Theses and Dissertations

Date of Award

8-1-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Human Genetics

First Advisor

Jacob Galan

Second Advisor

John Blangero

Third Advisor

Sarah Williams-Blangero

Abstract

Nonalcoholic fatty liver disease (NAFLD) disproportionately affects Hispanic populations and arises through interactions between genetic susceptibility and environmental exposures. Aflatoxins are potent hepatotoxic and carcinogenic mycotoxins, but their contribution to metabolic liver disease remains poorly understood. This dissertation investigated the role of aflatoxin exposure in NAFLD through an integrated approach combining multiomics, analytical chemistry, epidemiology, and genetics.

The first two objectives examined the molecular mechanisms of aflatoxin B1 (AFB1) toxicity using integrated proteomics, phosphoproteomics, and metabolomics. HepG2 cells were exposed to 1 or 10 µM AFB1 for 1 or 24 h and analyzed using quantitative mass spectrometry. Differential expression, pathway enrichment, protein–protein interaction networks, kinase and regulator activity inference, and metabolite enrichment revealed extensive dose- and timedependent molecular remodeling. Integration across omics layers identified coordinated disruption of oxidative stress responses, xenobiotic metabolism, mitochondrial function, fatty acid βoxidation, lipid and energy metabolism, DNA damage signaling, cell-cycle regulation, proteostasis, and inflammatory pathways. These findings characterize molecular events linking AFB1 exposure to hepatic metabolic dysfunction.

The third objective was to develop and validate a rapid and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay for simultaneously quantifying AFB1, AFB2, AFG1, AFG2, and the chronic-exposure biomarker AFB1–lysine (AFB1–Lys) in human plasma. The assay demonstrated strong linearity, sensitivity, accuracy, precision, and recovery, providing a reliable platform for high-throughput biomonitoring.

The final objective applied LC–MS/MS biomonitoring to South Texas Hispanic familybased cohorts. Plasma analyses demonstrated widespread aflatoxin exposure. In the South Texas Family Study, AFB1–Lys was positively associated with hepatic steatosis, supporting cumulative AFB1 bioactivation as a potential environmental risk factor for NAFLD. Significant heritability estimates indicated that interindividual variation in aflatoxin internal dose is partly influenced by inherited differences in metabolism, detoxification, and disposition. Collectively, this work establishes a translational framework connecting AFB1-induced molecular disruption, plasma exposure biomarkers, host genetics, and fatty liver risk. These findings advance understanding of aflatoxin-related metabolic liver injury and provide a foundation for identifying susceptible individuals and reducing environmentally mediated liver disease in high-risk populations.

Comments

Copyright 2026 Marco Antonio Arriaga. All Rights Reserved. https://proquest.com/docview/3408953640

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