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

Project Summary Pregnant women, living in the vicinity of Superfund sites, who are exposed to polycyclic aromatic hydrocarbons (PAHs) that emanate from these sites, are at a higher risk for preterm delivery. Preterm neonates, often require supplemental oxygen (hyperoxia), and contributes to the development of bronchopulmonary dysplasia (BPD), the most common and serious pulmonary morbidity in preterm neonates. The mechanisms by which PAHs potentiate BPD in infants are not well understood. The central hypothesis of the research proposed in thjus project is that pregnant mice exposed to a mixture of PAHs, i.e. benzo[a]pyrene (BP), , benzo(b)fluoranthrene (BbF), and dibenz[a,h]anthracene (DBA)], which are which are present in Superfund sites, at environmentally relevant concentrations, 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 Ah receptor (AHR), Cyp1a1 and 1b1 (Cyp1a1/1b1 double knockouts), or Cyp1a1, 1a2, and 1b1 (Cyp1a1/1a2/1b1 triple knockouts) by mechanisms entailing a combination of genotoxic and epigenetic mechanisms. We will also test the hypothesis that the premature infants exposed prenatally to PAHs or other chemicals have a greater risk of developing BPD than those exposed to lesser or no PAHs, and that human pulmonary cells or mice exposed to remediated PAHs will exhibit lesser toxicity than parent PAHs. To test these hypotheses, we propose the following Specific Aims: 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 + DBP + IDP) 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 AHR, Cyp1a1/1b1, or Cyp1a1/1a1/1b1. 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) or other environmental chemicals (based on unbiased metabolomics or exposome data from project 2) 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. 4. To determine the toxicity of un-remediated and remediated PAHs from soils from Superfund Sites (e.g., Patrick Bayou) in (i) human pulmonary cells (e.g., BEAS-2B or A549 cells) in vitro and (ii) in vivo using wild type mice. 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.