Biomonitoring Exposures to Environmental and Dietary Carcinogens by Targeted and Untargeted Mass Spectrometry
2022-07
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Biomonitoring Exposures to Environmental and Dietary Carcinogens by Targeted and Untargeted Mass Spectrometry
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2022-07
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Humans are exposed to a wide variety of exogenous chemicals that may be implicated in DNA damage and cancer. Typical sources of carcinogen exposure include the diet, environment, and tobacco smoke. There is an epidemiological link between smoking cancer, as well as cooked and red meat consumption, and cancer. Despite extensive study, the chemicals responsible for carcinogenesis are unconfirmed. Specific and sensitive markers of DNA damage by discrete chemicals are needed confirm existing paradigms of carcinogenesis. Chapter 1 outlines the epidemiology and mechanisms by which chemicals from the diet and tobacco can lead to colorectal cancer and bladder cancer.
Tobacco smoking is a well-established cause of bladder cancer, as is occupational exposure to high levels of carcinogenic aromatic amines, such as 4-aminobiphenyl and 2-naphthylamine, which are also present in tobacco smoke at low levels. The levels of these compounds in tobacco smoke may be insufficient to bladder carcinogenesis. Other related compounds, such as alkylaniline derivatives, and structurally-related heterocyclic aromatic amines, are present at much higher levels in tobacco smoke and may be risk factors for bladder cancer. Chapter 2 outlines our methodologies to assay a nonpolar, basic fraction of tobacco smoke condensate, containing aromatic amines and heterocyclic aromatic amines, by liquid chromatography coupled to mass spectrometry (LC/MS). These compounds were measured by targeted and untargeted LC/MS as well as with the use of high field asymmetric waveform ion mobility spectrometry coupled to LC/MS to add an additional dimension of separation and reduce sample complexity.
Chapter 3 presents our original research in the development of highly sensitive, validated LC/MS methods to measure DNA adducts and abasic sites from cooked meat and tobacco carcinogens in colorectal tissue. These methods were developed using a rat animal model dosed with carcinogens that form DNA adducts associated with colorectal cancer based on previous epidemiological and mechanistic evidence. In Chapter 4, we applied this methodology to human colorectal DNA samples from colorectal cancer patient biopsy samples. We did not detect DNA adducts of exogenous carcinogens but did detect endogenously-formed DNA and abasic sites in these samples. We then contextualized these results within greater paradigms of colorectal cancer carcinogenesis.
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University of Minnesota Ph.D. dissertation. July 2022. Major: Medicinal Chemistry. Advisors: Robert Turesky, Lisa Peterson. 1 computer file (PDF); xiii, 179 pages.
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Konorev, Dmitri. (2022). Biomonitoring Exposures to Environmental and Dietary Carcinogens by Targeted and Untargeted Mass Spectrometry. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/258779.
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