The Exposome: A New Frontier in Disease Research

What is the Exposome?

The human exposome encompasses all of the environmental exposures that an individual will encounter throughout their lifetime,¹ including chemicals, physical agents, biological agents, and psychosocial factors, and how those exposures influence health and disease.

The exposome is a complex and dynamic system, constantly changing as we age, move to new places, and change our lifestyles. A person’s genetics, epigenetics, health status, and physiology, as well as how each of these has been influenced by previous exposures, can impact the effects of new or present exposures.²

Exposome Categories

The human exposome can be divided into three broad categories centered around internal and external exposures:²

• General external environment: This includes environmental factors such as air pollution, water pollution, soil contamination, and noise pollution.
• Specific external environment: This includes factors such as occupational exposures, recreational exposures, and household exposures.
• Internal environment: This includes factors such as diet, lifestyle, and stress (many of which are modifiable risk factors).

The complexity of the human exposome is due to the fact that a person can experience multiple exposures all at one time, and these exposures can be highly variable throughout a person’s lifetime.

The Importance of Studying the Exposome

The exposome was first introduced in 2005,¹ and although it is a relatively new concept, there is growing evidence that the exposome is an important factor contributing to disease risk. In fact, the general premise of the exposome is that it is complementary to the human genome and that studying both together will contribute to our ability to address several chronic diseases.² This hypothesis is bolstered by the fact that studies have repeatedly suggested that environmental factors have a much greater impact on disease development than genetic factors alone.³

The Impact of the External Environment on Homeostasis

Humans constantly come into contact with a variety of exposures, which continually impact our biological systems. It’s becoming increasingly clear that a complete understanding of human biology will require external exposure assessment as well as our bodies adapt to the reality of our modern lifestyles.

Air pollution is one of the most concerning external exposures to various agencies, including the National Institutes of Health (NIH) and the Centers for Disease Control (CDC). Particulate matter (PM) is of particular concern and is, therefore, a regulated air pollutant. Because PM is so small, it can be inhaled into the deepest parts of the lungs. It has been connected to several negative health outcomes, including heart attack, decreased lung function, and even premature death⁴. People living near wildfires are especially vulnerable to the health effects of PM exposure. Chemical leaks, such as that caused by the recent train derailment in East Palestine, Pennsylvania, can also put populations at risk for negative health impacts resulting from chemical exposures.

Microplastics in the environment are also a growing concern, not just for their negative impact on ecosystems, but also because they have been found inside human bodies. In 2021, researchers introduced the “plasticenta”—the presence of microplastics in human placenta⁵. While the implications of this on the future health of babies are unknown, this is a sobering finding given the many recognized negative health impacts of the toxins present in microplastics on human health⁶.

Exposomics: the Study of the Exposome

The study of the exposome, also known as exposomics, is typically performed via four major approaches, usually in some combination:

• Environmental monitoring: The measurement of levels of environmental pollutants in the air, water, soil, and food.
• Questionnaires: Questionnaires collect information about an individual’s environmental exposures, such as occupation, lifestyle, and residential history.
• Genetic studies: Genome-wide association studies (GWAS) evaluate markers across the human genome associated with susceptibility to environmental exposures.
• Metabolites and Biomarkers: Biomarkers are physiological markers used to assess environmental exposures. Examples include DNA damage, levels of specific chemicals in the blood, changes in the microbiome, and differential gene expression. Often, small molecules called analytes (metabolites), measured in blood, tissue, cells, urine, feces, and even the microbiome, serve as useful biomarkers for a variety of health and disease states.

Tools used in studying the exposome

Newer technologies such as omics, sensors, and geographic or spatial information are all facilitating a better understanding of the exposome. Different tools are needed to measure the three different exposome categories introduced earlier:³

• General external exposures may be measured via Geographic Information Systems, surveys, etc.
• Specific external exposures may be measured via environmental and personal biosensors, survey instruments, job exposure matrices, etc.
• Internal exposures may be measured via different ‘omics techniques (both of the individual and of the individual’s microbiome).

