The Exposome: You need to care. Now.

When the Human Genome Project (HGP) result was announced in the presence of the US President and UK Prime Minister, the whole world listened and thought that all dangerous diseases would be a thing of the past [1].

One of the quotes from the US President was, “In coming years, doctors increasingly will be able to cure diseases like Alzheimer's, Parkinson's, diabetes, and cancer by attacking their genetic roots. Just to offer one example, patients with some forms of leukemia and breast cancer already are being treated in clinical trials with sophisticated new drugs that precisely target faulty genes and cancer cells with little or no risk to healthy cells. In fact, it is now conceivable that our children's children will know the term cancer only as a constellation of stars. [2]" 

However, even two decades after the announcement, no gene therapy exists and cures for many of the mentioned diseases are still far from reality. 

One of the missing steps in the HGP was not considering environmental exposure [3,4]. A gene cannot impart its function correctly if the environment is not suitable. A key example to understand this theory is the disease phenylketonuria (PKU) [5]. 

PKU is a rare genetic disorder with a mutation in the phenylalanine hydroxylase gene. A person born with two mutated gene copies cannot metabolize the amino acid phenylalanine [5]. The accumulation of phenylalanine can lead to neurodevelopmental disorders. Although the disease is genetic, its occurrence in the body can be prevented by providing an environmental intervention (a special low phenylalanine formula) to newborn babies [5].

The Rise of the Exposome: A Historical Perspective

A phenotype results from the combination of genes and environment. With the advent of HGP, large-scale genome-wide association studies have been conducted to understand their role in diseases. However, these studies are still lacking.

To give a broader perspective of the environment in health and disease association, Wild proposed the exposome concept in 2005, and Miller and Jones later modified it [3,6,7]. Holistic consideration of environmental exposures, including the lifestyle that can impact a person's health over their lifetime, is the basic tenet of the exposome concept. The working definition of the exposome is [8]:

The exposome: the cumulative measure of environmental exposures and corresponding biological responses that can be derived from biological samples (blood, urine, tissue).

The debate of nature versus nurture was put to rest by introducing the exposome concept [3], the definition of which considers environmental factors (nurture) and the associated biological responses (nature). 

Classification of Environmental Exposures for Exposome Studies

The environmental exposures for exposome studies can be categorized into three parts [9]:

Outdoor Exposome

Outdoor exposomes are characterized by natural ecology (air pollution, noise, water pollution) and geology, as well as the diurnal cycles, seasons, and green spaces. 

Individual Exposome

The individual exposome comprises exposure of socioeconomic nature and to the chemical over the lifetime. 

Lifestyle Exposome

The lifestyle exposome discusses the crucial issue of lifestyle as well as money, exercise, and bad habits like smoking.

Multi-omics Approach to Studying the Exposome

As the exposome represents a holistic picture of the human environment and disease, there is a need for integrating a multi-omics approach to get an in-depth understanding. By combining several omics, such as proteomics, metabolomics, genomics, and transcriptomics, multi-omics investigations thoroughly explore the molecular processes underpinning human phenotypes [4,8,10]. Hence, the synergy of the exposome is demonstrated by expanding it from an anthropocentric perspective to all ecological levels of the organization.

Genome

Genomic studies help to understand the overall impacts of genes on an individual. A study found that the genome-exposome connection and modeling of these effects could increase the accuracy of phenotypic prediction [11].

Transcriptome

Combining transcriptomic analysis, which will reveal the mRNA expression of an individual with an exposome, will give a broader understanding of how these exposures have an underlying effect on a disease. A study in preeclamptic patients and their controls analyzed transcriptomic profiles with an exposome [12]. The study found that underlying transcriptomic profiles are caused by understudied chemicals in the human placenta [12].

Proteome

Proteomics plays an important role in identifying novel biomarkers in exposome studies. Multi-omics technologies were applied in an integrative study to quantify exposure levels and to measure the downstream effects of environmental exposures by the epigenome, transcriptome, and proteome [13].

Metabolome

With the advancement in mass spectrometry, studying metabolites and overall metabolomics has become simpler. To understand the exposome holistically in conjunction with metabolomics, studies are conducted with exposure-response relationships in untargeted metabolomic analysis [14]. These studies have provided insight into the molecular mechanisms of the causes of exposure-related diseases as external exposure was linked to internal dose and biological response [14]. If you are a practitioner and would like to learn more about metabolomics, go to homehope.org and check out the metabolomics module to learn how to use it in clinical practice.

Phenome

The phenome represents the totality of biological characteristics displayed by an individual. A study investigated how the exposome shapes an individual's phenome longitudinally [15]. In this study, a single person was monitored for 52 days and all multi-omics approaches along with exposome data were collected. The authors found with the multi-omics approach that exposomes were positively correlated with phenomes on more than 8,000 factors [15].

Microbiome

One of the key factors affecting the exposome is the individual gut microbiome. A study was conducted to find the correlation between the exposome and gut microbiome [15]. The authors found a strong association of the external exposome with the gut microbiome and its associated biological processes, particularly inflammation [15].

Ways to Identify Exposomes for Public Health

Exposome studies help to identify molecular-level physiological changes at earlier stages in healthy groups before the appearance of clinical symptoms. The exposome study is conducted at two levels: biological and environmental exposure.

