POLYCYCLIC AROMATIC HYDROCARBONS: ULTRASENSITIVE DETECTION, EARLY LIFE EXPOSURES-CLINICAL OUTCOMES (PRETERM BIRTHS, CHRONIC LUNG DISEASE, AND NEUROCOGNITIVE DEFICITS), PREVENTION AND REMEDIATION

多环芳烃：超灵敏检测、生命早期暴露-临床结果（早产、慢性肺病和神经认知缺陷）、预防和补救

• 批准号: 10382017
• 负责人: BHAGAVATULA MOORTHY
• 金额: $ 1.61万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-28 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382017
• 关键词: Acids; Adult; Adult Respiratory Distress Syndrome; Air; Alveolar; Animals; Aromatic Polycyclic Hydrocarbons; Attenuated; Benzo(a)pyrene; Bronchopulmonary Dysplasia; Chronic lung disease; Clinical; Collaborations; Combined Modality Therapy; Corn Oil; Detection; Dose; Epoxide hydrolase; Exposure to; Glycols; Goals; Hyperoxia; Laboratories; Linoleic Acids; Lung; Maternal Exposure; Measures; Mus; Neurocognitive Deficit; Newborn Infant; Oral; Outcome; Oxygen; Pregnancy; Premature Birth; Premature Infant; Prevention; Pulmonary Valve Insufficiency; Research Training; Risk; Testing; Urea; Visit; Wild Type Mouse; Woman; cytokine; early life exposure; environmental chemical; experience; exposed human population; externship; inhibitor/antagonist; leukotoxin; lung injury; novel marker; postnatal; pregnant; prenatal exposure; remediation; superfund site

Project Summary The major objective of this project is to provide research and training experience to Dr. Guobin Xia as a KC Donnelly Externship trainee. He will visit Dr. Bruce Hammock’s laboratory at UC Davis for his externship. Supplemental oxygen is frequently given to preterm infants and adults with pulmonary insufficiency, but hyperoxia contributes to lung injury, which in turn leads to bronchopulmonary dysplasia (BPD) in preterm infants and ARDS in adults. Environmental chemicals such as polycyclic aromatic hydrocarbons (PAHs), which are present in Superfund sites are known to increase the risk of preterm birth (PTB) in women living near Superfund sites. In this project, Dr. Guobin Xia, a postdoctoral associate in my laboratory, in collaboration with Dr. Bruce Hammock (UC Davis), will test the hypothesis that maternal exposure of wild type (WT) mice to the PAH benzo[a]pyrene (BP) on gestational days 16-19, followed by postnatal hyperoxia (80% oxygen) for 14 days will lead to exacerbation of alveolar simplification of newborn mice on postnatal day (PND) 15 , and that combined treatment of newborn mice with soluble epoxide hydrolase (sEH) inhibitor (sEHI) 1- trifluoromethoxyphenyl-3-(1-propionyl-4-yl)urea (TPPU) and oxygen will lead to protection against lung injury, compared to vehicle-treated mice. He hypothesizes that linoleic acid metabolites such as leukotoxin diols [dihydroxyoctadecenoic acids (DiHOMEs)] are elevated in mice exposed to hyperoxia, and this phenomenon is exacerbated in mice pretreated with BP, leading to increased lung injury. We postulate that mice treated with TPPU will show protection against lung injury. We propose the following Specific Aim: 1. To test the hypothesis that prenatal exposure of wild type (WT) (C57BL/6J) mice to the PAH BP will result in exacerbation of lung injury and alveolar simplification following postnatal hyperoxia, and this effect will be attenuated in newborn mice treated with sEH inhibitor, TPPU. Timed pregnant WT mice will be treated orally with corn oil (vehicle control) (CO) or BP (15 mg/kg), on gestational days 16-19, and newborns will be delivered at full term (day 21). These doses are relevant to human exposures, and to women living near Superfund sites. The newborns will be divided into two groups, with one group receiving TPPU only every other day by i.p for 14 days, and other group will be given the vehicle CO. These mice will be further divided in to 2 groups, one group to be maintained in room air, and the other exposed to hyperoxia (80% O2) for 14 days, and animals will be sacrificed on postnatal day (PND) 15 or PND 30. Lung injury and abnormal lung alveolarization will be assessed. We will also assess cytokine levels, levels of oxylipins, including leukotoxin diols, will measured in lungs by UPLC/MS-MS on PND15. If successful, leukotoxin diols have the potential of being developed as novel biomarkers of BPD.

项目摘要 该项目的主要目的是为Guobin Xia博士提供研究和培训经验 KC Donnelly实习生。他将访问布鲁斯·汉莫克（Bruce Hammock）博士在加州大学戴维斯分校的实验室，以进行实习。 经常将补充氧气给予早产儿和肺部功能不全的成年人，但 高氧导致肺损伤，进而导致早产的支气管肺发育不良（BPD） 成人的婴儿和ards。环境化学物质，例如多环芳烃（PAHS）， 众所周知，在超级基金站点中存在会增加居住在附近的妇女的早产风险（PTB） 超级基金网站。在这个项目中，我的实验室的博士后助理Guobin Xia博士与 布鲁斯·汉莫克（Bruce Hammock）博士（UC Davis）将检验以下假设。 PAH Benzo [a] pyrene（BP）在妊娠日16-19，其次是产后高氧（80％氧）的14 天数将导致新生小鼠在产后（PND）15的肺泡简化加剧，并且 新生小鼠与固体环氧化物水解酶（SEH）抑制剂（SEHI）的联合处理1- 三氟甲氧基-3-（1-丙基-4-基）尿素（TPPU）和氧气将导致防止肺损伤， 与车辆处理的小鼠相比。他假设亚油酸代谢物，例如白细胞毒素二醇 在暴露于高氧的小鼠中，[二羟基二十二烯酸（二核酸）]升高，这种现象是 在用BP预处理的小鼠中加剧，导致肺损伤增加。我们假设接受了治疗的小鼠 TPPU将显示防止肺部受伤。我们提出以下特定目标：1。测试 假设野生型（WT）（C57BL/6J）小鼠对PAH BP的暴露会导致加剧 产后高氧后的肺损伤和肺泡简化，这种作用将减弱 用SEH抑制剂TPPU处理的新生小鼠。定时怀孕的WT小鼠将用玉米油口服治疗 （车辆控制）（CO）或BP（15 mg/kg），在妊娠日16-19天，新生儿将在全学期分娩 （第21天）。这些剂量与人类的暴露以及居住在超级基金遗址附近的妇女有关。 新生儿将分为两组，其中一组仅每隔一天由I.P收到TPPU 14 几天和其他组将被授予车辆公司。这些小鼠将进一步分为2组，一个 要在房间空气中维持的组，另一组暴露于高氧（80％O2）14天，动物将 在产后日（PND）15或PND 30处处死。肺损伤和异常肺肺泡化将为 评估。我们还将评估细胞因子水平，催产素的水平，包括白细胞毒素二醇，将在 PND15上的UPLC/MS-MS肺部。如果成功，白细胞毒素二醇有可能被开发为 BPD的新型生物标志物。