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

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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.