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Dihydroxyacetone exposure induces metabolic reprogramming and mitochondrial dysfunction

二羟基丙酮暴露诱导代谢重编程和线粒体功能障碍

基本信息

批准号：
10322107
负责人：
Natalie Rose Gassman
金额：
$ 30.36万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-19 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10322107
关键词：
Acute Address Advanced Glycosylation End Products Affect Animals Antioxidants Blood Circulation Cardiovascular Models Cardiovascular system Cell Cycle Arrest Cell Death Cell Death Induction Cell Line Cell model Cell physiology Cells Cellular Stress Chronic DNA Damage DNA Repair Dihydroxyacetone Dihydroxyacetone Phosphate Disease Dose Electronic cigarette Endothelial Cells Epidemiology Epithelial Cells Equilibrium Exposure to Free Radicals Future Genetic Transcription Glycerol Glycolysis Goals Homeostasis Human Inhalation Inhalation Exposure Ion Channel Isotope Labeling Kidney Link Liver Lung Measures Metabolic Metabolic Pathway Metabolic dysfunction Metabolic stress Metabolism Mitochondria Modeling Organelles Outcome Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Permeability Propylene Glycols Protein Glycosylation Proteins Public Health Reactive Oxygen Species Research Schedule Signal Transduction Skin Skin tanning Testing Time Tissues Translating Umbilical vein Work absorption biomarker validation cofactor cytotoxic e-cigarette aerosols electronic cigarette use electronic cigarette user electronic liquid genotoxicity innovation kidney cell lung microvascular endothelial cells meter mitochondrial dysfunction oxidation programs stress reduction sugar vaper vaping

项目摘要

Each puff of an e-cigarette generates micromolar amounts dihydroxyacetone (DHA) from the combustion of propylene glycol and glycerol. Up to 40-55% of e-liquid content is converted to DHA in each puff from an e- cigarette, making DHA a high-volume component found in all e-cigarette vapors, which the vaper inhales with each puff of the e-cigarette. DHA is approved for external use as a sunless tanning agent, but serious concerns have been raised about inhalation exposures through spray tanning and now e-cigarette use. We have shown that DHA is genotoxic, cytotoxic, and induces mitochondrial dysfunction in skin and kidney cells, but the effects of inhalation exposures to DHA are currently unknown. The long-term goal of the proposal is the identification and validation of markers for cellular and metabolic stress induced by DHA exposure that can be examined in tissues from vapers to understand the consequences of repeated inhalation exposures to DHA. The objective of this proposal is to address the gap in existing studies, which have only focused on skin models, by examining the exposure effects of DHA at both acute and chronic doses in pulmonary and cardiovascular cells. Our central hypothesis is that exposure to DHA alters metabolic pathways, promotes oxidative stress, disrupts Ca2+ homeostasis, and leads to mitochondrial dysfunction. The rationale for this work is that DHA exposures to the lung and cardiovascular system allow direct absorption of DHA into cells. DHA-induced changes in metabolism and mitochondrial function would compromise overall cellular function, leading to disease. Three specific aims will test the central hypothesis: 1) DHA incorporation into metabolic pathways alters glycolysis and induces glycosylation protein damage; 2) DHA exposure alters NAD(P)H pools inducing oxidative stress, and 3) DHA exposure alters cytosolic Ca2+ levels and disrupts mitochondrial function. The first aim will test the sub-hypothesis that DHA alters metabolic pathways by tracing DHA metabolism using isotopologues of DHA and identifying metabolite disequilibrium. The second aim will test the sub-hypothesis that an excess of DHA changes cofactor pools and induces oxidative stress. The third aim will test the sub-hypothesis that DHA alters Ca2+ signaling to induce mitochondrial dysfunction, in addition to causing metabolic stress and oxidation-reduction imbalance. The study is innovative because it extends beyond the genotoxic and cytotoxic characterization of DHA to measure DHA’s ability to reprogram pulmonary and cardiovascular cells metabolically. The research is significant because e-cigarette users are chronically exposed to DHA, which will directly impact pulmonary and cardiovascular cell homeostasis and cause severe declines in cellular function or even induce cell death. This work will establish essential markers for DHA exposure to allow future epidemiological work to associate DHA exposure to disease.

每吸一口电子烟会产生微摩尔量的二羟基丙酮（DHA）