From the moment of conception, genes determine our development and health. But they do not do it alone. Health is also influenced by our environment. Consider a healthy lifestyle, for instance. Healthy habits are unquestionably beneficial: from reducing the likelihood of developing chronic diseases to extending lifespan [1-3]. Other environmental elements also have a great impact on our health, including many socioeconomic factors such as household income, our neighborhood, and air pollution [4,5]. In other words, our environment can have a more profound impact on our health than a healthy lifestyle.

Identical twins, also called monozygotic twins, illustrate the impact the environment can have on our health. Identical twins are perfect genetic copies. As a result of the division of a fertilized egg into two genetically identical embryos, they have the same DNA. Surprisingly, external differences emerge between the twins as they grow up. Despite identical genetic codes and similar habits, identical twins show significant differences, even differential disease onset [6].

This article discusses the impact of the environment on our health and well-being. It will do so by exploring the young discipline of exposomics. Let’s revisit some basic concepts to better understand exposomics before we dive into it!

The Phenotype

Humans are not simply the result of the genetic code. At least, not entirely. In our epigenetics article, we discussed a range of mechanisms that regulate gene expression. As a result of external stimuli, these mechanisms up- and down-regulate specific genes to adapt to changes in the environment. One of the current dogmas of biology states that the phenotype (Y) results from the genotype (G), the environment (E), and their interactions (GE) [7]. The equation is as follows:

Y = G + E + GE

Let's take a closer look at these three concepts.

• Phenotype: From the Greek φαίνω (phaínô), meaning ”to show, to appear,” and τυπος (tupos), meaning “mark, type.” An organism's phenotype refers to all its physical traits, such as its appearance, development, and behavior. Additionally, it includes other measurable characteristics such as hormone levels, telomer length, or the number of red cells in the blood [7,8]. A disease’s development can also be considered as a phenotype [9].
• Genotype: The genotype can be defined as the complete genetic material of an individual. Although genotype is often used in the context of alleles or gene variants, it is almost a synonym for genome [10].
• Environment: The environment encompasses all the external elements that can interact with the genotype. These include external elements like temperature, light, drugs, and chemicals, as well as internal factors like metabolite levels or hormones, for instance [11].

Genetic and phenotypic data can be measured accurately using modern techniques. Genomic science studies an organism's genome, which contains its genetic material. In other words, genomics analyzes the genotype. Phenotyping requires a multidisciplinary approach, including diagnostic laboratory analyses, proteomics, metabolomics, and other "-omics" sciences (you can read more about it in our metabolomics article here).

The study of genotype and phenotype is crucial to understanding health and disease. A person's genotype may affect their chances of developing a particular condition (for instance, if they carry a mutation that may lead to metastatic cancer). Phenotypes can indicate a person's health status (by detecting metastases in the body) or the effectiveness of treatment (if the metastasis shrinks after chemotherapy). A crucial component of the equation, however, is missing: the environment. Health and disease are influenced by the environment. How can we measure the environment? Can we predict whether an individual will get sick based on their environment? This is where exposomics comes in.

What is Exposomics?

Exposomics can be described as the study of the exposome by analyzing large datasets like other “-omics” sciences. Christopher Wild used the word "exposome" for the first time in an article published in 2005. As he defined it, “At its most complete, the exposome encompasses life-course environmental exposures (including lifestyle factors), from the prenatal period onwards [12].” More recently, Gary W. Miller proposed a more comprehensive, accurate definition of exposome: “The cumulative measure of environmental influences and associated biological responses throughout the lifespan including exposures from the environment, diet, behavior, and endogenous processes [13].” In other words, the exposome includes all the non-genetic factors influencing our health.

What is Included in the Exposome?

An individual's exposome consists of all the environmental influences to which they are exposed throughout their life. The list of influences is almost endless. The factors affecting our health have been organized into categories to make them easier to understand:

• Physical-chemical elements: These are all the physical and chemical entities that interact with our organisms. Temperature, humidity, electromagnetic fields, ambient light, or radiation are all physical elements that affect our bodies. Chemicals, on the other hand, are among the most important elements studied by exposomics. These include outdoor and indoor air pollution, pesticides, persistent organic pollutants, food contaminants, soil contaminants, and drinking water contaminants, among others.
• Lifestyle: Physical activity, sleep behavior, diet, drug and alcohol use, and smoking are the most important aspects of our lifestyle that affect our health. For instance, a healthy lifestyle correlates with a lower risk of developing diseases like cancer or cardiovascular disorders [2,14].
• Social: The socioeconomic conditions of an individual can significantly affect their health and their chances of developing a disease, resulting in health disparities among the population [15]. The socioeconomic factors include household income, inequality, social capital and networks, cultural norms, and psychological and mental stress.
• Endogenous processes: The biological processes that determine our health status. Metabolic activity, cellular activity, and the microbiome are all part of this process. To learn more about the effects of the microbiome on our health, check out our article on the gut immune system.
• Ecosystems: Food and alcohol outlets, built environments, population density, walkability, and green space availability. For instance, urban design can promote physical activity and health by including more green spaces and natural environments within modern cities [16].

