Advisor(s)
Natalie Gassman
Committee Member(s)
Daniel Smith Jr
Erin Ahn
Robert Van Waardenburg
Vamsee Raju
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Pharmacology and Toxicology
Date of Award
1-6-2025
Abstract
Dihydroxyacetone (DHA) is a triose sugar found as an active ingredient in sunless tanning products (STPs) and by-product in electronic cigarettes (e-cigarettes). DHA can rapidly be absorbed into cells and tissues and incorporated into several metabolic pathways through its conversion into dihydroxyacetone phosphate (DHAP). Previous studies have shown that DHA promotes cytotoxicity and genotoxicity primarily characterized in skin models. The extent of these effects in systemic models is highly cell-type specific. Here we investigate the cytotoxic, genotoxic, and metabolic effects of DHA across several cell models. First, we investigated the effects of DHA in a metabolically active cell line, hepatocellular carcinoma HepG3. Millimolar doses of DHA were cytotoxic and suppressed glycolysis and oxidative phosphorylation pathways. Mitochondrial ROS increased lead to mitochondrial-specific injury. Nutrient sensing through mTOR was altered at both short and long time points. Overall, DHA promoted mitochondrial stress and altered nutrient signaling. Further cytotoxic and genotoxic characterization was continued in the HepG3 and investigated across a cell line panel of heart and lung models using the human bronchial epithelial cells BEAS-2B, lung carcinoma cells A549, cardiomyocyte Ac16. Low millimolar doses of DHA were cytotoxic and induced cell cycle arrest except in the Ac16. DNA adducts were induced 24 h after DHA exposure, primarily in oxidative and crosslink-type lesions. Metaphase spreads revealed significant increases in chromosomal aberrations with corresponding changes in ploidy in the BEAS-2B and HepG3. These data demonstrate DHA is a clastogen, inducing cell-specific genotoxicity and chromosomal instability. DHA exposures in rat cardiomyocytes H9c2 promoted dose-dependent effects. At a non-cytotoxic dose of 2 mM DHA, cells experienced an increase in cell survival and metabolic reprogramming through increases in acetyl Co-A (ACC) and fatty acid synthase (FASN) proteins leading to fuel utilization changes compared to the low cytotoxic dose of 1 mM DHA. Reductive stress at 2 mM dose was also characterized resulting in metabolic adaption and mitochondrial protection. This work suggests increased exogenous exposure to DHA through STPs or e-cigarette aerosol can impact cell function and survival. Prolonged physiological effects on tissues and organs may depend on their metabolic state and frequency of exposure to DHA sources.
ProQuest ID
Recommended Citation
Hernandez, Arlet, "Cytotoxic, Genotoxic, And Metabolic Effects Of Dihydroxyacetone In Heart, Liver And Lung Models" (2025). All ETDs from UAB. 7255.
https://digitalcommons.library.uab.edu/etd-collection/7255
