GUIDE TO THE EXPOSOME
Introduction
Introduction
The exposome refers to the complete set of environmental exposures and associated biological responses that shape health across the human lifespan. First introduced in 2005, the concept was developed to complement the genome in understanding the complex causes of chronic disease¹. Unlike the genome, which is relatively fixed, the exposome is dynamic and shaped by a wide range of external and internal factors, including pollutants, diet, stress, behavior, and endogenous processes such as inflammation and metabolism. By capturing this full spectrum of exposures and responses, the exposome provides a powerful lens through which to study disease etiology, health disparities, and the impact of the environment on human biology2,3.
1.2 Components of the Exposome
The exposome is typically classified into 3 interconnected domains: internal, specific external, and general external (Figure 1.1)4,5. Each domain represents a different layer of environmental exposure that, together, can influence long-term health outcomes.
1.2.1 Internal Exposome
The internal exposome includes the body’s endogenous biological responses to environmental exposures. It encompasses processes such as metabolism, immune response, hormonal activity, oxidative stress, gut microbiome interactions, and epigenetic modifications. These internal factors not only reflect the body’s response to external stressors but also help mediate the biological pathways linking exposure to disease risk6,7.
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- Metabolism and metabolic byproducts: Metabolic processes in the body produce reactive molecules such as reactive oxygen species and other toxic metabolites that can damage DNA, proteins, and lipids. When metabolism is dysregulated, such as in obesity or diabetes, these byproducts accumulate and contribute to oxidative stress and chronic inflammation. Over time, these processes can drive the development of cardiometabolic diseases, neurodegeneration, and cancer3.
- Gut microbiota: The gut microbiome plays a key role in health by breaking down dietary and environmental compounds into bioactive molecules, including short-chain fatty acids and secondary bile acids. These metabolites influence host metabolism, immune function, and brain signaling. Disruptions to this microbial ecosystem, known as dysbiosis, are associated with diseases such as inflammatory bowel disease, metabolic syndrome, and neurodevelopmental disorders8.
- Hormonal and immune responses: Hormone levels (e.g., cortisol, estrogen, insulin) and immune signals (e.g., cytokines, prostaglandins) vary in response to factors such as stress, infection, age, and diet. These systems regulate physiological balance, inflammation, and tissue repair. Chronic disruption of hormonal or immune signaling, whether due to prolonged stress, poor diet, or environmental exposures, can increase susceptibility to a wide range of conditions, including autoimmune disease, cardiovascular disorders, and metabolic dysfunction8,9.
- Epigenetic modifications: Environmental exposures such as diet, stress, infections, and chemical pollutants can lead to changes in gene regulation through mechanisms like DNA methylation, histone modification, and microRNA expression. These epigenetic changes do not alter the underlying DNA sequence but can influence how genes are expressed, potentially across the lifespan and even generations. Such modifications have been linked to a variety of diseases, including cancer, metabolic disorders, and neurodevelopmental conditions2,8
1.2.2 Specific External Exposome
When considering the exposome, one must remember that the specific external exposome refers to individual-level exposures from the environment that are often changeable through lifestyle or policy.
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- Chemical pollutants: This category includes air pollutants (e.g., PM2.5, ozone), industrial chemicals (e.g., benzene, dioxins), synthetic compounds such as per- and polyfluoroalkyl substances (PFAS), and ingredients in consumer products (e.g., phthalates, bisphenol A). Many of these substances act as endocrine disruptors, carcinogens, or neurotoxins5,9.
- Occupational exposures: Workers in many industries encounter hazardous substances such as asbestos, silica, solvents, and heavy metals. Long-term exposure is associated with diseases like mesothelioma, chronic obstructive pulmonary disease, and occupational cancers10.
- Infectious agents: Pathogens such as viruses, bacteria, and parasites can influence disease risk directly and by modulating immune and inflammatory responses11.
- Lifestyle factors: Behaviors such as smoking, alcohol use, diet, and physical activity are critical contributors to disease risk and may exacerbate the effects of other environmental stressors3.
1.2.3 General External Exposome
The general external exposome encompasses broad social, economic, and environmental conditions that shape both individual and population-level exposures. These factors can further influence vulnerability to specific exposures and play a significant role in driving health disparities.
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- Socioeconomic status influences the nature and extent of exposures through its effects on residential environments, access to healthcare, nutritious food, clean water, housing stability, and proximity to environmental hazards. Populations with lower socioeconomic status are disproportionately exposed to environmental hazards, such as air and noise pollution, and experience higher levels of chronic psychosocial stress. These cumulative exposures contribute to pronounced health disparities across an individual’s lifetime12.
- The ‘built environment’, a term which includes homes, workplaces, schools, and transportation systems, plays a central role in shaping exposure to physical, chemical, and microbial agents. Factors such as ventilation, building materials, indoor air quality, and surface microbiomes can influence long-term health risks, especially for individuals who spend the majority of their time indoors13.
- Climate change and geographic factors significantly influence the exposome by altering the types, frequency, and severity of environmental exposures such as extreme heat, air pollution, and vector-borne diseases. Differences and shifts in climate conditions can result in unequal exposure risks across populations and contribute to disparate health outcomes14.
- Chronic psychosocial stress, including factors like social instability, discrimination, and adverse childhood experiences, can disrupt core physiological systems, including stress-response, immune, and neuroendocrine pathways. These disruptions have been linked to a wide range of adverse health outcomes, particularly when stress is sustained or experienced during sensitive developmental periods15.
