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

项目摘要 该项目的主要目的是为夏国斌博士提供研究和培训经验， KC唐纳利实习生。他将访问布鲁斯汉莫克博士在加州大学戴维斯分校的实验室为他的外部。 经常给早产儿和肺功能不全的成人补充氧气， 高氧可导致肺损伤，进而导致早产儿支气管肺发育不良（BPD） 婴儿和成人的ARDS。环境化学品，如多环芳烃（PAH）， 已知存在于超级基金地点的药物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，夏国斌博士，我实验室的博士后助理，与 博士布鲁斯吊床（加州大学戴维斯分校），将测试野生型（WT）小鼠的母体暴露于 妊娠第16-19天PAH苯并[a]芘（BP），随后出生后高氧（80%氧气）14 天将导致出生后第15天（PND）新生小鼠肺泡简化加重， 用可溶性环氧化物水解酶（sEH）抑制剂（sEHI）1- 三氟甲氧基苯基-3-（1-丙酰基-4-基）脲（TPPU）和氧将导致对肺损伤的保护， 与溶剂处理的小鼠相比。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（DiHOME）]在暴露于高氧的小鼠中升高，并且这种现象是 在用BP预处理的小鼠中加剧，导致肺损伤增加。我们假设， TPPU将显示对肺损伤的保护。我们提出以下具体目标：1。测试 假设野生型（WT）（C57 BL/6 J）小鼠产前暴露于PAH BP将导致病情加重 肺损伤和肺泡简化出生后高氧，这种影响将减弱， 用sEH抑制剂TPPU处理的新生小鼠。定时妊娠WT小鼠将接受玉米油经口给药 （载体对照）（CO）或BP（15 mg/kg），并在足月时分娩新生儿 (day 21）。这些剂量与人类接触和生活在超级基金场址附近的妇女有关。的 将新生儿分为两组，一组仅用TPPU，隔日一次，腹腔注射，共14 将这些小鼠进一步分成2组，一组为对照组，另一组为载体CO。 另一组暴露于高氧（80%O2）环境中14天， 在出生后第15天（PND）或PND 30天处死。肺损伤和异常肺泡化将是 评估。我们还将评估细胞因子水平，包括白细胞毒素二醇在内的氧化脂质水平， PND 15时通过UPLC/MS-MS测定肺。如果成功，白细胞毒素二醇有可能被开发为 BPD的新生物标志物。

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.