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：
10097623
负责人：
Natalie Rose Gassman
金额：
$ 34.65万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
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：
2021-01-01 至 2021-08-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10097623
关键词：
Acute Address Advanced Glycosylation End Products Affect Animals Antioxidants Blood Circulation Cardiovascular Models Cardiovascular system Cell Cycle Arrest Cell Death 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 Lead Link Liver Lung Measures Metabolic Metabolic Pathway Metabolic dysfunction Metabolic stress Metabolism Mitochondria Modeling Organelles Outcome Oxidation-Reduction Oxidative Stress 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 mitochondrial dysfunction oxidation 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，其燃烧都会产生微摩尔量的二羟基丙酮 (DHA) 每次抽吸时，电子液体中高达 40-55% 的丙二醇和甘油会转化为 DHA。香烟，使得 DHA 成为所有电子烟蒸气中的高含量成分，电子烟使用者吸入的电子烟蒸气中含有 DHA。每吸一口电子烟DHA都被批准作为免晒晒黑剂外用，但严重。人们对喷雾晒黑和现在电子烟的吸入暴露提出了担忧。已表明 DHA 具有基因毒性、细胞毒性，并会诱导皮肤和肾细胞中的线粒体功能障碍，但吸入 DHA 的影响目前尚不清楚。该提案的长期目标是。识别和验证 DHA 暴露引起的细胞和代谢应激标记物对电子烟使用者的组织进行检查，以了解反复吸入 DHA 的后果。该提案的目的是弥补现有研究中的差距，这些研究仅关注皮肤模型，通过检查 DHA 在急性和慢性剂量下对肺部和我们的中心假设是，接触 DHA 会改变代谢途径，促进心血管细胞的生长。氧化应激，破坏 Ca2+ 稳态，并导致线粒体功能障碍。其工作原理是，DHA 暴露于肺和心血管系统，可以使 DHA 直接吸收到细胞中。 DHA 引起的新陈代谢和线粒体功能的变化会损害整体细胞功能，导致疾病的三个具体目标将检验中心假设：1）DHA 融入代谢。 2) DHA 暴露会改变 NAD(P)H 池诱导氧化应激，3) DHA 暴露会改变胞质 Ca2+ 水平并破坏线粒体第一个目标是通过追踪 DHA 来检验 DHA 改变代谢途径的子假设。使用 DHA 同位素体进行代谢并识别代谢物不平衡的第二个目标是测试。第三个目标是过量的 DHA 会改变辅助因子库并诱发氧化应激。测试 DHA 改变 Ca2+ 信号传导以诱导线粒体功能障碍的子假设，此外这项研究具有创新性，因为它扩展了代谢应激和氧化还原失衡。除了 DHA 的基因毒性和细胞毒性特征之外，还可以测量 DHA 重新编程肺部的能力这项研究意义重大，因为电子烟使用者是长期使用者。接触DHA，会直接影响肺和心血管细胞的稳态，导致严重的后果细胞功能下降甚至诱导细胞死亡这项工作将建立 DHA 的重要标记。暴露，以便未来的流行病学工作能够将 DHA 暴露与疾病联系起来。