The Challenge of Measuring the Exposome

According to Miller's definition, the exposome can be measured ("The cumulative measure of environmental influences…") [13]. The accurate and comprehensive measurement of the exposome is one of the current challenges in exposomics. Quantifying the environment is crucial to predicting a particular disease's likelihood or establishing preventive measures. However, the extremely changing nature of environmental elements, as well as the large number of substances we are exposed to and their interactions with our organisms, make the quantification of exposomes extremely difficult.

Methodologies: High-Resolution Mass Spectrometry

The technological advancements of recent years have provided valuable tools for measuring, for example, the large amount of chemicals we are constantly exposed to. These technologies include mass spectrometry, wearables, sensors, biostatistics, and bioinformatics, among others. A primary technology for measuring chemicals, metabolites, and pollutants is high-resolution mass spectrometry (HRMS), which can detect a wide variety of chemical species in a range of media. This expands the analytical range beyond the targeted and untargeted screening of known metabolites and pollutants [17]. A single HRMS analysis can measure tens of thousands of endogenous and exogenous chemical compounds, describing the system and its changes in response to environmental elements [18]. The external molecules detectable by HRMS include pharmaceuticals, pesticides, plasticizers, flame retardants, preservatives, and microbial metabolites [19]. These exogenous compounds were often viewed as noise and artifacts by metabolomics analyses, but in reality, they carry direct evidence of the complex environments to which living organisms are exposed [20].

The Size of the Exposome

Several relevant databases are available for HRMS-based exposomics, ranging from specialized lists [21] to huge resources such as PubChem, which contains 96 million entries [22]. Scientists conducting exposome analyses rely heavily on these databases for chemical information. Additionally, databases are crucial in the standardization of data formats, data sharing, and integration [23]. To have an idea of the size of the chemical space, since the 1950s more than 140,000 chemicals have been produced and used massively. From these, around 5,000 are estimated to be dispersed in the environment and pose a threat to the population [20]. However, this number may dramatically increase when studying local communities or specific occupational settings [24].

The Intricate Network of the Exposome

The difficulty of measuring the exposome does not stem only from the large number of chemicals present in the environment. The intricate interactions between chemicals and cells are also crucial in understanding how exposomes affect our health. Each chemical interacts with various cellular components, which are considered as a multilayer network [25]. The cell then processes the chemicals and produces secondary metabolites that are also affecting cellular components. Additionally, exposome analyses may include various levels of exposure, from bioavailability to the protein-binding information of thousands of compounds. Moreover, chemicals rarely interact with cells as single agents, but rather as a complex mixture of compounds. This, in turn, will affect the interaction of every single chemical of the exposome [20]. Last but not least, exposomics analyses must combine these measurements with other layers of environmental elements and interactions, such as social factors and lifestyle.

A Multidisciplinary Approach

A growing number of tools and resources are emerging as potential solutions to the titanic challenge of quantifying the exposome. In particular, bioinformatics and other computational tools can be used to interrogate the large sets of data obtained from exposomics analyses [26,27].

Alongside measuring the effects of chemical and physical elements of the exposome on our health, exposomics analyses need to account for many other variables, including socioeconomic status and lifestyle. The scope of exposomics also includes inflammation, stress, or gut flora interaction as endogenous processes that impact our health [28]. All these environmental factors are related to public health problems such as allergies, infertility, impaired brain development in children, and various types of cancers [24]. Thus, addressing exposome-related questions requires a multidisciplinary approach. A coordinated and systematic effort by basic scientists, clinicians, policymakers, funders, and the general public will be necessary to address the importance of analyzing the exposome in a health context. The applications are multiple, as a complete evaluation of the exposome can directly benefit epidemiology, public health, and precision diagnostics [29].

Exposomics in Health Optimization Medicine and Practice (HOMe/HOPe)

The first clinical specialty to not only identify the field of exposomics as an essential area of study but to also create a clinical framework to understand it is HOMe/HOPe.

Exposomics is one of the core modules of the Essential Certification in HOMe/HOPe due to the sheer size and impact it has on everyone, from the prenatal period to old age.

The Exposomics module dives into the Exposed Unit (EU) and its impact on the human holobiont, otherwise known as the human holo-organism. This organism is made up of human cells + our trillions of hangers-on (bacteria, fungus, virus, and more) that live on and inside of us. 

Future healthcare practitioners need to understand the EU in detail and this module can help. Check out the Exposomics module in the HOMe/HOPe Essential Course here.

Conclusion

When Christopher Wild mentioned the exposome for the first time, he highlighted the importance of putting effort into studying all the environmental elements that could lead to the onset of disease [12]. As an epidemiologist, Wild perceived a lack of tools and resources to measure the environmental factors affecting health. He identified the importance of defining and quantifying the environmental elements to which we are exposed as that will provide insight into the events and mechanisms resulting in disease. Deciphering the exposome will also allow us to design better prevention strategies by providing us with valuable epidemiological and public health information. Ultimately, a systematic, comprehensive study of the exposome could revolutionize health systems and empower society to live healthier lives.

Written by Ferran Riaño-Canalias, PhD

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