Environmental Impact on Perinatal Lung Metabolism

描述(由申请人提供) 这项建议描述了代谢专家和环境卫生研究人员之间的紧密合作，他们将合作描述由使用(A)烟尘颗粒和(B)二手烟或环境烟草烟雾(ETS)的模型空气颗粒物引起的新生和年轻成年大鼠哮喘型呼吸功能障碍的发展。首先，研究人员将比较浓度为1毫克/立方米的烟尘和ETS对新生和年轻成年大鼠呼吸功能障碍的影响。这些影响将通过比较这些模型粒子的物理参数和颗粒物组成来进行关联。其次，研究人员将建立有机污染物从孕妇的肺部到血浆的初级代谢和运输途径。第三，研究人员将研究胎鼠、新生大鼠和幼年成年大鼠肺部的代谢异常。通过这种方法，将在颗粒物的类型、其有机成分、肺发育中代谢变化的时间以及呼吸道功能障碍的发生和进展之间建立联系。这种独特的生物医学设计与代谢组评估相结合，将检验如下假说：(A)围产期暴露于空气中有机物可导致幼年大鼠肺部成熟及细胞结构和功能的改变，(B)沉积在母亲S肺内的有机成分除可引起免疫反应的继发性改变或神经内分泌细胞释放支气管收缩介质外，还可直接导致肺部疾病的发生，如免疫反应的继发性改变，以及(C)呼吸功能障碍的发展与特征性代谢变化有关，并可与非特异性应激相关变化相区别。这些假说的测试将由尖端分析和代谢组学技术的组合在高通量水平上实现。主要的分析工具将是气相色谱(GC)XGC-飞行时间(TOF)质谱仪(MS)，结合自动峰注释，实现代谢变化的多元统计比较以及空气模型颗粒物的成分分析。数据的补充将包括全扫描液相色谱(LC)-离子陷阱质谱仪和无偏生物标志物检测，以及LC-三重四极杆MS/MS对肺组织中有机污染物所致代谢物的多目标表征。

DESCRIPTION (provided by applicant) This proposal describes a tightly unified effort between metabolomic specialists and environmental health researchers who will collaboratively characterize the development of asthmatic-type respiratory malfunctions in newborn and young adult rats, caused by model airborne particles using (a) soot particles and (b) secondhand smoke or environmental tobacco smoke (ETS). First, the investigators will compare the effects of soot and ETS at a concentration of 1 mg/m3 on the development of respiratory malfunctions in newborn and young adult rats. These effects will be correlated by comparing these model particles with respect to physical parameters and particulate matter composition. Second, the investigators will establish routes of primary metabolization and transport of organic pollutants from pregnant mothers' lungs to blood plasma. Third, the investigators will study metabolic aberrations in fetal, newborn and young adult rat's lungs. By this, links will be established between the type of particulate matter, its organic composition, the timing of metabolic changes in lung development, and the onset and progression of airways dysfunction. This unique combination of biomedical designs with metabolomic assessments will test the hypotheses that (a) perinatal exposure to organic constituents of airborne matter cause alterations in maturation as well as cellular structure and function in the lungs of young adult rats, (b) organic components deposited in the mother 's lung are directly involved in the development of pulmonary diseases such as airway hyper-reactivity, in addition to secondary alterations in immune response or release of bronchoconstrictive mediators by neuroendocrine cells, and (c) the development of respiratory malfunctions are associated with characteristic metabolic changes and can be distinguished from non-specific stress-related changes. Testing of these hypotheses will be enabled by a combination of cutting-edge analytical and metabolomic techniques at a high throughput level. Primary analytical tools will be gas chromatograph (GC)xGC-time of flight (TOF) mass spectrometry (MS) in combination with automatic peak annotation, enabling multivariate statistical comparisons of metabolic changes as well as compositional analysis of airborne model particles. Data will be complemented by full scan liquid chromatography (LC)-ion trap mass spectrometry and unbiased biomarker detection, and multi-target characterization of metabolites as a result of organic pollutants in lung tissues by LC-triple quadrupole MS/MS.