A Fresh Look at Measuring the Exposome
Study assesses an IMS-MS strategy, and proposes new informatics
The human exposome is the totality of all environmental exposures in a person's lifetime, internal and external, including those before birth. The exposures are from all the chemical, biological, and social agents that influence human health.
Measuring the exposome at the molecular level remains a challenge. For one, humans encounter a lot of anthropogenic molecules in their daily lives. In turn, there are complex systemic responses to these exposures.
A paper by researchers from the Pacific Northwest National Laboratory (PNNL) explores a new option for improving the coverage, dynamic range, and throughput of such measurements. It describes incorporating ion mobility spectrometry (IMS) into current analytical methods based on mass spectrometry (MS). The paper also proposes a new informatics strategy for coping with increased analytical data.
Better and More Observations
Implementing IMS in exposome studies will lead to more frequent observations of previously undetected chemicals and metabolites. The throughput of IMS-MS alone will provide the opportunity to analyze many thousands of longitudinal samples over lifetimes of exposures, and will capture evidence of transitory accumulations of chemicals or metabolites.
Moreover, by including liquid chromatography (LC) in an LC-IMS-MS approach to analysis, scientists can increase the dynamic range of the overall measurement, resulting in the detection of lower-abundance molecules.
The Complexities of Exposure
More than 90 percent of human disease comes from two sources: individual genetic factors encoded in the genome, and from the exposome, the totality of non-genetic environmental factors. Non-genetic factors can be both external (chemicals in the soil, water, and diet, for instance) and internal (exposures correlated to molecular changes).
With such a complex set of exposures to consider, it is a challenge for analytical chemists to measure the exposome. Methods for measuring it are far less developed than those for obtaining genetic information.
Conventional analytical approaches need to be expanded to handle higher sample throughput, to accurately measure thousands of chemicals, and to characterize chemical exposures across larger populations. Genomics, transcriptomics, and proteomics - "omics" technologies - focus on a narrow chemistry. But measurements to characterize small molecules - metabolomics - require techniques suitable to the very diverse space involved in metabolite chemistry.
The new paper, led by PNNL scientists Thomas O. Metz and Justin G. Teeguarden, reviews the state-of-the-art methods for measuring the small, organic molecular components of the exposome.
Broadly, there are two such methods. Targeted analysis provides a narrow snapshot of the chemistry involved. That means high confidence in chemical identification, but low sample throughput and low coverage of possible exposure molecules. Untargeted analysis measures all analytes in a sample. Though challenges of identification remain, this approach is better suited to comprehensively measuring the exposome's vast chemical space.
IMS as a new tool for analysis is an "appealing technique" for enhancing current exposome methods, the authors write. They favor the drift tube IMS format (DTIMS), which increases the dynamic range of existing LC-MS methods; provides "ultra-high" throughput even when combined with just MS; and leads to more frequent observations of previously undetected chemicals and metabolites.
Coping with Data
The volume of data from these new chemical observations will outpace the development of the reference data needed to make confident chemical identification. So the authors also explore a new informatics approach that uses computationally predicted collisional cross section (CCS) to assist in identification. (CCS is predicted from the structures of the molecules themselves.) An initial evaluation, using 11 metabolites, revealed a promising low error rate of around 2 percent.
For a full-scale implementation of IMS into standard exposomics workflows, challenges remain in analytical and data processes. For one, analytical methods need to be developed and tested in practice to validate robustness and to minimize any false annotation potential for exposome studies.
What's Next? Technologies are being tested to overcome the current resolution limitations of DTIMS, which are tied to the fact that drift tubes cannot practically go beyond a few meters. Stepping into the gap, the authors say, are Structures for Lossless Ion Manipulation (SLIM) devices capable of ultra-high resolutions.
Sponsors: This work was supported by the Laboratory Directed Research and Development program at the Pacific Northwest National Laboratory (PNNL), and is a contribution of the Global Forensic Chemical Exposure Assessment for the Environmental Exposome project at PNNL, the Microbiomes in Transition initiative at PNNL, and the National Institutes of Health National Institute of Environmental Health Sciences.
Reference: Metz TO, ES Baker, EL Schymanski, RS Renslow, DG Thomas, TJ Causon, IK Webb, S Hann, RD Smith, JG Teeguarden. "Integrating ion mobility spectrometry into mass spectrometry-based exposome measurements: what can it add and how far can it go?" Bioanalysis (2017). Jan: 9(1):81-98. DOI 10.4155/bio-2016-0244.
Published: March 24, 2017