Biological Identification 

Urine

Generally, studies investigating environmental exposure collect two spots of urine from the individual, one before bedtime and another during the morning void [16]. Urinary metabolites are assessed using nuclear magnetic resonance (NMR) [16,17]. Dietary-metabolite associations were established with urinary metabolites in children, including urinary creatine with consumption of meat, urinary hippurate with vegetable intake, and urinary proline betaine with fruit intake [17].

Blood

The most critical component in the biological identification of exposomes comes from the patient’s blood. The collected blood is used at a multi-omics level by studying blood DNA methylation (epigenomics), gene expression of blood (genomics), blood miRNA and mRNA expression (transcriptomics), plasma protein analysis (proteomics), and serum metabolites (metabolomics) [16]. The Human Early Life Exposome (HELIX) study found significant changes in child DNA methylation if the mother is exposed to cadmium, molybdenum, and smoking [16].

Stool

Stool samples are important in understanding the microbiome's effect on the exposome. Stool samples are collected for studies according to the Human Microbiome Project-Sampling Protocol [15]. The sample is then analyzed by 16S (bacterial) rRNA, untargeted metabolomics with LC-MS (liquid chromatography-mass spectrometry) for an in-depth result of the gut microbiome [15,18].

Exposure Identification

Outdoor Exposome

Identifying outdoor exposomes (air pollution, built environment, noise, green and blue space, and meteorological data) must be collected to study the exposome. One of the most economical and powerful tools for assessing population-level exposures to air pollutants (e.g., particulate matter/PM, ozone, NO2, and CH2O) and other outdoor exposomes is remote-sensing data obtained from earth-revolving satellites [19]. GIS information and existing land-use regression models are also used for analyzing outdoor exposomes [16].

Individual Exposome

The individual exposome represents the biomarkers of chemical exposures. Individuals are exposed to many different types of chemicals throughout their lifetime, affecting their overall exposome. The biomarkers include organochlorine compounds (OCs) and brominated compounds (PBDEs) in serum, perfluoroalkyl substances (PFASs) in plasma, metals and essential minerals in whole blood, and non-persistent chemicals (phthalates, phenols, organophosphate pesticides/OPs, and cotinine) in urine samples [16]. 

Lifestyle Exposome

Standardized questionnaires are used to study the lifestyle exposome [16]. These questionaries asses the Mediterranean diet, physical activity by the individual, sleeping patterns, socioeconomic status (family affluence scale and subjective wealth), the social capital of the family, exposure to environmental tobacco smoke, water consumption habits, cooking and heating methods at home, cleaning products, bedroom location, noise perception, use of mobile phones and other devices, use of green spaces, commuting behavior, holidays, and sun exposure [16,20-22]. 

Modifying the Exposome

The exposome directly impacts public health; hence, it is of utmost importance to address it when possible. Many of them are completely under our control (smoking, physical activity, and diet), while others are influenced more at a population or societal level (air pollution and healthcare access) [23]. There are many ways which can help in reducing the burden on the exposome:

Reduction in intake of plastics and chemicals via food

With a fast-paced lifestyle, ultra-processed food (UPF) intake has increased significantly [23]. UPF contains fewer nutrients and more plastics, phthalates, and preservatives. Modeling studies have found that reducing UPF will improve cardiovascular diseases sharply [24].

Improving metabolic detoxification pathways

Another way to enhance the exposome for fighting disease is to boost detoxification pathways [23]. The human body's most common metabolic detoxification pathways are phase I cytochrome P450 enzymes, phase II conjugation enzymes, Nrf2 signaling, and metallothionein [25]. Changing the diet to comprise whole food is suggested to improve detoxification pathways and remove the antioxidants [25]. Additionally, the use of methylene blue improves Nrf2 signaling [26].

Removing chemicals from the environment

PFAS and PBDE are some of the most toxic chemicals in the environment and must be removed from water and soil [23]. Several strategies such as adsorption, hydrothermal and thermal treatment, photolysis, photocatalytic degradation, reductive debromination, advanced oxidation processes (AOPs), and biological degradation have been used for the degradation and removal of PFAS and PBDE [27]. Most water filters containing activated carbon and reverse osmosis have been shown to effectively remove PFAS from water [28]. Other harmful chemicals like arsenic, cadmium, and trichloroethylene in water can be removed by adsorption and hydrothermal treatment at the filtration station.

Lifestyle changes

Adopting a healthy lifestyle will benefit the individual to improve the exposome. A healthy lifestyle includes regular physical activities, exposure to the sun, no smoking, unprocessed food, a Mediterranean diet, lesser red meat consumption, and quality sleep [23,29-32].

Diseases associated with the Exposome

The exposome impacts public health, and many diseases are associated with it. Here is a list of a few clinically relevant diseases [23,33,34]:

• Cardiovascular disease
• Neurological diseases
• Respiratory syndrome
• Metabolic syndrome
• Aging
• Allergic diseases

Outlook

In 2020, the European Union committed over 100 million euros to study the impact of the environment on human health in the world's largest network of projects under the European Human Exposome Network (EHEN).

Exposomics is increasingly supported by exposure science, biomonitoring, mechanical knowledge, human-relevant micro-physiological systems, and multi-omics approaches to generate big data. Further studies on exposome-wide associated studies (EWAS) allow us to broaden our present understanding to include the great unknowns of risks to human health. Hence, there is demand for starting a Human Exposome Project.

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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