Proj3:Role of cytochrome P450 (CYP)1A/1B1 enzymes in the potentiation of neonatal lung injury in newbron mice exposed prenatally to PHs, and increased risk of premature infants to chronic lung disease

项目摘要 居住在超级基金地点附近的孕妇，她们可能接触到多环 从这些部位发出的芳香烃(PAHs)早产的风险更高 送货。早产要求新生儿接受补充氧气。 (高氧)，这又可能导致慢性肺部疾病/支气管肺发育不良 (BPD)。我们假设，出生前接触多环芳烃将加剧出生后的影响 早产儿的补充氧气。多环芳烃增强BPD的机制 婴儿并没有被很好地理解。这个项目的中心假设是产前 给予多环芳烃[即苯并[a]芘(BP)，或苯并(A)芘(BP)的混合物， 苯并(B)荧菲(BBF)和二苯并[a]菲(DBA)]，它们被定义为 美国环保局认定的B2类致癌物，会不同程度地加重肺损伤和肺泡 在新生小鼠出生后高氧后的简化，这一效应将在 缺乏细胞色素P450(Cyp)1a1或1a2基因的小鼠 遗传毒性和表观遗传机制的结合。我们还将测试以下假设： 产前暴露于多环芳烃的婴儿患BPD的风险高于暴露于PAHs的婴儿 较少或没有多环芳烃，暴露于修复的多环芳烃的人肺细胞将表现出 毒性低于母体多环芳烃。为了检验这些假设，我们提出了以下具体假设 目标：(1)。具体目的1.检验产前暴露野生型(WT)(C57BL/6J)的假设 小鼠给多环芳烃、BP或多环芳烃的混合物(BP+BBF+DBA)可导致肺损伤加重和 出生后高氧后肺泡简化，这种影响将在缺乏该基因的小鼠中改变 对于Cyp1a1、1a2或1b1。2.确定产前多环芳烃将通过哪些机制改变 新生小鼠对高氧的易感性。3.为了检验母亲暴露在 PAH(存在于超级基金网站)早产的风险更大，而且这些 与接触较少或不接触BPD的婴儿相比，婴儿患BPD的易感性增加。 这些目标的实现可能导致新的预防/治疗战略 早产儿的BPD，这可能是由于母体散发的多环芳烃 超级基金网站。

Project Summary Pregnant women, living in the vicinity of superfund sites, who may be exposed to polycyclic aromatic hydrocarbons (PAHs) that emanate from these sites, are at a higher risk for preterm delivery. Preterm delivery requires the neonate to be subjected to supplemental oxygen (hyperoxia), and this in turn could lead to chronic lung disease/ bronchopulmonary dysplasia (BPD). We hypothesize that prenatal PAH exposure will exacerbate the effects of postnatal supplemental oxygen in preterm neonates. The mechanisms by which PAHs potentiate BPD in infants are not well understood. The central hypothesis of this project is that prenatal administration of PAHs [i.e. benzo[a]pyrene (BP), or a mixture of benzo(a)pyrene (BP), benzo(b)fluoranthrene (BbF), and dibenz[a]anthracene (DBA)], which are which are defined as class B2 carcinogens by USEPA, will differentially exacerbate lung injury and alveolar simplification in neonatal mice following postnatal hyperoxia, and that this effect will be altered in mice lacking the gene for cytochrome P450 (Cyp)1a1 or 1a2 genes by mechanisms entailing a combination of genotoxic and epigenetic mechanisms. We will also test the hypothesis that the infants exposed prenatally to PAHs have a greater risk of developing BPD than those exposed to lesser or no PAHs, and that human pulmonary cells exposed to remediated PAHs will exhibit lesser toxicity than parent PAHs. In order to test these hypotheses, we propose the following Specific Aims: (1). Specific Aim 1. To test the hypothesis that prenatal exposure of wild type (WT) (C57BL/6J) mice to the PAH BP or a mixture of PAHs (BP + BbF + DBA) will result in exacerbation of lung injury and alveolar simplification following postnatal hyperoxia, and this effect will be altered in mice lacking the gene for Cyp1a1, 1a2 or 1b1. 2. To determine the mechanisms by which prenatal PAHs will alter the susceptibility of neonatal mice to hyperoxia. 3. To test the hypothesis that mothers exposed to PAHs (that are present in superfund sites) are at a greater risk for preterm delivery, and that these infants will show increased susceptibility to develop BPD than those with lesser or no exposure. Accomplishments of these aims could lead to novel strategies for the prevention/treatment in premature infants of BPD, which is probably potentiated by maternal PAHs that emanate from Superfund sites.