High resolution mass spectrometry to investigate the human exposome: Where are We?

Abstract Despite the significant role of the environment in health and disease, the accurate assessment of environmental exposures remains underdeveloped compared to genetic factors. To address this, the concept of the exposome was introduced in 2005 as a complement to the genome. High-resolution mass-spectrometry (HRMS) has emerged as a key technology for the comprehensive assessment of the chemical exposome. However, non-target HRMS based exposomics still faces numerous challenges, with the majority of features detected by HRMS (the “dark matter” of the chemical exposome) remaining unannotated. The lack of standardized workflows across the field often results in poorly comparable studies. Nevertheless, many positive developments have arisen in recent years, with open data revealing interesting trends in HRMS coverage. This review will examine and discuss the entire non-target HRMS exposomics workflow, from experimental design (study design and sample preparation) to the computational analysis and biological interpretation. It will also delve into key concepts, including the sometimes blurred distinction between the metabolome and the chemical exposome and the importance of exposomics within the “omics cascade”. Visualizations are used to support this discussion, including a detailed look at the chemical coverage of key categories of open exposomics resources. The review ends by exploring current challenges and strategies to advance towards harmonized exposomics studies, which are essential for greater biological insights and personalized medicine goals.