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.

项目概要 该项目的主要目标是为夏国斌博士提供研究和培训经验 KC Donnelly 实习生。他将参观布鲁斯·哈莫克博士在加州大学戴维斯分校的实验室进行实习。 经常给患有肺功能不全的早产儿和成人补充氧气，但是 高氧血症会导致肺损伤，进而导致早产儿支气管肺发育不良 (BPD) 婴儿和成人 ARDS。环境化学品，如多环芳烃 (PAH)、 众所周知，超级基金网站上存在的这些物质会增加居住在附近的妇女早产 (PTB) 的风险。 超级基金网站。在这个项目中，我实验室的博士后夏国斌博士与 Bruce Hammock 博士（加州大学戴维斯分校）将测试以下假设：野生型 (WT) 小鼠的母亲暴露于 妊娠第 16-19 天进行多环芳烃苯并[a]芘 (BP) 检测，随后进行产后高氧血症（80% 氧气）持续 14 天 天将导致新生小鼠在出生后第15天（PND）15的肺泡简化加剧，并且 可溶性环氧化物水解酶 (sEH) 抑制剂 (sEHI) 1- 联合治疗新生小鼠 三氟甲氧基苯基-3-(1-丙酰基-4-基)脲 (TPPU) 和氧气可防止肺损伤， 与媒介物处理的小鼠相比。他假设亚油酸代谢物如白细胞毒素二醇 [二羟基十八碳烯酸 (DiHOMEs)] 在暴露于高氧的小鼠中升高，这种现象是 在接受 BP 预处理的小鼠中，这种情况会加剧，导致肺损伤加剧。我们假设用以下药物治疗的小鼠 TPPU 将显示出针对肺损伤的保护作用。我们提出以下具体目标： 1. 测试 假设野生型 (WT) (C57BL/6J) 小鼠产前暴露于 PAH BP 将导致病情恶化 出生后高氧血症导致肺损伤和肺泡简化，这种影响在出生后会减弱 用 sEH 抑制剂 TPPU 治疗的新生小鼠。定时怀孕WT小鼠将用玉米油口服治疗 （载体对照）(CO) 或 BP (15 mg/kg)，妊娠第 16-19 天，新生儿将足月分娩 （第 21 天）。这些剂量与人类暴露以及居住在超级基金地点附近的妇女有关。这 新生儿将被分为两组，其中一组仅每隔一天通过腹膜内注射接受 TPPU，共 14 次 天，其他组将被给予载体 CO。这些小鼠将被进一步分为 2 组，一组 一组保持在室内空气中，另一组暴露于高氧（80% O2）14天，动物将 在出生后 (PND) 15 或 PND 30 处死。肺损伤和肺泡化异常将被 评估。我们还将评估细胞因子水平、氧脂质水平，包括白细胞毒素二醇，将在 在 PND15 上通过 UPLC/MS-MS 检测肺部。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。