High throughput exposomic studies for new insights into smoke exposures in occupational and population health

Abstract

Exposomics aims to characterize the totality of exposures over the lifespan, and their impact on human health. Currently, chronic exposure to harmful chemicals from air pollution and/or tobacco smoke, along with a suboptimal diet, remain leading causes for preventable mortality and morbidity worldwide. As a result, new analytical methods are needed to measure robust biomarkers of smoke exposure and food intake for improved risk assessment of clinical events. This thesis aims to develop high throughput methods to rapidly quantify urinary biomarkers of environmental smoke in high-risk occupations, and diverse global populations using multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS) technology. Chapter II outlines an inter-laboratory method comparison for the targeted analysis of urinary 1-hydroxypyrene (HP) when using gas chromatography-high resolution mass spectrometry (GC-HRMS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) on urine samples collected from firefighters. This work revealed the critical role of incomplete enzymatic deconjugation on method bias and underreporting of true smoke exposures. Chapter III introduces a high throughput MSI-CE-MS/MS method (< 3 min/sample) to directly analyze the intact glucuronide conjugate of HP (HP-G) in urine without complex pre-column enzyme deconjugation and derivatization procedures. Importantly, firefighters deployed under emergency conditions at the 2016 Fort McMurray wildfire had creatinine normalized HP-G concentrations below the biological exposure index, likely caused by delays in urine collection under emergency conditions, at early stages of firefighting. Chapter IV extends from targeted biomonitoring of occupational smoke exposure, towards elucidating the relative risk of tobacco smoking in an international cohort of participants (n=1000) from the Prospective Urban and Rural Epidemiological (PURE) study. Comprehensive analysis of nicotine metabolites in urine by MSI-CE-MS allowed for reliable determination of the total nicotine equivalent and nicotine metabolic ratio as robust indicators of recent tobacco smoke exposure and nicotine dependence, respectively. This method also offers a more accurate approach for biochemical verification of smoking status in large-scale epidemiological studies that are prone to social desirability and gender bias when relying on standardized questionnaires. Lastly, Chapter V employs a nontargeted metabolomics workflow using MSI-CE-MS to identify urinary metabolites that may serve as objective dietary biomarkers of food intake in participants across 14 countries from the PURE cohort. A panel of robust and generalizable metabolites were validated for biomonitoring of complex dietary exposures, that may further exacerbate the hazards of tobacco smoking. In summary, this thesis contributes high throughput analytical tools for characterizing the human urine exposome to better decipher the roles of smoke exposure, and suboptimal diet on chronic disease burden among diverse populations and regions worldwide.