Integrated risk assessment and molecular characterization of pulmonary response to e-cigarette exposure

电子烟暴露肺部反应的综合风险评估和分子表征

• 批准号: 10244990
• 负责人: Vladimir B Mikheev
• 金额: $ 55.58万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244990
• 关键词: Aerosols; Aldehydes; Animal Model; Atmosphere; Biological; Cells; Chemicals; Clinical; Complement; Complex Mixtures; Deposition; Devices; Disease; Dose; Electronic cigarette; Event; Exposure to; Flavoring; Functional disorder; Generations; Glycerol; Goals; Hazard Assessment; Heating; High temperature of physical object; Human; Individual; Inflammation; Inflammatory Response; Inhalation; Inhalation Toxicology; Liquid substance; Lung; Measures; Mediating; Metals; Methods; Modification; Molecular; Monitor; Mus; Nicotine; Nitrogen Dioxide; Oxidation-Reduction; Oxidative Stress; Oxygen; Pattern; Perception; Physiological; Post-Translational Protein Processing; Process; Propylene Glycols; Proteins; Proteome; Proteomics; Relative Risks; Research; Respiratory System; Risk Assessment; SKIL gene; Sampling; Scientist; Site; Structure of parenchyma of lung; Technology; Temperature; Time; Tissues; Toxic effect; Translating; Translations; Vegetables; Water; aerosolized; base; cigarette smoke; cigarette smoking; comparative; dosimetry; e-cigarette aerosols; electronic liquid; hazard; insight; multidisciplinary; nanoparticle; novel; oxidation; pharmacokinetic model; physiologically based pharmacokinetics; predicting response; respiratory; response; toxicant; translation to humans; vapor; volatile organic compound

PROJECT ABSTRACT E-cigarette (e-cig) aerosol/vapor is a complex mixture of the original components of the e-liquid (propylene glycol (PG), vegetable glycerol (VG), nicotine, water, and flavoring additives), and of other constituents (such as aldehydes, metals, nanoparticles, and some unknown compounds) produced by chemical transformation of the original components exposed to the electrically heated metal wire in the presence of oxygen. Emerging research is beginning to challenge the “relatively safe” perception of e-cigarettes. Recent studies suggest e-cig aerosol/vapor provokes an inflammatory response and oxidative stress (reminiscent of cigarette smoke where oxidative stress and inflammation are among the first clinically defined events associated with toxicity and disease due to cigarette smoking) however details of the underlying molecular mechanisms remain unclear. Furthermore the contributions that specific e-liquid constituents have in mediating them as well as the impact of oxidation products of e-liquid constituents generated by the e-cigarette heating process, are poorly understood. Focusing on oxidative stress and inflammation as intermediate measures of biological responses predictive of tissue dysfunction leading to disease initiation we will assess the hazard potential of e-liquid main components (PG, VG, nicotine, and flavorings). We hypothesize that individual components of e-liquid produce distinct signatures of early oxidative/nitrative damage in cells and tissue. Our objectives are to elucidate the signatures of reversible and irreversible oxidative modifications induced by e-cig aerosol and use them to evaluate the relative hazards of different e-liquid constituents in conjunction with computational fluid dynamic- physiologically-based pharmacokinetic (CFD/PBPK) models for comparative respiratory dosimetry. Most commonly used measures of cell redox state (i.e., GSH content) provide little insight into the types or sites of damage induced critical for a mechanistic understanding. Recent advances in quantitative redox proteomics at PNNL make it feasible to identify these modifications and determine their site-specific occupancies at a proteome-wide scale. The Research Grade E-cigarette (REC) device developed at Battelle provides a unique capability to generate and characterize aerosol/vapor from individual e-liquid components with or without the use of a heated coil, allowing effects of both the major e-liquid components as well as potential toxicants that result from (coil) heating of the e-liquid in the presence of oxygen to be identified and quantified. Using these novel enabling technologies, we will define what compounds or aerosol size fraction are most harmful and how they contribute to the effects of inhalation of e-cig aerosol and individual aerosolized e-liquid components on pulmonary response. We will accomplish our goal through the following aims: (1) Characterize aerosol/vapor of e-cigarette generated at moderate and high heating temperature (2) Molecularly characterize pulmonary response to e-cig aerosol/vapor and e-cig aerosol/vapor components exposure in mice (3) Predict regional (airway) deposition and site-specific tissue dose and translation to humans using CFD/PBPK models.

