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.

项目摘要 孕妇，居住在超级基金地点附近，她们可能会暴露于多环 从这些地点散发出的芳族碳氢化合物（PAHS）的早产风险更高 送货。早产需要对新生儿进行补充氧气 （高氧），这又可能导致慢性肺部疾病/支气管肺发育不良 （BPD）。我们假设产前PAH暴露会加剧产后的影响 早产新生儿中的补充氧气。 PAHS增强BPD的机制 婴儿不太了解。该项目的中心假设是产前 PAHS的管理[即苯并[a] pyrene（bp）或苯并（a）pyrene（bp）的混合物， 苯并（B）氟（BBF）和Dibenz [a]蒽（DBA）]，它们被定义为 B2类致癌物通过USEPA，将差异加重肺损伤和肺泡 产后高氧后新生小鼠的简化，这种作用将在 缺乏细胞色素P450基因（CYP）1A1或1A2基因的小鼠通过需要的机制 遗传毒性和表观遗传机制的组合。我们还将检验以下假设 在产前暴露于PAHS的婴儿患BPD的风险比暴露于 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来 毒性比父母PAH的毒性较小。为了检验这些假设，我们提出以下特定 目标：（1）。特定目的1。检验野生型（WT）（C57BL/6J）的产前暴露的假设 小鼠到PAH BP或PAH的混合物（BP + BBF + DBA）将导致肺损伤加剧，并且 产后高氧后的肺泡简化，缺乏基因的小鼠将改变这种作用 对于CYP1A1，1A2或1B1。 2。确定产前PAH的机制 新生小鼠对高氧的敏感性。 3。检验母亲暴露于母亲的假设 PAHS（超级基金站点中存在）的早产风险更大，而这些 婴儿将显示出比较少或没有暴露的婴儿更容易受到发展BPD的敏感性。 这些目标的成就可能导致预防/治疗的新策略 BPD的过早婴儿，可能是由源自产妇的PAH增强的 超级基金网站。