The Role of the Exposome in Brain Health: A Comprehensive Overview

The exposome refers to the cumulative environmental exposure that an individual encounters throughout their lifetime.

In our previous article, we gave a brief overview of the exposome and advocated incorporating multi-omics studies to get an in-depth understanding. Everyday an American is potentially exposed to more than 80,000 toxic chemicals, yet their impact on neuro-diseases is not well understood.

Studies have shown that exposure to toxic chemicals in the early stages of life could have permanent consequences for neurodevelopment and neurodegeneration in later life. With advanced research in neurodevelopmental and neurodegenerative disorders, it is now clear that genetic risk factors cannot fully explain them. 

Understanding the role of individual environmental chemical exposures is critical. In this article, we will explore the role of the exposome in brain health, including the impact of toxic chemicals on neurodevelopment, neurodegeneration, and mental health.

Agricultural Pesticides in Neurodevelopment

Agricultural pesticides are commonly available to humans via dietary means, and their impact on neurodevelopment has been studied extensively. According to a study published in Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop by the National Academies of Sciences and Medicine, exposure to three toxic chemicals, namely lead, organophosphate pesticides (OP), and methyl mercury, are responsible for greater IQ loss than medical conditions such as preterm birth, neurodevelopmental disorders, and socioeconomic and nutrition-related factors [1]. Further studies in animals have found that exposure to pesticide (glyphosate) is linked to oxidative stress, neurotransmitter alterations, and depressive-like behaviors, signifying that agricultural pesticides are also strong neurotoxicants for humans [2].

Air Pollutants in Neurodevelopment

Recent studies have shown that even air pollutants are neurotoxicants [3-5]. Air pollution causes biological reactions such as increased oxidative stress and inflammation in the brain and peripheral areas, which may help to accelerate the development of cerebrovascular disease and the buildup of neuropathology in the brain [4-6].

EWAS for Neurodevelopment

Recently, many exposome-wide association studies (EWAS) have been undertaken to understand the overall impact of environmental exposure, socio-economical parameters, and dietary habits on neurodevelopment in pregnant mothers and their children. In these EWAS studies, the pregnant mother's biological samples (blood, urine, hair, breast milk, cord blood, and urine) are collected each trimester. The questionnaires are used to note the dietary habits during pregnancy. Children’s biological samples (urine and blood) are collected for postnatal studies, and Bayley-III modules are used to analyze cognitive development.

Recent examples of these approaches include a large-scale EWAS study that evaluated prenatal and postnatal exposure to heavy metals and sociodemographic parameters [7]. The study found that heavy metal exposure was correlated with impaired mitochondrial respiration, which leads to oxidative stress and cellular damage response [7]. Another study from Poland found that cognitive development during the first year of children was positively correlated with exposure to copper in the first week of pregnancy [8,9]. The study also found that alcohol consumption during pregnancy negatively affected the motor development of children. The metabolomic analysis revealed that cognitive and language ability is affected by alterations in mitochondrial respiration which result in the production and accumulation of reactive oxygen species (ROS), causing cellular damage response. The study also found that language development in the second year of child growth was positively associated with daycare attendance. The impact on children's neurodevelopment was also associated with the mother's gestational age [8].

The Exposome in Neurological Diseases

• Autism Spectrum Disorder (ASD)

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impaired glutamatergic synapse formation, development, and maintenance. ASD is classified after assessing children's behavior and developmental delays by physicians. Currently, there are no available diagnostic tests for ASD where any biological fluid could be analyzed. Attempts have been made to predict or test early ASD in children using the exposome approach. One of the exposome studies found 191 features after metabolomic analysis that were associated with ASD [11]. Glutathione metabolism malfunctioning was also linked with ASD [11].

