine the normal TSH reference range [START_REF] Jonklaas | Reference intervals in the diagnosis of thyroid dysfunction: treating patients not numbers[END_REF]. T4 and T3 are produced in response to TSH under negative feedback from the hypothalamic-pituitary-thyroidal (HPT) axis (Figure I) [START_REF] Sievert | Thyroid disorders at Midlife: An Evolutionary Perspective[END_REF]. A hypothyroid state is diagnosed when TSH levels are elevated and free T4 is decreased as compared to the reference interval (5), whereas hyperthyroidism is diagnosed if TSH levels are decreased and free T4 levels are elevated [START_REF] Luck | The thyroid gland[END_REF][START_REF] Joseph-Bravo | TRH, the first hypophysiotropic releasing hormone isolated: Control of the pituitary-thyroid axis[END_REF]. The diagnosis and treatment of thyroid dysfunction is often considered simple and done in a primary care setting [START_REF] Thienpont | Harmonization of serum thyroid-stimulating hormone measurements paves the way for the adoption of a more uniform reference interval[END_REF].

[ Adaptation to iodine deficient environments. Although the Ituri forest in the Congo basin is an iodine-deficient region with high prevalence of goitre (42.9%), in the village-dwelling Bantu population, Efe pygmees, who have inhabited this region for ten thousands of years, suffer from unexpected low goitre rates (9.4%) (162). Genetic studies have consequently found two genes involved in the thyroid hormone pathway to show strong signatures for positive selection in Mbuti and Baiaka pygmies, who are closely related to the Efe and live in the same forest (163). This suggests that these populations have adapted to an iodine-deficient diet through genetic adaptation (161). Whether other populations have evolved other genetic or cultural adaptations in response to similar dietary challenges, such as in the case of lactose intolerance where various populations evolved different adaptations, would be an interesting future avenue to explore.

Adaptation to cold environments Basal metabolism rates are closely associated with T4 levels in Evenki herders and Russians living in Siberia [START_REF] Leonard | Metabolic Adaptation in Indigenous Siberian Populations[END_REF]. However, Evenki women display higher free T4 levels than Russian women living in the same area, which could be an adaptation to the cold temperatures of the Siberian winters by elevating metabolism rates [START_REF] Leonard | Metabolic Adaptation in Indigenous Siberian Populations[END_REF]164). Investigations of the mitochondrial DNA of Siberian populations have furthermore shown a strong selection on genetic variants that contribute to enhanced metabolic heat production, which suggests that their mitochondria might react more strongly to thyroid hormones' metabolic influences [START_REF] Leonard | Metabolic Adaptation in Indigenous Siberian Populations[END_REF]165).

While various single nucleotide polymorphisms exists in genes coding for the deiodinase enzymes, as well as the TSH and T3 receptors, corresponding to differences in TSH and T3 levels (161,166), there is a dearth of research on the historical and ecological causes for genetic polymorphism in thyroid function in humans. Further genetic studies in various localities are needed to elucidate how evolutionary processes (natural selection, drift, migration, mating) acting on genetic variants have contributed to genetic polymorphism in thyroid function.

Box 3: Integrating thyroid function into a life history framework

Thyroid hormones are involved in the regulation of the key fitness functions of growth, reproduction and immunity. Firstly, thyroid hormones stimulate growth by affecting the expression of genes involved in cellular growth and differentiation, and by stimulating DNA synthesis in osteoblasts and other cells (167). Secondly, the thyroid axis interacts with reproductive function by influencing the metabolism of oestrogens and androgens and the unbound levels of these sex hormones (168). In a study of 86 euthyroid women in Michigan, were not lactating or taking hormonal medications, greater total T4 was associated with higher levels of urinary metabolites of progesterone and oestrogen, whereas at the same time elevated free T4 was associated with a shorter follicular phase and cycle length (169). Thirdly, thyroid hormones play an important role in somatic maintenance by enhancing oxygen use in the mitochondria, thereby increasing cellular energy availability for muscular work or thermoregulation (4) and stimulating the immune system (170). As a consequence, individuals with an underactive thyroid often display immune deficits and are left more vulnerable to infection. By contrast, elevated thyroid hormone levels are associated with improved pathogen clearance due to the importance of thyroid hormones for the maturation and differentiation of the innate and adaptive immune cells and for the immune processes of phagocytosis, cytokines production and release (170).

