Perspective Metz, Baker, Schymanski et al.
relationships because they better represent concentra- tions at or near the biological site of action. The exten- sive set of sample matrices – from blood, breath, hair and nails to soil and water – as well as the range of complexity or ‘space’ comprising xenobiotic chemicals and endogenous molecules, is a challenge for analytical chemists attempting to measure the exposome. As the exposome is the ‘totality’ of exposure, each measure- ment will provide a snapshot (or piece of the puzzle) that can be used to build the bigger picture. The use of ‘omics’ technologies to characterize the
exposome [2,6–9], originally proposed by Wild [1], con- siders two distinct approaches: direct measurement of chemical exposures by measuring parent compounds and their transformation products in environmental samples or parent compounds and their metabolites in biofluids and tissues using similar analytical approaches as implemented in metabolomics, and inference of an exposure based on biological signatures (i.e., the ‘phenome’) obtained by one or more complementary approaches, such as transcriptomics or proteomics. A significant difference among these omics approaches is that genomics, transcriptomics and proteomics focus on a narrow chemistry – polymers of nucleotides and amino acids – whereas direct measurement of chemical exposure and of the metabolome requires dedicated or, better, complimentary approaches suitable for a very diverse chemical space [10–15] (Figure 1). Although the average molecular composition of a peptide [16] is not significantly different from that of a metabolite [17], the peptide chemistry is constrained to the typical pep- tide bonding between a fixed set of amino acids. In contrast, the metabolite chemistry is constrained only by the organism (for endogenous metabolites) and the boundaries of chemistry itself, while some xenobiotic compounds of anthropogenic origin even push the boundaries of chemistry. In the search for causes of human disease, the
genomics revolution brought unprecedented ability to obtain genetic information across individuals and populations, and a deeper appreciation for the impor- tance of exposure as causative agent, yet tools for measuring the exposome were far less developed. For example, while advancements are continually being made in methods for broadly and accurately identify- ing metabolites in metabolomics studies [18–31], these developments are still relatively immature compared with the ease, robustness and throughput with which the proteomics community confidently identifies pep- tide sequences [32–34]. The expansion of more conven- tional analytical approaches to handle higher sample throughput, and to measure thousands of chemicals, will allow comprehensive characterization of chemi- cal exposures across larger populations. Combined
29 Bioanalysis (2017) Bioanalysis (2017) 9(1), 81–98(1)
with emerging untargeted analytical methods (e.g., in metabolomics), there is the expectation that previously unknown or unexpected exposures will be identified, improving the search for environmental drivers of dis- ease and providing exposure data to guide chemical selection for toxicity testing. Applied to both human (e.g., blood and urine) and environmental samples (e.g., water, air, dust and soil), and linked through geographical information systems, these new analyti- cal approaches will also advance the search for sources of exposure, even when the identity of some chemicals involved remain unknown. In this perspective paper, we will briefly review
the state-of-the-art in measuring the small, organic molecular components of the exposome and discuss the potential use for ion mobility spectrometry-mass spectrometry (IMS-MS) and the physicochemical property of collisional cross section (CCS) in both exposure assessment and molecular identification in m etabolomics studies.
State-of-the-art in measuring the exposome Current exposure science leverages many disciplines to assess level(s) of environmental exposure and risk thereof, including epidemiology, toxicology and ana- lytical chemistry, with the latter being used for envi- ronmental and biological monitoring [5]. In this sec- tion, state-of-the-art approaches used in environmental and biomonitoring are illustrated. Specifically, meth- ods used to identify molecular signatures of exposure, whether evidence of parent compounds and their metabolites (i.e., direct measurement) or of pathogens, or the host’s complex biological response to these mol- ecules and organisms (i.e., indirect measurement) will be discussed. We further limit our discussion to direct measurements of chemical exposure and indirect infer- ence of an exposure based on biological signatures con- tained in the metabolome. Macromolecules and metals will not be covered. Regardless of whether direct or indirect measures
of exposure are performed, the technical approaches used largely fall under one of two categories: targeted or untargeted. The next two sections will provide an overview of these two approaches, citing specific exam- ples and covering benefits and caveats of each.
Targeted analysis Methods for targeted analysis in assessment of the exposome focus on a single analyte, a class of chemi- cally similar analytes or a set of analytes whose chem- istries are sufficiently similar to allow their measure- ment in a single analysis, all of which aim to address specific questions of exposure. The analytical proto- cols for such methods, including sample preparation,
future science group
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