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

• 批准号: 10513737
• 负责人: Natalie Rose Gassman
• 金额: $ 31.49万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 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/10513737
• 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; lung microvascular endothelial cells; mitochondrial dysfunction; oxidation; stress reduction; sugar; vaper; vaping

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.

电子烟的每一次抽吸都会从燃烧中产生微摩尔量的二羟基丙酮（DHA）。 丙二醇和甘油。在每一口烟中，高达40-55%的电子液体含量从电子烟中转化为DHA。 电子烟，使DHA成为所有电子烟蒸汽中的高容量成分， 每吸一口电子烟DHA被批准作为一种无阳光晒黑剂外用，但严重 人们对通过喷雾晒黑和现在的电子烟使用吸入暴露提出了关切。我们 已经证明二十二碳六烯酸具有遗传毒性、细胞毒性，并会诱导皮肤和肾细胞的线粒体功能障碍， 但吸入暴露于DHA的影响目前尚不清楚。该提案的长期目标是 DHA暴露诱导的细胞和代谢应激标志物的鉴定和验证， 检查来自vapers的组织，以了解重复吸入暴露于DHA的后果。 该提案的目的是解决现有研究中的差距，这些研究仅关注皮肤 模型，通过检查急性和慢性剂量的DHA暴露对肺和 心血管细胞我们的中心假设是，暴露于DHA会改变代谢途径， 氧化应激，破坏Ca 2+稳态，并导致线粒体功能障碍。这样做的理由 研究发现，DHA暴露于肺和心血管系统，使细胞直接吸收DHA。 DHA诱导的代谢和线粒体功能的变化会损害整体细胞功能， 导致疾病。三个具体的目标将测试中心假设：1）DHA纳入代谢 途径改变糖酵解并诱导糖基化蛋白质损伤; 2）DHA暴露改变NAD（P）H库 诱导氧化应激，和3）DHA暴露改变胞质Ca 2+水平并破坏线粒体 功能第一个目标是检验DHA通过追踪DHA改变代谢途径的子假设 使用DHA的同位素体和鉴定代谢物不平衡来测定代谢。第二个目标将考验 亚假设过量的DHA改变辅因子库并诱导氧化应激。第三个目标将 测试DHA改变Ca 2+信号传导以诱导线粒体功能障碍的子假设， 引起代谢应激和氧化还原失衡。这项研究是创新的，因为它扩展了 除了DHA的遗传毒性和细胞毒性特征之外， 和心血管细胞的代谢。这项研究意义重大，因为电子烟使用者长期 暴露于DHA，这将直接影响肺和心血管细胞的稳态，并导致严重的 细胞功能下降甚至诱导细胞死亡。这项工作将建立DHA的基本标志物 今后的流行病学工作将DHA暴露与疾病联系起来。