Considering the role of thyroid hormones in these different physiological axes from a life history perspective, diversity in thyroid hormone levels can be expected to correlate with energetic investments in growth, reproduction and somatic maintenance over the lifespan. Although other hormones such as sex steroids are also involved in regulating energetic trade-offs, thyroid hormone modulation may play a unique role as it is not necessarily limited to specific life stages, but may act over longer time scales. We therefore argue that the HPT axis should be considered as alongside other key physiological axes that mediate life-history trade-offs and energetic investments over the lifespan (171), especially because of thyroid hormones' important role in determining basal metabolic rate and thereby long term energetic expenditure (Figure II).

[ENTER FIGURE II HERE]

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Box 4: Thyroid function, reproductive development and the fertility-longevity trade-off

Research from human reproductive ecology has shown that under conditions of chronic energetic stress early in life, delaying maturation and downregulating ovarian function is sometimes adaptive by yielding the maximum lifetime reproductive output possible in a resource-limited ecology (172). Given the influence of thyroid function on the reproductive axis, we hypothesise that in energetically challenging circumstances, lowered thyroid function plays a role in determining the pace of reproductive development and fertility. Lowered thyroid function may indeed contribute to delayed pubertal development [START_REF] Santos | Hashimoto's Thyroiditis in Adolescents[END_REF] and although subclinical underactive thyroid function only mildly affects the menstrual cycle (173), for hypothyroid individuals menstruation is often less frequent (174). Furthermore, women with severe hypothyroidism often fail to ovulate (174) and an underactive thyroid is a common cause of spontaneous abortion during the fertile years (175), although after conception, live birth rate is not always affected (176). This suggests that an underactive thyroid might lead to an increased interbirth interval, whereas in hyperthyroid women, menstrual cycles are shortened and occur more frequently, but remain ovulatory (177). It is not clear how far these plastic changes in reproduction can be attributed to constraints in early life or the current environment. Studies in natural fertility populations with various modes of subsistence are necessary to further investigate possible associations between energetic conditions, thyroid function and reproduction.

Thyroid function might also play a key role in mediating the trade-off between longevity (i.e. stress resistance) and reproduction, although this has remained largely unexplored in humans. Studies in Wistar rats suggest that an underactive thyroid might contribute to an increased lifespan by reducing the overall metabolic rate, oxidative stress, and cell senescence whereas artificially inducing hyperthyroidism using T4 supplementation shortened life duration, most likely due to accelerated ageing (178,179). Although much less is known about the effect of hyperthyroidism on lifespan in humans, some studies have noted that, even at subclinical levels, hyperthyroidism is associated with a higher risk of cardiovascular diseases [START_REF] Chaker | Subclinical hypothyroidism and the risk of stroke events and fatal stroke: An individual participant data analysis[END_REF]180), in contrast to subclinical hypothyroidism [START_REF] Surks | Subclinical Thyroid Disease[END_REF]. Studies showed that centenarians are much more likely to have slightly elevated TSH, as do their closest family members and offspring (178,181,182), which suggests that longevity and thyroid function are to some degree inherited (161). How far these effects might also be due to developmental influences, however, remains unclear.

Figure descriptions:

Figure 1: Global variation in female TSH reference intervals across reproductive life stages Because of the way reference ranges are constructed, the 2.5-97.5th percentiles and medians of TSH measurements in different populations across the world will vary depending on the geographical location, ethnicity of the participants, age and reproductive life stage of the participants, assay manufacturer, statistical method used, and the laboratory where the test has been conducted. We chose to look at female reference ranges only because thyroid disorders a more prevalent in women and most studies report a significant difference between female and male TSH reference intervals. Where possible we display the disease-free population to reflect the diversity of normal, 'healthy' TSH reference intervals used around the world. In this figure we only display the TSH reference intervals that we published between 2017 and early 2020, for further information on the methods used in the systematic search and the references for the intervals displayed in this figure please see supplementary table 1. The ability to use of iodine, iodides, and iodinated compounds is thought to date back as far as the prokaryote ancestor of all eukaryote life. Later these molecules might have played an important role in the evolution of multi-cellular life, cell-to-cell signalling and the regulation of cellular metabolism. The endostyle, which is the precursor of the vertebrate thyroid gland, developed in chordates circa 500 million years ago. The evolution of the enzymatic machinery of the endostyle, may have been vital for the evolution of terrestrial life. All vertebrates share a thyroid gland and thyroid hormones with a similar chemical structure, however in both birds and mammals thyroid function was further upregulated leading to endothermy, the ability to regulate body temperature. Finally, in humans further selection pressure on the thyroid led to elevated total T4 concentrations compared to our Chimpanzee cousins. Energetic challenges due to various ecological factors will induce alterations in thyroid function regulation depending on the life history stage. Variation in thyroid function can be understood at multiple levels: genetic, developmental, and acclimatisation. Given evolutionary constraints and ecological contexts, thyroid function plays a role in regulating the energetic trade-offs between the functions of reproduction, growth and somatic maintenance, which includes immunity and basal metabolic rate. This framework can contribute to re-evaluate biomedically accepted cut-offs that are considered pathological. Yet, not enough is known about normal patterns of variation, a prerequisite to understand the aetiology and onset of thyroid dysfunction.

