The chemical exposome encompasses the sum of all exposures during an individual’s lifetime. This group of compounds, when combined with genetic traits, determine chronic disease, thus, to fully understand human health issues, it is imperative to improve exposome measurements to match genomic technologies. My dissertation focuses on expanding the coverage of the chemical exposome and developing tools and techniques that will increase the reliability of untargeted mass spectrometry based studies.
In Chapter 1, I address the many challenges faced when trying to measure all compounds contained within the chemical exposome. Exposome compounds cover a large range of biological concentration, many different structural classes, and are extensively modified in the body via detoxification pathways. I explore the potential strategies researchers can employ to address these difficulties, from instrumental acquisition and sample preparation, to compound identification and other data processing tools.
In Chapter 2, I discuss the utilization of hydrogen-deuterium exchange (HDX) for identifying unknown compounds in metabolomics and exposomics studies. HDX is a method by which all of the acidic protons in a compound are exchanged with deuterium prior to mass spectrometric analysis with the goal of using the resulting mass shift to illuminate potential substructures. In this work, we compared the efficacy of different deuterium incorporation methods, explored the filtering potential of this method on 253 test compounds and large chemical databases, and identified 101 compounds in mouse mammary tumors. The results of this study show that HDX can alleviate researchers’ reliance on mass spectral databases for identifying compounds in biological samples.
Chapter 3 focuses on an untargeted exposomics method that was developed to measure chemical exposures that influence female reproductive health. In the human body, xenobiotic compounds are transformed through metabolism to increase polarity and allow for excretion in the urine. These transformations commonly consist of phase I hydroxylation reactions mediated by CYP450 enzymes and phase II conjugations mediated by transferases. In the urine, the most common conjugate forms are glucuronides and sulfates. Our urinary exposomics method takes advantage of this knowledge. By using B-glucuronidase/aryl sulfatase, we can cleave the phase II conjugates into their phase I forms, and easily extract these less polar analytes from the polar urinary matrix. This method was used to measure exposure compounds in 50 women from Orange County, CA at three different time points. The compound measurements were then used to build linear mixed effects models to predict the chemical variables that influence hormonally derived endocrine endpoints. Models were built for menstrual cycle length, cycle peak luteinizing hormone, follicular estrone-1,3-glucuronide, and estrone-1,3-glucuronide slope. Chemical variables that had not previously been associated with reproductive function were identified for each of these endocrine endpoints. These models illuminate novel chemical exposures for future causative studies on reproductive health.
|Commitee:||Young, Thomas, Nicklisch, Sascha C.T.|
|School:||University of California, Davis|
|Department:||Agricultural and Environmental Chemistry|
|School Location:||United States -- California|
|Source:||DAI-B 82/5(E), Dissertation Abstracts International|
|Subjects:||Environmental science, Biochemistry, Analytical chemistry, Genetics, Public health|
|Keywords:||Compound identification, Exposomics, Hydrogen-deuterium exchange, Metabolomics, Untargeted mass Spectrometry, Reproductive health, Genetic traits, Genomic technologies|
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