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

Proj3：细胞色素 P450 (CYP)1A/1B1 酶在产前暴露于 PH 的新生小鼠中增强新生儿肺损伤中的作用，并增加早产儿患慢性肺病的风险

• 批准号: 10116394
• 负责人: BHAGAVATULA MOORTHY
• 金额: $ 36.09万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-28 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10116394
• 关键词: A549; Age; Air; Alveolar; Animals; Anthracenes; Aromatic Hydrocarbons; Aromatic Polycyclic Hydrocarbons; Aspirate substance; Benzo(a)pyrene; Biological Assay; Birth Rate; Bronchopulmonary Dysplasia; CYP11A1 gene; CYP1A1 gene; Carcinogens; Cells; Chemosensitization; Chronic lung disease; Clinical; Collaborations; Corn Oil; Cytochrome P450; DNA; DNA Adducts; DNA lesion; Data; Detection; Dose; EZH2 gene; Environmental Health; Enzymes; Epigenetic Process; Etiology; Exhibits; Exposure to; Genes; Human; Hyperoxia; In Vitro; Infant; Inosine Diphosphate; Lead; Life; Lung; Mass Fragmentography; Melissa; Methylation; Molecular; Morbidity - disease rate; Mothers; Mus; Neurocognitive Deficit; Newborn Infant; Oral; Outcome; Oxygen; Parents; Pathway interactions; Placenta; Precision Health; Predisposition; Pregnancy; Pregnant Women; Premature Birth; Premature Infant; Prevention; Prevention strategy; Pyrenes; RUNX3 gene; Research Support; Retrospective Studies; Risk; Role; Site; Testing; Toxic effect; Toxicity Attenuation; Umbilical Cord Blood; Walkers; Weaning; Wild Type Mouse; Woman; early life exposure; epigenomics; experimental study; exposed human population; genotoxicity; high risk; in vivo; insight; lung injury; neonatal lung injury; neonatal mice; neonate; neurobehavioral; neurobehavioral test; novel strategies; postnatal; pregnant; premature; prenatal; prenatal exposure; preterm newborn; prevent; professor; remediation; sample archive; superfund site; supplemental oxygen; transcriptome sequencing; transcriptomics

Project Summary Pregnant women, living in the vicinity of superfund sites, who may be exposed to polyclic 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.

项目概要 居住在超级基金站点附近、可能接触综合医院的孕妇 从这些部位散发的芳香烃 (PAH) 导致早产的风险较高 送货。早产需要新生儿补充氧气 （高氧），这反过来可能导致慢性肺病/支气管肺发育不良 （BPD）。我们假设产前接触 PAH 会加剧产后的影响 早产儿补充氧气。 PAHs 增强 BPD 的机制 婴儿还不太了解。该项目的中心假设是产前 PAH 的管理 [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 USEPA 认定的 B2 类致癌物将不同程度地加剧肺损伤和肺泡损伤 出生后高氧血症后的新生小鼠的简化，并且这种效应将在 小鼠缺乏细胞色素 P450 (Cyp)1a1 或 1a2 基因，其机制包括 遗传毒性和表观遗传机制的结合。我们还将检验以下假设： 产前接触 PAH 的婴儿比接触 PAH 的婴儿患 BPD 的风险更大 较少或没有 PAH，并且暴露于修复的 PAH 的人类肺细胞将表现出 比母体 PAH 的毒性更小。为了检验这些假设，我们提出以下具体建议 目标：（1）。具体目标 1. 检验产前暴露于野生型 (WT) (C57BL/6J) 的假设 小鼠接触PAH BP或PAHs混合物（BP + BbF + DBA）会导致肺损伤加剧， 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 对于 Cyp1a1、1a2 或 1b1。 2. 确定产前多环芳烃改变胎儿的机制 新生小鼠对高氧的敏感性。 3. 检验母亲接触过的假设 PAH（存在于超级基金网站中）面临着更大的早产风险，并且这些 与接触较少或没有接触的婴儿相比，婴儿更容易患 BPD。 这些目标的实现可能会导致预防/治疗的新策略 早产儿 BPD 可能是由母体散发的多环芳烃 (PAHs) 增强的 超级基金网站。