Figure I: The hypothalamic-pituitary-thyroidal (HPT) axis

Thyroid hormone production is regulated by the hypothalamic-pituitary-thyroid (HPT) axis. First hypothalamic neurons secrete thyrotropin-releasing hormone (TRH), causing the release of thyroid stimulating hormone (TSH) from the pituitary. TSH binds to receptors on the thyroid, a gland which produces two closely related thyroid hormones; thyroxine (T4), and triiodothyronine T3. Through differential expression of deiodinase enzymes converting the pro-hormone T4 to its active T3 form, tissues adjust the concentration ratio of free thyroid hormones to local metabolic needs.

Figure II:

The hypothalamus as a central coordinator of life-history programmes. The hypothalamus is the starting point of the four endocrine axes that neatly correspond to the branches of life-history theory of growth, reproduction, and somatic maintenance. These are the hypothalamic-pituitary-somatotropic, hypothalamic-pituitary-gonadal, and hypothalamic-pituitary-adrenal axis respectively, and we are adding the HPT axis as an important addition to this framework proposed by Wang et al. (2019) (171). The final outputs of these axes are hormones: the HPSaxis governs the pituitary secretion of growth hormone and the hepatic secretion of IGF-1 involved in protein metabolism and growth; the HPG-axis coordinates the release of reproductive hormones from the gonads; and the HPA-axis regulates the adrenal secretion of glucocorticoids in response to environmental stress, adjusting the partitioning of resources between competing demands. Not displayed in this figure are the important interactions between these physiological axes. By modulating optimal energy investment in peripheral tissues, these hormones are the physiological mediators by which organisms adjust maturation trajectories and modify cellular functions across different tissues and organ systems in response to environmental cues. Through affecting neuroendocrinology of the hypothalamus, early childhood conditions could potentially create new set points for the coordination of the different axes, which might play a role in mediating life history trade-offs and the timing of key transitions such as maturation.

  Universal iodine supplementation may seem like the easiest solution, but the effect of iodine supplementation on the development of thyroid dysfunction follows a Ushaped curve -both too little or too much iodine can contribute to an increased AITD prevalence (2) -which is why variation in local geography, cultural practices regarding food, and evolutionary history should be taken into account when designing public health interventions. Similarly, other novel environmental exposures that might contribute to thyroid disease, such as air pollution and environmental pollutants, as well as night shift working and other risk factors associated with an urbanized, modern lifestyle deserve further consideration from biological anthropologists and public health practitioners alike (117-119). Smoking, for example, may increase T4. Indeed lower TSH levels and hyperthyroidism are more prevalent amongst smokers (120), whereas obesity, by increasing leptin levels, might contribute to the development of thyroid autoimmunity and hypothyroidism (121).

