Exploring the possibility that axon abnormalities caused by iodine deficiency are linked an increased risk of autism

Author: Ding Hong Zheng
Mentor: Dr. Emma Sarro
Stonybrook University

Abstract

Autism is a neurological and developmental disorder that has been increasing worldwide in the recent decades. Meanwhile, iodine is an essential nutrient for normal axon development and has been consumed inadequately in recent years in many countries. Therefore, both Autism and iodine deficiency is a global health problem that needs much greater recognition worldwide to improve the health and wellness of people. In this study, the relationship between iodine deficiency during prenatal development, axon growth, and the incidence of Autism was investigated using both primary and secondary data. We present evidence that suggests abnormal axon development caused by iodine deficiency during maternal development is associated with increasing Autism prevalence worldwide.

Keywords: axon development, brain connectivity, iodine deficiency, Autism, worldwide prevalence of Autism

Introduction

Autism Spectrum Disorder (ASD) is a neurological and developmental disorder with a broad range of conditions, including deficits in social communication, language impairment, compulsive and repetitive behavior, and abnormalities in learning. Studies conducted before 1985 reported the prevalence of Autism among children under 18 years old to be 0.5 per 1,000 children. However, according to the most recent studies conducted by the CDC, the prevalence has increased to 12 per 1,000 children (Kopetz & Endowed, 2012). Therefore, Autism is a global health crisis that needs much greater recognition worldwide to improve the lives of those individuals affected by this devastating disorder. Currently, there doesn’t seem to be a known single cause for Autism, other than theories around the idea that it is a developmental disorder that is related to abnormalities in brain structure and function (Belmonte et al., 2004).

Since Autism is developmental, it makes sense to look at potential connections to prenatal access to nutrients. In general, nutrition plays an essential role in developing our nervous system. Certain nutrients significantly affect brain development, including iron, zinc, copper, Vitamin A, and iodine (Prado & Dewey, 2014). Specifically, iodine is an essential component of thyroid hormones which regulates metabolism and developmental processes including neurite differentiation, synaptogenesis, and neuronal migration (Velasco et al., 2018 & Wei et al., 2013). Specifically, iodine has been associated with proper development of axons. Iodine can be obtained from dietary sources including iodized salt, seafood, and dairy products (Centers for Disease Control, 2012 & National Institutes of Health, 2022). Iodine deficiency can cause hypothyroidism, goiter, cretinism, and developmental abnormalities. It was observed in previous studies that exposure to a mild iodine deficiency diet could lead to maternal hypothyroxinemia in rats, causing a reduction in proteins essential in the axon development pathway, including CRMP2 and Tau1 (Wei et al., 2013). Therefore, iodine deficiency can delay axon development, marking it as a potential causal factor leading to Autism as Autistic individuals tend to have abnormal brain connectivity (Kern et al., 2015).

To investigate our hypothesis that iodine deficiency is linked to Autism through its role in axon development, it is important to explore the prevalence of Autism based on geographical variability and then connect this to what is known around access to iodine geographically. Specifically, we will be exploring how iodine deficiency during prenatal development, which is detrimental to axon growth, is linked to Autism prevalence worldwide. Suppose we can link global Autism prevalence to the level of iodine people consume in different geographical regions; we may be able to suggest that diet could be a potential improvement for such a complicated syndrome.

Methods

In this meta-analysis, the literature search was conducted primarily using the Google Scholar search engine to collect all the primary and secondary data. The search parameters were set to return articles dated after 2000. The return articles were further refined by prioritizing the ones with a more recent publication. However, a few articles dated around 1990 were included to highlight the changes in iodine status and consumption. For this search, the parameter was set to return articles dated after 1990. Keywords used to search included: axon development, brain connectivity, iodine deficiency, Autism, worldwide prevalence of Autism.

Relying on the search engines mentioned above, roughly 31 articles were included in our analysis. Our data collection has four major steps of data searching, including nutrients that impair axonal development, axon abnormalities in Autism, Autism and its geographical differences, and iodine deficiency across different geographical regions. The findings of the literature reviewing these topics were synthesized and analyzed to derive conclusions of our research. This paper aims to investigate the relationship between iodine deficiency during prenatal development, axon growth, and the incidence of Autism. Abnormal axon development, caused by iodine deficiency during maternal development, was hypothesized to be a possible causal factor of Autism. Then using the worldwide prevalence of Autism, geographical differences of Autism based on regional iodine status were investigated.