项目摘要 电子烟（e-cig）气溶胶/蒸汽是电子液体（丙烯）原始成分的复杂混合物 乙二醇（PG）、植物甘油（VG）、尼古丁、水和调味添加剂）和其它成分（例如 如醛、金属、纳米颗粒和一些未知化合物）， 原始部件在氧气存在下暴露于电加热的金属丝。新兴 研究开始挑战电子烟“相对安全”的看法。最近的研究表明电子烟 气溶胶/蒸汽引起炎症反应和氧化应激（让人想起香烟烟雾， 氧化应激和炎症是与毒性相关的最早临床定义的事件， 吸烟引起的疾病），然而，潜在的分子机制的细节仍然不清楚。 此外，特定的电子液体成分在介导它们方面的贡献以及电子液体成分的影响。 对由电子烟加热过程产生的电子液体成分的氧化产物知之甚少。 关注氧化应激和炎症作为预测生物反应的中间指标 我们将评估电子烟液主要成分的潜在危害 (PG VG、尼古丁和调味剂）。我们假设电子液体的各个成分产生不同的 细胞和组织中早期氧化/硝化损伤的特征。我们的目标是阐明 可逆和不可逆的氧化修饰诱导的电子烟气雾剂，并使用它们来评估 不同电子液体成分与计算流体动力学结合的相对危害- 基于生理学的药代动力学（CFD/PBPK）模型，用于比较呼吸剂量测定。最 通常使用的电池氧化还原状态的测量（即，GSH含量）提供的类型或网站的洞察力很少 损伤引起的关键的机械的理解。定量氧化还原蛋白质组学研究进展 PNNL使识别这些修饰并确定它们的位点特异性占位性成为可能， 全蛋白质组规模。在巴特尔开发的研究级电子烟（REC）设备提供了一个独特的 在具有或不具有所述气溶胶/蒸气的情况下从单独的电子液体组分生成和表征气溶胶/蒸气的能力 使用加热的线圈，允许主要的电子液体成分以及潜在的有毒物质的影响， 由在待识别和量化的氧气存在下电子液体的（线圈）加热产生。使用这些 新的使能技术，我们将确定什么化合物或气溶胶大小的部分是最有害的，以及如何 它们有助于吸入e-CIG气雾剂和单独的雾化电子液体组分对 肺反应我们将通过以下目标实现我们的目标：（1）表征气溶胶/蒸汽的 中高温加热温度下产生的电子烟（2）肺部分子特征 小鼠对电子烟气溶胶/蒸汽和电子烟气溶胶/蒸汽组分暴露的反应（3） （气道）沉积和位点特异性组织剂量以及使用CFD/PBPK模型对人类的转化。

项目成果

Analysis of the Aerosol Generated from Tetrahydrocannabinol, Vitamin E Acetate, and Their Mixtures.

• DOI: 10.3390/toxics10020088
• 发表时间: 2022-02-15
• 期刊: Toxics
• 影响因子: 4.6
• 作者: Mikheev VB;Ivanov A
• 通讯作者: Ivanov A

Mass spectrometry-based direct detection of multiple types of protein thiol modifications in pancreatic beta cells under endoplasmic reticulum stress.

• DOI: 10.1016/j.redox.2021.102111
• 发表时间: 2021-10
• 期刊: Redox biology
• 影响因子: 11.4
• 作者: Li X;Day NJ;Feng S;Gaffrey MJ;Lin TD;Paurus VL;Monroe ME;Moore RJ;Yang B;Xian M;Qian WJ
• 通讯作者: Qian WJ

Stoichiometric Thiol Redox Proteomics for Quantifying Cellular Responses to Perturbations.

• DOI: 10.3390/antiox10030499
• 发表时间: 2021-03-23
• 期刊: Antioxidants (Basel, Switzerland)
• 作者: Day NJ;Gaffrey MJ;Qian WJ
• 通讯作者: Qian WJ

Resin-Assisted Capture Coupled with Isobaric Tandem Mass Tag Labeling for Multiplexed Quantification of Protein Thiol Oxidation.

• DOI: 10.3791/62671
• 发表时间: 2021-06-21
• 期刊: Journal of visualized experiments : JoVE
• 作者: Gaffrey MJ;Day NJ;Li X;Qian WJ
• 通讯作者: Qian WJ

Defining the S-Glutathionylation Proteome by Biochemical and Mass Spectrometric Approaches.

• DOI: 10.3390/antiox11112272
• 发表时间: 2022-11-17
• 期刊: ANTIOXIDANTS
• 影响因子: 7
• 作者: Li, Xiaolu;Zhang, Tong;Day, Nicholas J. J.;Feng, Song;Gaffrey, Matthew J. J.;Qian, Wei-Jun
• 通讯作者: Qian, Wei-Jun