  https://mc.manuscriptcentral.com/emph Persistent infections of the thyroid and the manipulation of the host's immune system by microbial organisms and viruses can also contribute to AITD (145-147). For Hashimoto's thyroiditis, viruses such as herpes simplex, rubella, mumps and Epstein-Barr might play a role in disease development, whereas retroviruses such as HIV are associated with Graves' disease (145,147). Through either bystander activation or molecular mimicry, the inflammatory cellular immune response to a viral infection can cause the activation of autoreactive immune cells that target thyroid antigens themselves and persist even after the infection has cleared (148).The spread of the novel coronavirus could pose a novel environmental trigger contributing to increased thyroid dysfunction post outbreak. In 61 survivors of SARS, 3% had transient subclinical thyrotoxicosis and nearly 7% had underactive thyroid following recovery (149). One of the pathological organ changes described after the SARS epidemic in 2002 was increased thyroid follicular cell death (150), which in combination with enhanced cytokine production and systematic inflammation, could lead to the activation of autoreactive immune cells against thyroid antigens and a breakdown in tolerance. Similarly, in the current COVID-19 pandemic significant alterations in thyroid function have been noted: compared to patients suffering from non-COVID-19 pneumonia, COVID-19 patients have significantly decreased TSH and total T3 levels depending on the severity of the disease (151). Furthermore, several case reports suggest that in some survivors of the disease, SARS-COV-2 may act as a trigger of for autoimmune hyperthyroidism (Graves) and thyrotoxicosis (152-155), even if initial disease course was mild (155).

Figure 2 .

 2 Figure 2. A simplified phylogeny of thyroid function.The ability to use of iodine, iodides, and iodinated compounds is thought to date back as far as the prokaryote ancestor of all eukaryote life. Later these molecules might have played an important role in the evolution of multi-cellular life, cell-to-cell signalling and the regulation of cellular metabolism. The endostyle, which is the precursor of the vertebrate thyroid gland, developed in chordates circa 500 million years ago. The evolution of the enzymatic machinery of the endostyle, may have been vital for the evolution of terrestrial life. All vertebrates share a thyroid gland and thyroid hormones with a similar chemical structure, however in both birds and mammals thyroid function was further upregulated leading to endothermy, the ability to regulate body temperature. Finally, in humans further selection pressure on the thyroid led to elevated total T4 concentrations compared to our Chimpanzee cousins.

Figure 3 :

 3 Figure 3: An ecological framework for variation in thyroid function.Energetic challenges due to various ecological factors will induce alterations in thyroid function regulation depending on the life history stage. Variation in thyroid function can be understood at multiple levels: genetic, developmental, and acclimatisation. Given evolutionary constraints and ecological contexts, thyroid function plays a role in regulating the energetic trade-offs between the functions of reproduction, growth and somatic maintenance, which includes immunity and basal metabolic rate. This framework can contribute to re-evaluate biomedically accepted cut-offs that are considered pathological. Yet, not enough is known about normal patterns of variation, a prerequisite to understand the aetiology and onset of thyroid dysfunction.

: Human genetic polymorphism in thyroid function

  ENTER FIGURE I HERE]Throughout human evolution, various evolutionary processes, including natural selection, likely shaped diversity in human thyroid physiology across populations living in different geographies in the face of different ecological pressures (161).

https://mc.manuscriptcentral.com/emph Box 2

https://mc.manuscriptcentral.com/emph Downloaded from https://academic.oup.com/emph/advance-article/doi/10.1093/emph/eoaa043/5970476 by guest on 01 January 2021

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Acknowledgements

The authors are grateful to Dr Charlotte Faurie, MD. for her comments on an earlier version of the manuscript and Kelly Dern for illustrations.

Box 5: Outstanding questions

Understanding natural variation:

1. What are the reference ranges for thyroid function in natural fertility, subsistence populations living in different ecologies? 2. How does ageing affect thyroid function in populations not living a Westernised industrial lifestyle? 3. Why is there variation in cretinism subtypes across different geographical regions? Genetic adaptation: 4. Are there substantial differences in thyroid function and genetic background between populations consuming a shore-based diet and those that live in iodine depleted regions? 5. What are the genes responsible for differences in thyroid function between humans and other primates? Developmental plasticity: 6. How does breastfeeding and childhood nutrition affect thyroid function in childhood, adulthood and postreproductive life? 7. Does socioeconomic adversity in infancy influence adult thyroid function? Acclimatisation: 8. How do different types of ecological stressors (e.g. infection, undernutrition, social competition) affect the expression of the deiodinase enzymes that locally convert T4 to T3? 9. How does being in COVID-19 pandemic lockdown affect thyroid function?