Figure 1.1: The exposome (internal, specific external, and general external) is a compilation of all the physical, chemical, biological, and social influences that impact biology.
Metabolomics as a Tool in Exposome Research
Metabolomics has emerged as a central tool in exposome research due to its ability to provide a high-resolution snapshot of both exogenous and endogenous small molecules in the body. Metabolomics can detect signatures of environmental exposures, dietary intake, microbial metabolism, and physiological responses by analyzing biofluids such as blood or urine. This makes it uniquely suited for characterizing the internal exposome and identifying early disease biomarkers. Furthermore, untargeted metabolomics approaches allow the discovery of previously unrecognized exposure–disease associations. Recent work has demonstrated the utility of large-scale platforms capable of quantifying over 1,000 chemicals, enhancing the scope of exposome profiling16. In addition, evolving metabolomics methodologies, such as those based on liquid chromatography–mass spectrometry (LC-MS), provide the tools necessary to connect exposure signatures with biological outcomes in environmental health studies17. Figure 1.2 demonstrates the coverage of Metabolon platforms for studying the exposome.
Figure 1.2: Metabolon’s services include the Global Discovery Panel and Metal Ions Panel, which comprehensively cover the specific external and internal exposomes:
1.4 Summary
The exposome offers a comprehensive and dynamic framework for understanding how environmental factors contribute to health and disease across the lifespan. The exposome enables researchers to map the complex web of interactions between the environment and biology by categorizing exposures into internal, specific external, and general external domains. As tools for measuring and integrating these exposures continue to improve, the exposome holds promise for uncovering novel disease pathways and informing precision public health strategies. Nonetheless, exposome research remains inherently complex, as capturing the full range of lifetime exposures and individual responses is difficult. In the next chapters of this guidebook, we will explore some of these complexities, examine the challenges associated with exposome research, ways metabolomics and Metabolon can address these challenges, and then explore real world examples that show how exposome research has helped shape public health policy and advance precision medicine initiatives.
References
1. Wild, C. P. Complementing the genome with an “exposome”: The outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol. Biomarkers Prev. 14*(8, 1847–1850 (2005).
2. Miller, G. W. & Jones, D. P. The nature of nurture: Refining the definition of the exposome. Toxicol. Sci. 137*(1, 1–2 (2014).
3. Rappaport, S. M. & Smith, M. T. Environment and Disease Risks. Science 330, 460–461 (2010).
4. Wild, C. P. The exposome: from concept to utility. Int. J. Epidemiol. 41, 24–32 (2012).
5. DeBord, D. G. et al. Use of the “Exposome” in the Practice of Epidemiology: A Primer on -Omic Technologies. Am. J. Epidemiol. 184, 302–314 (2016).
6. Dennis, K. K., Marder, E. & Balshaw, D. M. Biomonitoring in the era of the exposome. Environ. Health Perspect. 125*(4, 502–510 (2017).
7. Walker, D. I., Valvi, D. & Rothman, N. The metabolome: A key measure for exposome research in epidemiology. Curr. Epidemiol. Rep. 3, 93–103 (2016).
8. Niedzwiecki, M. M., Walker, D. I. & Vermeulen, R. The exposome: Molecules to populations. Annu. Rev. Pharmacol. Toxicol. 59, 107–127 (2019).
9. Vrijheid, M. The exposome: A new paradigm to study the impact of environment on health. *Thorax 69*(9, 876–878 (2014).
10. Peters, S., Undem, K. & Solovieva, S. Narrative review of occupational exposures and noncommunicable diseases. Ann. Work Expo. Health 68, 562–580 (2024).
11. Adams, K., Weber, K. S. & Johnson, S. M. Exposome and immunity training: How pathogen exposure order influences innate immune cell lineage commitment and function. Int. J. Mol. Sci. 21*(22, 8462 (2020).
12. Deguen, S., Amuzu, M., Simoncic, V. & Kihal-Talantikite, W. Exposome and social vulnerability: An overview of the literature review. Int. J. Environ. Res. Public. Health 19, 3534 (2022).
13. Dai, D., Prussin, A. J. & Marr, L. C. Factors shaping the human exposome in the built environment: Opportunities for engineering control. Environ. Sci. Technol. 51*(14, 7759–7774 (2017).
14. Abdelzaher, H. M., Tawfik, S. M. & Nour, A. A. Climate change, human health, and the exposome: Utilizing OMIC technologies to navigate an era of uncertainty. Front. Public Health 10*. PMID, 36211706 (2022).
15. Minnis, H., Harmelen, A. L. & Gajwani, R. The bio-exposome: Intracellular processes, stress physiology and the environment. Nat. Ment. Health 2*(2, 132–140 (2024).
16. González-Domínguez, R., Sayago, A. & Fernández-Recamales, Á. Characterization of the human exposome by a comprehensive and quantitative large-scale multi-analyte metabolomics platform. Anal. Chem. 92*(5, 3764–3773 (2020).
17. Stanciu, A. R., Gillespie, C. & Britz-McKibbin, P. Environmental exposures and health risks: A metabolomics perspective on exposomics research. Annu. Rev. Anal. Chem. 18, 47–71 (2025).
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Explore the complexity and associated challenges of studying the exposome by downloading our complete Guide to the Exposome, which provides a comprehensive examination of the state of exposome research and how metabolomics can help generate meaningful insights in this field.
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