Pregnant women who are exposed to polycyclic aromatic hydrocarbons (PAHs) are at a higher risk for preterm delivery. Preterm delivery often 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. A growing number of studies have shown an association between changes in the microbiome and a variety of adverse health outcomes. However, little is known regarding a causal link between changes in gut and/or lung microbiome and the potentiation of BPD in infants exposed prenatally to PAHs. The central hypothesis of this project is that prenatal administration of PAH [i.e. benzo[a]pyrene (BP), which is defined as class B2 carcinogen, will differentially exacerbate lung injury and alveolar simplification in neonatal mice following postnatal hyperoxia, and that the dysbiosis of the maternal and/or neonatal microbiome of the gut and/or lung (gut-lung axis) mechanistically contributes to this phenomenon. We will also test the hypothesis that mice lacking the genes for Cyp1a1 or 1b1 will display altered susceptibilities to PAH/hyperoxia-mediated lung injury, and that the gut microbiome plays a mechanistic role in the phenomenon. The following aims are proposed:
Specific Aim 1 : To test the hypothesis that prenatal exposure of wild type (WT) (C57BL/6J) mice or mice lacking the gene for Cyp1a1 or 1b1 to the PAH BP will result in dysbiosis of the maternal microbiome, which will in turn contribute to the exacerbation of lung injury and alveolar simplification following postnatal hyperoxia, and that exposures occurring at some developmental windows are more likely to exert long-term effects than other windows of exposure.
Specific Aim 2 : To test that the hypothesis that newborns born to dams treated with antibiotics (to deplete the microbiome) will be more susceptible to prenatal PAH and postnatal hyperoxic lung injury than those not treated with antibiotics (aim 1), and that maternal microbiome in part will be transmitted to the offspring.
Specific Aim 3 : To test the hypothesis that germ free (GF) mice will be more susceptible to neonatal hyperoxic lung injury than conventional (CV) mice, and that these mice will be rescued by transfer of intestinal microbial contents of CV mice.
This aim has two sub-aims: (i) (GF (WT, Cyp1a1-null, Cyp1b1-null) or CV mice will be treated prenatally with CO or BP, and exposed to neonatal hyperoxia as described in aim 1, and the GF newborns will be given vehicle or given intestinal contents of the corresponding CV mice on PND 1, 7, and 14, while being maintained in room air or exposed to hyperoxia. (ii) To test the hypothesis that prenatal exposure of gnotobiotic (GB) mice that consists of specific species of bacteria will be less susceptible to PAH/hyperoxia-mediated neonatal lung injury than GF mice, and that the GF mice given these bacterial species will be rescued against the lung injury phenotype. Accomplishments of these aims will lead to the unraveling the mechanistic role of microbiome in the protection against neonatal lung injury in mice that have been prenatally exposed to PAHs.
Pregnant women who are exposed to polycyclic aromatic hydrocarbons (PAHs) are at a higher risk for preterm delivery, and it is known that prenatal PAH exposure exacerbates lung injury in infants given supplemental oxygen postnatally. A growing number of studies have shown an association between changes in the microbiome and a variety of adverse health outcomes. In this project we will test the hypothesis that prenatal administration of PAH [i.e. benzo[a]pyrene (BP), which is defined as class B2 carcinogen, will differentially exacerbate lung injury and alveolar simplification in neonatal mice following postnatal hyperoxia, and that the dysbiosis of the maternal and/or neonatal microbiome of the gut and/or lung (gut-lung axis) mechanistically contributes to this phenomenon.
