What is new about the exposome?

Nicolas Venisse

Toxicology and Pharmacokinetics Department
Clinical Investigation Centre
University Hospital, Poitiers, France

This month we highlight a recent Compass piece by Nicolas Venisse, written on behalf of the Toxicology and Environmental Health Committee. This relatively recent committee was founded in 2017 and has already achieved an important place in the Association. Nicolas writes about the exposome, a concept that is receiving increased attention due to recent technological advancements in analytical chemistry and data processing. Work in this area promises to shed light on the complex relationships between environmental factors and diseases.

The exposome concept has been first defined in 2005 by Wild¹ to describe the environmental counterpart of the genome. The exposome has been proposed as a new paradigm to “encompass life-course environmental exposures (including lifestyle factors), from the prenatal period onwards”. It includes exposure to synthetic chemicals, dietary constituents, psychosocial stressors and physical factors. It has the potential to identify environmental contributors to health and disease but requires the development of reliable exposure assessment tools. Assessing the chemical exposome is a challenging task since the concentrations of environmental pollutants are typically orders of magnitude lower than concentrations of drugs and endogenous chemicals².

Fifteen years after the introduction of the exposome concept, Vermeulen et al³ have reviewed recent progress in the assessment of the chemical exposome and how it can affect human health. In this review, authors advocate for a coordinated and international effort to provide reliable exposomic data enabling environment-wide association studies to identify new environmental factors in disease. According to the authors, this effort should rely on the development of large scale non targeted screening methods for chemicals and the development of chemoinformatic and bioinformatic tools. They particularly highlight the prominent role of high-resolution mass spectrometry (HRMS) in expanding the analytical window beyond targeted analysis. Several databases providing access to chemical data are available to help in the identification of unknown chemicals. This is the case of the U.S. Environmental Protection Agency’s CompTox Chemistry Dashboard that includes physicochemical, environmental fate and transport, exposure, usage, in vivo toxicity and in vitro bioassay data of nearly 900,000 chemicals. This database also includes an advanced search feature designed to support non-targeted mass-spectrometry research.

In a recent article, Pourchet et al⁴ also make some recommendations for the determination of the human chemical exposome using either large- scale suspect or non-targeted screening methods based on high-resolution mass spectrometry (HRMS). Their approach mainly focuses on liquid- chromatography coupled to HRMS, either with Time-of-Flight (ToF) or Orbitrap devices, and their recommendations cover all aspects of the analytical procedure from sample extraction to data processing. For sample preparation of common biological matrices such as blood and urine, they propose simple and non-selective methods in order to cover a wide range of analytes. Recommended methods range from simple “dilute and shoot” to turbulent flow chromatography or online solid- phase extraction. Chromatographic separation could be achieved using a C18 reversed-phase column with a conventional binary gradient (water/ methanol or water/acetonitrile) or a ternary gradient (water/methanol/ acetonitrile) to take advantage of the specific properties of each solvent. Combined detection in the positive and negative ionization mode is required to provide broader detection capabilities. Combining exact mass measurement with fragment ion information related to the structure of the compound obtained using, for example, data dependent acquisition, increase the level of confidence for identification of target and unknown pollutants. The authors also make recommendations regarding the crucial issue of marker’s identification and call for harmonization in the reporting of screening results especially regarding the confidence level associated with compound annotation. Schymanski et al⁵ have already proposed a 5-level confidence system pertinent to screening methods in environmental sciences: level 1 represents the best situation where the proposed structure has been confirmed using measurement of a reference standard with MS, MS/MS and retention time matching while level 5 represents the situation where solely exact mass is available. Finally, Pourchet et al. propose the development of an extended and qualitatively consolidated European MS reference library⁴. The aforementioned developments and harmonization efforts will be carried out within the framework of the European Human Biomonitoring initiative (HBM4EU, 2017-2021).

The concept of exposome has recently gained increased significant attention. Technological advancements in analytical chemistry through the development of HRMS and data processing will contribute to increase our knowledge on the complex relationships between environmental factors and diseases. Exposomic research is an excellent opportunity to develop multidisciplinary collaborations between exposure scientists, toxicologists, analytical chemists and epidemiologists.

References
¹Wild, C.P. Complementing the genome with an “exposome”: the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol. Biomarkers Prev. 2005 ; 14, 1847–1850.
²Rappaport, S.M., et al. The blood exposome and its role in discovering causes of disease. Environ. Health Perspect. 2014; 122, 769–774.
³Vermeulen, R., et al. The exposome and health: Where chemistry meets biology. Science. 2020; 367, 392–396.
⁴Pourchet, M., et al. Suspect and non-targeted screening of chemicals of emerging concern for human biomonitoring, environmental health studies and support to risk assessment: From promises to challenges and harmonisation issues. Environ Int. 2020 Jun;139:105545.
⁵Schymanski, E.L., et al. Identifying small molecules via high resolution mass spectrometry: communicating confidence. Environ. Sci. Technol. 2014 ; 48, 2097–2098.

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