Grant: Discovery Grants Program - Individual

The exposome encompasses the totality of environmental exposures during a lifetime. In chemistry and chemical biology, these exposures manifest as endogenous and exogenous chemicals that result from diet, lifestyle, radiation, stress, and exposure to environmental pollutants. Unlike the genome, the exposome is variable and thus requires frequent, cost-effective and reliable measurements of exposures that evolve over time, most appropriately by sampling small quantities of blood (e.g. dried-blood spots). Such measurements will be vital in order to identify the causes of most chronic diseases, but the obstacles to further progress are formidable: c. 90% of unknown pollutants in a drop of blood are not detectable using existing analytical platforms; and the identities of most environmental toxicants and their role in causing chronic disease are unknown! My group's research will address these challenges through the development of innovative mass spectrometry (MS) techniques, viz. flow modulated multidimensional gas chromatography-atmospheric pressure ionization (GCxGC-API), complemented by state-of-the-art computational tools. The proposed analytical platform affords unparalleled separation and significantly improves detection limits when coupled with an API source that is resilient to high flows. Despite its promise, this has not been previously attempted! The development of this approach will enable: the identification of unknown pollutants with 3-50 microliters of blood (1 PhD, 1 BSc), a remarkable improvement over existing methodologies that require pooled sampling and excessive blood volumes >300uL; and innovative hyphenation of ionization (1 MSc) and activation (1 PhD, 1 BSc) techniques that will provide new information critically needed to identify unknown toxicants. Nontargeted screening (NTS) is the term-of-art for qualitative experiments aimed at identifying unknown organic compounds using MS. The prevailing thought is that a compound's structure must be elucidated prior to assessing environmental significance, but this approach is impractical considering sample complexity. We suggest that that the environmental significance of an unknown chemical may be inferred from its behavior (and reactivity) in the mass spectrometer without a priori knowledge of its structure. Trainees in my lab will: develop automated software that accelerates pollutant discovery (1 PhD, 1 BSc); investigate and exploit the rich chemistry occurring in the mass spectrometer that mirrors in vivo metabolism and can be used to differentiate toxic from non-toxic chemicals (1 PhD, 1 BSc); and finally, conduct reconnaissance studies (3 MSc, 1 BSc) aimed at answering the question: What risk do these newfound pollutants pose to the environment and health? It is anticipated that the results from this research program will help guide the creation of effective environmental regulation; and guide industry on the development of safer, more sustainable chemicals.