Additionally, prioritizing potential diagnostic traits can be helped by the family-based correlation of ASD-associated features [11]. Baby teeth provide evidence that the cycles involved in the metabolism of zinc and copper are dysregulated in ASD, which could be used to predict who will eventually acquire the condition [12]. The researchers utilized the teeth to recreate healthy and autistic children's prenatal and early life exposures to nutrients and harmful substances [12].

• Neurodegenerative Disorders

It is believed that a complex interplay between genetic (genome) and environmental variables (exposome) plays a role in the etiology of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). According to a study by Baranger et al., prenatal cannabis exposure is associated with a mental health burden in children from childhood to early adolescence [26]. Neurodegenerative diseases have been linked to a number of neurotoxicant exposure-related processes, including impacts on synaptic function and endo-lysosomal pathways, oxidative stress, epigenetic alterations, and cellular mosaicism.

• Alzheimer's Disease (AD)

A study published in the Proceedings of the National Academy of Sciences found that air pollution was a risk factor for AD [14]. Air pollution triggers oxidative stress and inflammation that leads to the accumulation of hallmark neuropathologies associated with AD. The study showed that higher PM2.5 concentrations and brain amyloid beta (Aβ) plaques could be correlated [14]. It is therefore important to take airborne hazardous contaminants related to Aβ pathology. Similar studies have found a linkage between air pollutants and AD [15]; gray matter atrophy in women exposed to higher PM2.5 concentration increases the risk of AD [16]. Recently, “AD Exposome” was constituted to fill significant knowledge gaps about how environmental factors affect AD's hereditary and non-genetic risk and associated dementias [17].

• Parkinson's Disease (PD)

There is growing evidence linking air pollution and PD. A study by Nagata et al. found that sexual orientation disparities in early adolescent sleep are linked to PD [32]. A study on more than 200,000 individuals from six European nations found that prolonged exposure to air PM2.5, nitric oxide, and black carbon increases the chance of death from PD [18]. PM2.5 was found to be the most relevant pollutant for this risk. Another study with more than 75,000 participants found a significant risk of PD with longer exposure to higher concentrations of nitric oxide [19]. One of the most commonly used pesticides in the world, paraquat, has been linked in studies to a significant risk of PD [20]. An exposome study to understand the role of metabolites and exposure was performed on plasma and fecal samples [21]. The authors observed higher relevant features like alanine betaine or nicotinamide in the fecal samples, showing the role of gut microbiota in the development of PD.

• Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a progressive and incurable degenerative disease of the motor neurons in the brain, brain stem, and spinal cord. Environmental toxins have been associated with ALS. A study published in the Journal of the American Medical Association - Neurology found that exposure to environmental toxins is associated with ALS [23]. Early life metal dysregulation is also linked to ALS [24]. Dysregulated biodynamics in metabolic attractor systems precede the emergence of ALS [25].

The Exposome and Sleep

Sleep is an essential component of brain health, and its quality and duration can be impacted by the exposome. A study by Cheng et al. found that sleep duration is linked to brain structure and psychiatric and cognitive problems in children [31]. Another study by Jessel et al. found that sleep quality and duration in children that consume caffeine are impacted by dose and genetic variation [30]. Letzen et al. found that racial disparities in sleep-related cardiac function in young, healthy adults can impact cardiovascular-related health [33]. Separation of circadian and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism [28]. Habitual sleep and human plasma metabolomics are also linked [29].

Conclusion

The role of the exposome in brain health is significant. Agricultural pesticides, air pollutants, and environmental toxins can impact neurodevelopment and neurodegeneration, leading to neurodegenerative disorders like AD, PD, and ALS. Understanding the impact of the exposome on brain health is critical to prevent and manage these conditions. Additionally, sleep quality and duration can also be impacted by the exposome, leading to psychiatric and cognitive problems in children and cardiovascular-related health issues in young, healthy adults. Further research is needed to understand the full impact of the exposome on brain health and to develop effective prevention and management strategies.

If you are a practitioner, learn how detecting and correcting the exposome is possible by going to homehope.org and checking out the exposomics module.

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