Results

Iodine is critical for axon development

Iodine is an essential constituent of the thyroid hormones, including triiodothyronine (T3) and thyroxine (T4), which plays an important role in metabolism and development of the central nervous system (Velasco et al., 2018). Although iodine deficiency can lead to a broad range of disorders, it is the most severe in the early stages of pregnancy, as the fetus is extremely dependent on the placental transfer for iodine supply to support brain development (Levie et al., 2019). Indeed, it was found that maternal hypothyroxinemia caused by iodine deficiency in the early stages of pregnancy increases the risk of neurological deficits in the fetus, leading to mental retardation and lower verbal IQ scores (Levie et al., 2019; Wei et al., 2013). The detailed mechanism underlying these deficits involved the impairment of axon growth. It was found that maternal hypothyroxinaemia delayed axonal growth in rat offspring by disrupting the expressions of axon-growth-associated proteins, including GAP-43, Sema3A, GSK3β, CRMP2, and Tau1. For instance, in a normal axon formation mechanism, phosphorylation of GSK3β is required so that its downstream effector, CRMP2 will be in the dephosphorylated state. However, in rat offspring from maternal mild ID-induced hypothyroxinemia rats, an upregulated phosphorylated CRMP2 was observed, leading to impaired axon formation (Wei et al., 2013). Therefore, iodine is critical for axon development and, thus, important for forming neural circuitry.

Deficient axon development may be potential causal factor leading to Autism

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, communication, repetitive behaviors, and learning deficits (Uddin et al., 2013). According to the latest Centers for Disease Control and Prevention reports, one in 448-year children has been diagnosed with ASD, and the prevalence continues to grow (CDC, 2021). Therefore, it is important to promote public awareness of Autism and mandate an increased understanding of its neurobiological foundations. However, Autism is a complex disorder with varying symptoms and severity. There is no single known cause of Autism, and many have been proposed, but one possibility could be impairments in axon development. It was shown using functional magnetic resonance imaging (fMRI) that individuals with the disorder exhibit abnormal brain connectivity, with short-range overconnectivity and long-distance underconnectivity. Indeed, studies show that the severity of this aberrant connectivity positively correlates with the severity of Autism symptoms (Kern et al., 2015). In particular, the cerebellum is the most affected site in which cerebellar activation is abnormally low during a task of selective attention and unusually high during a simple motor task, indicating motor, cognitive, and social deficits (Belmonte et al., 2004). The underconnectivity is found between the prefrontal cortex and posterior brain areas, affecting complex integrative processing ability and underlying the cognitive, social, and language impairments characterized by Autism. On the other hand, overconnectivity is shown in cortex, frontal and temporal regions, amygdala, and parahippocampal gyri (Maximo et al., 2014). This overabundant connectivity between nonessential brain regions allowed low-level crosstalks, thereby increasing the noise in the system and hindering the signals from primary network components. Thus, the information transfer efficiency is reduced (Noonan et al., 2009). This may also cause early brain overgrowth in autistic children (Maximo, 2014). Since the connectivity of the brain is measured based on white matter encased axons, aberrant brain connectivity indicates abnormalities in the initial axon development, possibly during a prenatal period. Therefore, impairments in axonal growth could be a potential cause of Autism.

Geographical variability in Autism prevalence and it’s connection to iodine consumption

To examine this relationship further, it is crucial to explore the worldwide incidence of Autism and determine whether this pattern is linked back to iodine consumption. In recent decades, the prevalence of Autism has risen. For instance, The Center for Disease Control provided the statistics for children in the U.S: 1 child in 44 is autistic in 2018, which has increased from 1 in 88 children in 2008 (CDC, 2022). However, this notable rise is a global trend, not only confined to the United States, supporting that Autism is a worldwide health crisis. Population-based studies before 1985 recorded the Autism prevalence among children under age 18 to be approximately 0.5 per 1,000 children worldwide. However, according to CDC’s most recent studies, the prevalence has risen to 12 per 1,000 children (Kopetz & Endowed, 2012). Looking at the regional prevalence of Autism in 2016, the highest prevalence of children with Autism (per 100,000) was recorded in North Africa and the Middle East, while the lowest was in western Europe (Olusanya et al., 2018). The high variability in prevalence across different geographical regions suggests a link between the worldwide incidence of Autism and geographical and environmental factors.