Understanding thyroid disease using an evolutionary medicine approach: 10. Why is there more AITD in populations that in the past where chronically iodine depleted but are now (over)supplemented with the micronutrient? 11. What is the disease burden of AITD in populations living in different pathogen ecologies? 12. Do the proximate mechanisms that link pregnancy to changes in thyroid function play a role in the aetiology of thyroid disease during reproductive transitions? https://mc.manuscriptcentral.com/emph Because of the way reference ranges are constructed, the 2.5-97.5th percentiles and medians of TSH measurements in different populations across the world will vary depending on the geographical location, ethnicity of the participants, age and reproductive life stage of the participants, assay manufacturer, statistical method used, and the laboratory where the test has been conducted. We chose to look at female reference ranges only because thyroid disorders a more prevalent in women and most studies report a significant difference between female and male TSH reference intervals. Where possible we display the disease-free population to reflect the diversity of normal, 'healthy' TSH reference intervals used around the world. In this figure we only display the TSH reference intervals that we published between 2017 and early 2020, for further information on the methods used in the systematic search and the references for the intervals displayed in this figure please see supplementary


Damien Alloyeau

Abdelali Khelfa

Kinan Aliyah

Adrian Chmielewski

Jun Meng

Hakim Amara

Hazar Guesmi

Jaysen Nelayah

Guillaume Wang

Cyrille Hamon

Revealing the Dynamics of Functional Nanomaterials in Their Formation and Application Media with Liquid and Gas-phase TEM

établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Revealing the Dynamics of Functional Nanomaterials in Their Formation and Application Media with Liquid and Gasphase TEM Damien Alloyeau 1 , Abdelali Khelfa 1 , Kinan Aliyah 2 , Adrian Chmielewski 3 , Jun Meng 4 , Hakim Amara 5 , Hazar Guesmi 4 , Jaysen Nelayah 1 , Guillaume Wang 1 , Cyrille Hamon 2 , Doru Constantin 2 and Christian Ricolleau The development of efficient nanotechnologies requires fabricating functional nanomaterials with controlled morphology, composition and atomic structure, and determining if and how these structural parameters change under working conditions. Therefore, understanding the dynamics of nanostructures in their formation and application media is a crucial challenge for materials science. In that regards, in situ TEM in closed cells provides the unique opportunity to visualize at the appropriated scale the behavior of nanomaterials in well controlled liquid and gaseous environments. We have exploited liquid-cell TEM to study the growth and etching mechanisms of plasmonic nanostructures (Au and AuAg nanorods). We will show that this in situ technique allows identifying the individual role of chemicals in the reaction media, helping our understanding of nanomaterial synthesis. We will notably demonstrate the key role of capping agents in anisotropic growth and selective etching processes which illustrate the necessity to consider the hybrid nature (i.e. organic/inorganic) of functional nanomaterials to unravel their formation mechanisms. [1,2] We have also used gas-cell TEM to identify the nature of the active sites for O2 and H2 adsorption/dissociation on gold nanoparticles supported on TiO2. Our real-space observations of gold catalysts under "realistic" conditions (i.e. atmospheric pressure and high temperature) provide a clear picture of their structural evolution in functional state which sheds a new light on the facet-specific molecular adsorption of O2.[3] So far, the lack of statistical results and the questioning about the effects of the beam on nanomaterials dynamics have limited the impact of in situ TEM investigations in the fields of colloidal chemistry and heterogeneous catalysis. These intrinsic limitations have pushed us to corroborate all our TEM results with complementary in situ techniques (SAXS and absorption spectroscopy) or atomistic simulations to enhance the validity of our conclusions. Such correlative approaches are essential to allay the skepticism about in situ TEM results and maximize their impact in materials science.

Figure 1 .

 1 Figure 1. Figure 1. (a) Time-lapse STEM images showing the anisotropic deposition of silver on a gold bipyramid in aqueous media. Scale bar is 50 nm on all images. (b) Contour plots of the AuAg rods extracted every second from image analysis. Extracted with permission from ref. [2].

Figure 2 .

 2 Figure 2. In situ HAADF-STEM observations of Au nanoparticles on r-TiO2 (110) surfaces under O2 at atmospheric pressure. (a-d) Temperature series of low magnification HAADF-STEM images showing that rounding if Au nanoparticles at low temperature. (e-l) Temperature series of high magnification HAADFSTEM images over the temperature window where the octahedron-to-round morphology transition is observed. This shape transition is due to the growth of (110) facets on which O2 molecules preferentially react. Extracted with permission from ref. [3].