Omics-based Approaches to Studying the Exposome

Omics-based approaches, which include genomics, epigenomics, transcriptomics, proteomics, and metabolomics,^7-9 are important for identifying exposome biomarkers. Because they complement each other, a comprehensive assessment of the exposome should utilize some combination of omics techniques:

• Genomics: As described above, genomics and the exposome are complementary entities. Specific genetic variants can impact whether and how environmental exposure results in specific health outcomes. For example, the difference between two individuals’ biological responses to the same environmental exposures can be rooted in genetic factors.
• Epigenomics: The epigenome, which is the collection of all post-translational modifications (i.e., DNA methylation, histone modification, etc.), can be significantly impacted by environmental factors (including lifestyle factors such as diet and physical activity). In fact, researchers have suggested that the epigenome functions as an interface between environmental factors and the genome and that environmental impacts on the epigenome contribute to disease risk¹⁰.
• Transcriptomics: Closely related to genomics, transcriptomics is the study of the complete set of RNA transcripts produced by the human genome. Research has shown that the transcriptome can be heavily impacted by environmental exposures.
• Proteomics: Proteomics is the study of the full set of proteins encoded by the human genome. While proteomics can help researchers better understand the underlying cause of disease, the jury is still out on whether or not proteomics can provide any information about exposures.
• Adductomics: Adductomics is the measurement of modification to blood proteins, specifically, to characterize exposures that can’t be measured directly in biospecimens.
• Metabolomics and lipidomics: Metabolomics, the study of all metabolites present in a sample, is the definitive representation of phenotype, connecting clues from the genome, epigenome, transcriptome, and even proteome. It is a particularly powerful tool to use for both internal and external exposure assessment because it reveals the metabolic profile of an individual at a specific point in time and is highly impacted by the environment. Metabolomic readouts are not limited to human metabolites, either; the human microbiome, which can play a major role in the exposome-disease relationship, is also often studied using metabolomics.

The Connection Between the Exposome and Human Health Outcomes

Although exposome research is still in its infancy, a growing body of evidence connects the exposome to a broad range of adverse health outcomes, including several examples of chronic disease:³

• Cancer. Several cancers have been associated with the exposome. Breast cancer is a particularly powerful example: about one-third of breast cancer cases cannot be attributed to genetic factors alone, suggesting a significant environmental component. Studies have found that exposures to dioxins, air pollution, dichlorodiphenyltrichloroethane (DDT), and perflurooctanesulfonamide (PFOSA) during breast development are associated with an increased risk for breast cancer.¹¹ Occupational exposures to solvents and other mammary carcinogens such as gasoline components have also been connected to higher breast cancer risk.¹¹
• Cardiovascular disease (CVD). Similar to cancer, about one-third of CVD cases cannot be attributable to genetic factors alone. Studies have found that exposures to air pollution,¹² noise pollution, and light pollution are all associated with an increased risk for CVD. Occupational exposures to heavy metals, solvents, and other toxins have also been linked to higher CVD risk.¹²
• Respiratory disease (asthma and allergies). Several respiratory diseases have been associated with the exposome. Studies have found that exposures to air pollution, secondhand smoke, and allergens during childhood are associated with an increased risk for asthma.¹³ Occupational exposures to dust, fumes, and other respiratory irritants have also been connected to higher asthma risk.¹⁴ Additionally, air pollution and second-hand smoke are major contributors to the development of chronic obstructive pulmonary disorder (COPD) and lung cancer.¹⁵ Allergens, such as dust mites, pollen, and pet dander contribute to allergies and can cause asthma attacks in people with asthma.
• Stroke. Stroke, closely related to CVD, is a leading cause of death and disability. Several environmental exposures have been linked to an increased risk of stroke, including air pollution, secondhand smoke, and smoking¹⁶. Comorbidities that increase an individual’s risk for stroke include obesity, physical activity, and diabetes, which are on their own impact and/or are impacted by both internal and external exposures.
• Diabetes and obesity. Type 2 diabetes (T2D) and obesity are closely related and are two of the most common chronic diseases worldwide. Obesity tends to precede the development of T2D but not always. Both conditions can be significantly impacted by air pollution, diet, stress physical activity, and several social health determinants, including poverty, discrimination, and access to food and healthcare.^17,18
• Neurodegenerative diseases. Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, cause progressive damage to the brain and nervous system. These diseases are particularly complex and difficult to diagnose and are caused by a combination of genetic and environmental factors. Exposure to toxins, such as lead, mercury, and pesticides can increase an individual’s risk for developing neurodegenerative diseases,¹⁹ as can stress, physical inactivity, and diets high in processed foods, sugars, and unhealthy fats.²⁰
• Mental health conditions, such as depression and anxiety. Like neurodegenerative diseases, mental health conditions are a complex group of conditions resulting from complex interactions between genes and the environment. Childhood trauma, exposure to toxins, an unhealthy diet, physical inactivity, stress, social isolation, and poverty have all been shown to increase a person’s risk for developing a mental health condition.^21,22

