The exposome and health: Where chemistry meets biology

Abstract

Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The "exposome" concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.

Figure 1.. The exposome concept.

The exposome is an integrated function of exposure on our body including what we eat and do, our experiences, and where we live and work. The chemical exposome is an important and integral part of the exposome concept. Examples of external stressors are adapted from (39). These stressors are reflected in internal biological perturbations (Figure 3); thus, exposures are not restricted to chemicals (toxicants) entering the body, but also include chemicals produced by biological and other natural processes.

Figure 2.. Chemical complexity of HRMS and the exposome.

Top: Known versus unknown features in a typical HRMS measurement (data from (7)). Bottom: Selected data sources relevant to the chemical exposome (–14, 19). Arrows show the overlap of potential neurotoxicants in FooDB (foodb.ca), and FooDB components in NORMAN SusDat (prioritized chemicals of environmental interest).

Figure 3.. The impact of the exposome on subcellular networks.

A. Network medicine views the cell as a multilayer network, with three principal, interdependent layers: (i) regulatory network, capturing all interactions affecting RNA and protein expression; (ii) protein interaction network, that captures all binding interactions responsible for the formation of protein complexes and signaling; (iii) metabolic network, representing all metabolic reactions, including those derived from the microbiome, a network of interacting bacteria linked through the exchange of metabolites. Exposome-related factors can affect each layer of this multilayer network. B. The polyphenol EGCG, a biochemical compound in green tea, with potential therapeutic effects on type 2 diabetes mellitus (T2D), binds to at least 52 proteins (40). Network-based metrics reveal a proximity between these targets and 83 proteins associated with T2D, suggesting multiple mechanistic pathways to potentially account for the relationship between green tea consumption and reduced risk of T2D. C. Trichloroethylene (TCE) is a volatile organic compound that was widely used in industrial settings and is now a widespread environmental contaminant present in drinking water, indoor environments, ambient air, groundwater, and soil. Multiple lines of evidence support a link between TCE exposure and kidney cancer and probably non-Hodgkin lymphoma (33). TCE perturbs at least two different layers of the cellular network: it covalently binds to proteins from the protein interaction network, altering their function, and affects cellular metabolic network, eventually leading to ATP depletion. Network-based tools could be used to explore the mechanistic role of many other exposome chemicals on our health, and to build experimentally testable hypotheses.