Date of Award

1-1-2019

Document Type

Open Access Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Caroline Johnson

Abstract

1,4-dioxane is an environmental toxin found in drinking water that is highly associated with liver cancer. The interactions between environmental toxins and the human body can result in the development of tumorigenesis, it can also result in changes to metabolism and thus metabolites that circulate within the body. Some of these metabolites can be procarcinogenic, or can reflect changes to host processes that control metabolism. Stool contains copious information on metabolism that can provide an overview of the well-being of our body, and metabolites in the stool can provide information regarding the pathogenesis of disease and the toxicokinetics of toxicants. Particularly, bile acids, products of cholesterol that are metabolized initially in the liver, and then further processed in the intestine by microbial enzymes can be measured in the stool. In this study, we exposed mice to 5000 mg/L 1,4-dioxane in their drinking water and collected their stool at one week. Targeted metabolomics was performed to analyze bile acid concentrations, while untargeted metabolomics was performed as a discovery approach to identify novel metabolites of 1,4-dioxane exposure. Both approaches were performed using UHPLC coupled with Q-TOF mass spectrometry. Targeted bile acids metabolomics was analyzed with multiple comparison t-test with Benjamini, Krieger and Yekutieli correction. Untargeted multivariate analysis was analyzed with unsupervised principal component analysis and further analyzed with supervised partial least-squares discriminant analysis (PLS-DA) and orthogonal projection to latent structure analysis (OPLS-DA). The identified features and metabolites were further analyzed with multiple comparison t-test with Benjamini, Krieger and Yekutieli correction. In our study, a trend of bile acid biosynthesis dysregulation was observed, suggesting upregulation of lithocholic acid (LCA) and hyodeoxycholic acid (HDCA) in the exposed mice. Vitamin E, threonine, and citrulline were also found to be down regulated, suggesting disturbances in metabolism associated with antioxidant activity, urea cycle and coenzyme A synthesis. Overall, exposure to 1,4-dioxane dysregulated bile acid metabolism and potentially induced oxidative damage that is greatly associated with liver cancer. This increased understanding of the environment–host interactions brings about significant opportunities to create new therapeutic and surveillance approaches to promote human health and prevent disease.

Comments

This is an Open Access Thesis.

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