Challenges in Studying the Exposome

Exposomics is a promising field of research that has the potential to provide a better understanding of the complex relationship between environmental exposures and health outcomes. Armed with this information, we can implement intervention strategies to reduce exposure and design effective treatments for the diseases that often result.

Nevertheless, exposome research is inherently complicated. The complex and dynamic nature of the human exposome represents one major challenge. Internal factors, such as genetics and the microbiome, can play an important role in whether an individual develops disease in response to exposure to an external factor and that must also be taken into account. Exposures also vary with a person’s age, gender, race, ethnicity, and socioeconomic status and are highly variable throughout a person’s lifetime.

Exposures Vary with Life Stage

Exposure data has also shown that the impact of environmental exposures on adverse health outcomes can be strongly influenced by the life stage in which a person is in. Unborn children and infants are particularly susceptible to certain exposures that occur in utero and post-birth because their cells are growing rapidly and have immature DNA damage repair processes. For example, the offspring of women given diethylstilbesterol to prevent miscarriages in the 1950s and 60s have an increased risk of reproductive tract cancers, difficult pregnancies, and decreased fertility.²³

Similarly, older children and teenagers are likely to be differentially impacted by environmental exposures compared to adults. In adulthood, occupational exposures can change as we switch jobs or enter retirement, a time of life during which pharmaceutical exposures tend to increase.³ Additionally, because it can take years for the effects of exposures to manifest, exposure assessment may inadvertently exclude past exposures. The transient nature of many exposures also poses a challenge: they are easy to miss, particularly for research efforts that capture only a “snapshot in time” of the exposome.

Some Samples Used to Study Exposures are Difficult to Measure or Require Special Handling

Accurate exposure assessment is also complicated by the sheer number of potential exposures a person may encounter throughout their lifetime. Some exposures, such as air and water pollution, are notoriously difficult to measure. Certain biological samples that might be used for biomarker identification are also notoriously tricky. For example, blood and urine samples can be easily contaminated with substances, including chemical contaminants, that can interfere with sequencing and metabolomics data quality and complicate analysis. The detection of certain environmental toxins is particularly sensitive to the presence of pollutants or the impact of dietary and other lifestyle factors on these sample types.

Exposome Data can be Complex

Many of the approaches used to study the exposome, especially ‘omics techniques, yield complex data—often billions of data points — that require sophisticated data mining techniques leveraging a variety of computational tools. It can also be challenging to interpret genomic, transcriptomic, proteomic, and metabolomics datasets, particularly in the context of one another, because the relationship between the data and biological function isn’t always clear.

Metabolomics in particular is increasingly used by researchers studying the exposome, but the databases used to analyze high-resolution mass spectrometry (HRMS) data produced during many of these efforts often don’t contain very many metabolites related to environmental chemicals.²⁴ Untargeted HRMS research efforts are also less sensitive than targeted protocols, so they can easily miss exposures to very low levels of environmental factors.²⁴

Looking Forward

Studying the complex interactions between environmental exposures and health outcomes can make significant contributions to how we prevent, manage, and treat a range of diseases, including chronic diseases. As researchers identify and better understand the various relationships between human biology and external factors contributing to disease, we’ll be able to create better strategies for preventing harmful environmental exposures and limit the health effects associated with those exposures. Omics tools, particularly metabolomics, are likely to play a key role in scientific efforts to better understand and leverage the exposome to improve human health and longevity.