In the United States, for example, where the prevalence of Autism has been increasing for the past decades, a decrease in iodine consumption is also observed (CDC, 2022 & Wolf et al., 2020). Early studies in the 1900s have linked salt consumption to various health conditions, including hypertension, cardiovascular problems, and edema. Therefore, many people shifted to a low-salt diet, considering it a healthy eating habit (DiNicolantonio & O’Keefe, 2017). Indeed, more than 50% of males and females reported never using salt or ordinary table salt in a study conducted in 1989 (Federation of American Societies for Experimental Biology, 1995). Since salt is a major source of iodine in the United States, a reduction in dietary iodine intake was also observed. The U.S median urinary iodine concentration (UI) was 320 μg/L in 1971–1974 and 145 μg/L in 1988–1994 suggesting an approximately 50% reduction in dietary salt intake (Caldwell et al., 2005). Although later studies demonstrated that a low-salt diet was not a reasonable strategy to treat hypertension since only a quarter of individuals had found that effective, certain eating habits and practices were still changed against salt retention (DiNicolantonio & O’Keefe, 2017; Dasgupta et al., 2008). For instance, many people shifted toward using non-iodized salts, including kosher salt and sea salt. Analyzing the total salt sales at the retail level in the United States in 2009, 47% of the salt sold was non-iodized (Maalouf et al., 2015).

Milk and dairy products are also a major source of dietary iodine in the United States. However, there has been a reduced use of iodine-based disinfectants in the dairy industry in the recent decades (Dasgupta et al., 2008). The average iodine content of U.S dairy whole milk decreased from 602 ± 184 μg/L in 1978 to 155 ± 19 μg/L in 1989–1990 (Pennington, 1990). In addition, it was reported that children today consume less milk than children in the past decades (Enns et al., 2002), contributing to the emergence of iodine insufficiency. Specifically, the shifting toward plant-based alternative beverages, including soy and almond milk, has significantly contributed to the declining trends of beverage milk consumption. Indeed, the consumption of these non-dairy alternatives has increased by 61% in 2018 since 2013 (Wolf et al., 2020). The consumption of non-iodized salt and non-dietary milk suggested that one’s dietary habits could be greatly influential on the iodine status. In the United States, studies have shown that children from lower socioeconomic status neighborhoods are less likely to be diagnosed with Autism than children with higher socioeconomic status (Kelly et al., 2017). Meanwhile, non-iodized salts and non-dietary milk are more expensive than iodized salt and dietary milk.

This suggests a possible link between socioeconomic status limiting the access to non-iodized salts or non-dietary milk and the prevalence of Autism. It could be possible that mothers with lower socioeconomic status cannot afford the specialized salt and plant-based milk, but in turn, they will be able to obtain sufficient iodine from their diet to support the normal development of their fetus and lower the risk factors of Autism.

There are other countries in the world where both Autism and iodine deficiency has been a health crisis. For instance, as shown in Figure 1, Pakistan was in the top ten countries with the highest number of autistic children under five in 2016 (Olusanya et al., 2018). Meanwhile, Pakistan was also under severe iodine deficiency in 2002 according to Figure 2 (World Health Organization, 2004). Factors contributing to the iodine deficiency in Pakistan include a shortage of natural soil iodine and variability in weather. For instance, the landmass of Pakistan comprises large badlands, including a vast range of mountains, for which some are covered in snow and glaciers, while others have steep slopes that produce watershed areas undergoing erosion and landslides continuously. In addition, the frequencies of downstream floods have increased, with seven massive floods occurring over the past two decades, stripping away the topsoil and nutrients (Khattak et al., 2017). Soils low in iodine produce crops with low iodine contents, and therefore, residents consuming solely local food might not obtain enough iodine from their diet. Indeed, mountainous areas, such as the Himalayas that span five countries including Pakistan, have the most iodine-poor soil (Nature, 2011; National Institutes of Health, 2022). Therefore, no access to naturally occurring iodine in soil could be associated with elevated Autism prevalence in Pakistan as maternal iodine deficiency could lead to offspring with impaired axon development, and abnormal brain connectivity as observed in Autistic children.

Although the prevalence of Autism remains unknown in Africa, a study conducted in 2021 has found that 1 in 27 children who visited the hospital in Mali is autistic (The African Academy of Science, 2021). Again, though many causes could contribute to the development of Autism, iodine deficiency could be one of the factors. As ranked by the World Health Organization, the Central African Republic was under moderate iodine deficiency in 2002, shown in Figure 2 (World Health Organization, 2004). In the Central African Republic, cassava is a dominant food consumed daily in households. However, consuming insufficiently processed cassava results in increased thiocyanate formation, which metabolically behaves like iodine and, therefore, competitively interferes with iodine absorption (Peterson et al., 1995). Therefore, the food consumed by the people in the Central African Republic contributes to their iodine deficiency status and could be associated with local Autism prevalence.

