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 孕妇，住在超级基金站点附近，可能接触到多环 从这些场所散发出的芳香族碳氢化合物（PAH）， 交付.早产需要新生儿接受辅助供氧 （高氧），这反过来又可能导致慢性肺病/支气管肺发育不良 （BPD）。我们假设产前多环芳烃暴露会加剧产后多环芳烃暴露的影响。 早产新生儿补充氧气。多环芳烃增强BPD的机制 婴儿不太了解。这个项目的核心假设是， 施用多环芳烃[即苯并[a]芘（BP），或苯并（a）芘（BP）的混合物， 苯并（B）荧蒽（BbF）和二苯并[a]蒽（DBA）]，其定义为 B2类致癌物，将不同程度地加剧肺损伤和肺泡 简化新生小鼠出生后高氧，这种影响将改变， 小鼠缺乏细胞色素P450（Cyp）1a 1或1a 2基因的机制， 遗传毒性和表观遗传机制的结合。我们还将测试假设， 出生前暴露于多环芳烃的婴儿比暴露于 更少或没有多环芳烃，暴露于修复的多环芳烃的人类肺细胞将表现出 毒性低于母体多环芳烃。为了验证这些假设，我们提出了以下具体建议： 目的：（1）.具体目标1。为了检验产前暴露野生型（WT）（C57 BL/6 J） 小鼠暴露于多环芳烃BP或多环芳烃混合物（BP + BbF + DBA）会导致肺损伤加重， 出生后高氧后肺泡简化，这种效应在缺乏该基因的小鼠中会改变 Cyp 1a 1、1a 2或1b 1。2.为了确定产前多环芳烃将改变 新生小鼠对高氧的易感性。3.为了验证母亲暴露于 多环芳烃（存在于超级基金网站）是在早产的风险更大，这些 婴儿比那些接触较少或没有接触的婴儿更容易患上BPD。 这些目标的实现可能导致新的预防/治疗策略， 早产儿的BPD，这可能是加强了母亲的多环芳烃，散发出 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.