References

1. Wild CP. Complementing the genome with an “exposome”: The outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1847–1850.
2. Wild CP. The exposome: from concept to utility. Int J Epidemiol. 2012;41(1):24–32.References
3. Rappaport SM. Implications of the exposome for exposure science. J Expo Sci Environ Epidemiol. 2011;21(1):5–9
4. United States Environmental Protection Agency. Health and Environmental Effects of Particulate Matter (PM). https://www.epa.gov/pm-pollution/health-and-environmental-effects-particulate-matter-pm; Accessed June 14, 2023.
5. Ragusa A, Svelato A, Santacroce C et al. Plasticenta: First evidence of microplastics in human placenta. Environ Int. 2021;146:106274.
6. Campanale C, Massarelli C, Savino I et al. A Detailed Review Study on Potential Effects of Microplastics and Additives of Concern on Human Health. Int J Environ Res Public Health. 2020;17(4):1212.
7. DeBord DG, Carreón T, Lentz TJ et al. Use of the “Exposome” in the Practice of Epidemiology: A Primer on -Omic Technologies. Am J Epidemiol. 2016; 184(4): 302–314.
8. Juarez PD, Hood DB, Song MA et al. Use of an Exposome Approach to Understand the Effects of Exposures From the Natural, Built, and Social Environments on Cardio-Vascular Disease Onset, Progression, and Outcomes. Front Public Health. 2020; 8: 379.
9. Bessonneau V and Rudel RA. Mapping the Human Exposome to Uncover the Causes of Breast Cancer. Int J Environ Res Public Health. 2020;17(1): 189.
10. Tang WHW, Wang Z, Levison BS et al. Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk. N Engl J Med. 2013;68(17): 1575–1584.
11. Herceg Z and Vaissiere T. Epigenetic mechanisms and cancer: an interface between the environment and the genome. Epigenetics. 2011;6(7):804–819.
12. Juarez PD, Hood DB, Song MA et al. Use of an Exposome Approach to Understand the Effects of Exposures From the Natural, Built, and Social Environments on Cardio-Vascular Disease Onset, Progression, and Outcomes. Front Public Health. 2020;8:379.
13. Rao D. Impact of Environmental Controls on Childhood Asthma. Curr Allergy Asthma Rep. 2011;11(5): 414–420.
14. Sit G, Letellier N, Iwatsubo Y et al. Occupational Exposures to Organic Solvents and Asthma Symptoms in the CONSTANCES Cohort. Int J Environ Res Public Health. 2021; 18(17): 9258.
15. Korsbæk N, Landt EM, and Dahl M. Second-Hand Smoke Exposure Associated with Risk of Respiratory Symptoms, Asthma, and COPD in 20,421 Adults from the General Population. J Asthma Allergy. 2021;14: 1277–1284.
16. Reis J. Environmental Risk Factors for Stroke and Cardiovascular Disease. Encyclopedia of Cardiovascular Research and Medicine. 2018: 238–247.
17. Thayer KA, Heindel JJ, Bucher JR et al. Role of Environmental Chemicals in Diabetes and Obesity: A National Toxicology Program Workshop Review. Environ Health Perspect. 2012;120(6): 779–789.
18. Kolb H and Martin S. Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes. BMC Medicine. 2017;15:131.
19. Cannon JR and Greenamyre JT. The role of environmental exposures in neurodegeneration and neurodegenerative diseases. Toxicol Sci. 2011;124(2): 225-50.
20. Popa-Wagner A, Dumitrascu DI, Capitanescu B et al. Dietary habits, lifestyle factors and neurodegenerative diseases. Neural Regen Res. 2020;15(3): 394–400.
21. Helbich M. Mental Health and Environmental Exposures: An Editorial. Int J Environ Res Public Health. 2018; 15(10): 2207.
22. The National Child Traumatic Stress Network. Executive Summary: Understanding the Impact of Trauma and Urban Poverty on Family Systems: Risks, Resilience, and Interventions. https://www.nctsn.org/sites/default/files/resources/resource-guide/understanding_impact_trauma_urban_poverty_family_systems.pdf ; Accessed May 31, 2023.
23. Goodman A, Schorge J, Greene MF. The long-term effects of in utero exposures–the DES story. N Engl J Med. 2011;364(22): 2083–2084.
24. Rappaport SM. Implications of the exposome for exposure science. J Expo Sci Environ Epidemiol. 2011;21(1): 5–9.