There are other examples of this iodine deficiency and Autism prevalence relationship throughout the world. In Vietnam, a country with moderate iodine deficiency status in 2002 (Figure 2), the prevalence of Autism increased more than threefold from 2000 to 2007 and continues to grow (World Health Organization, 2004; Hoang et al., 2019). In addition, it was reported that less than 50% of the households in Vietnam were using salts with adequate iodine content in 2011 (Codling et al., 2015). Therefore, the correlation here is clear: increased Autism prevalence coexists with the iodine deficiency caused by low iodized salt intake.

Figure 1: Worldwide prevalence of Autism of children under five in 2016 (Hotez, 2018).

Note. The figure above shows the incidents of Autism in young children under five years of age, worldwide. The circled countries were the ones discussed in the paper, including the United States, Central African Republic, Pakistan, and Vietnam. Pakistan was in the top ten countries with the highest number of young Autistic children, while Vietnam and the Central African Republic were among the countries with relatively high Autism prevalence.

Figure 2: Degree of worldwide iodine deficiency status based on median UI (World Health Organization, 2002)

Note. The figure above demonstrates the iodine deficiency status worldwide. The circled countries discussed in the paper included the United States, Central African Republic, Pakistan, and Vietnam, with Pakistan under severe iodine deficiency and the Central African Republic and Vietnam under moderate iodine deficiency. Although the United States was marked as more than adequate iodine intake, its situation regarding iodine usage was discussed in the paper.

Discussion

This research focused on the relationship between iodine deficiency, axon development, and Autism occurrences globally. The possibility that axonal abnormalities caused by iodine deficiency are linked to geographical differences in Autism rates was investigated. We showed evidence that during axon development, iodine is indeed an essential micronutrient in which its deficiency could disturb the axon formation pathway (Wei et al., 2013). In addition, brain connectivity was found to be abnormal in autistic individuals, with short-range overconnectivity and long-distance underconnectivity, taking the responsibilities of various Autism symptoms including motor, cognitive, and social deficits (Kern et al., 2015; Belmonte et al., 2004). Globally, there is significant variability of Autism incidences, as shown in Figure 1, indicating the involvement of geographical and environmental factors in the development of Autism. In particular, it was found that the prevalence of Autism in the United States is linked to iodine deficiency caused by low iodized salt intake and drinking non-dairy milk. Interestingly, a relationship between socioeconomic status affecting the affordability of purchasing specialty salt and plant-based milk and the prevalence of Autism was observed, in which children from higher socioeconomic status families tend to have more incidence of Autism (Kelly et al., 2017). Various other countries also confirm this, including Pakistan, the Central African Republic, and Vietnam. Different geographical differences and constraints, including low-iodine soil caused by mountainous areas in Pakistan, local food (cassava) interfering with the metabolism of iodine in the Central African Republic, and low-iodized salt intake in Vietnam, all correlate with the increasing trends of Autism in respective countries (Khattak et al., 2017; Peterson et al., 1995; Codling et al., 2015).

This analysis highlights the importance of diet in the development of Autism. Iodine, as an essential nutrient not only for pregnant mothers and growing fetuses, but for people at all ages, should be consumed sufficiently according to the recommended dietary allowance. This will not only be an effective step to prevent mental illness as noted by the Centers for Disease Control and Prevention, but also Autism, which is a global health problem on the rise. Though Autism is usually thought to be lifelong and cannot be cured, there were cases in which the children who once had Autism later lost the hallmark symptoms. However, through intensive therapy, including behavioral therapy and speech therapy, starting at a young age, their Autistic symptoms were able to fade and shed the diagnosis (Carpenter, 2015). Therefore, it is important to continue exploring why some children can outgrow Autism, but some cannot. Does diet, specifically iodine intake, help in the process of outgrowing Autism?

In conclusion, various individual studies regarding the prevalence of Autism based on geographical variability and the differences in iodine consumption were analyzed and integrated to conclude that there is indeed a correlation between iodine deficiency and Autism, in which iodine deficiency is a risk factor for Autism. To confirm with the conclusion, further research should be conducted. For instance, it would be beneficial to study whether iodine deficiency in pregnant rodents would result in Autism-traits in offspring. Furthermore, the changes in Autistic symptoms should also be examined when iodine status is later reversed to sufficient intake after birth.

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About the author

Ding Hong Zheng

Ding Hong is a 4th-year college student at Stony Brook University. Her passion for Biology originated when she learned about the complexity of living organisms and their interactions with the environment in high school. In her spare time, she enjoys baking, gardening, and capturing the living world through photos.