2010 Progress Report: Research Project C: Perinatal Environmental Exposure Disparity and Neonatal Respiratory HealthEPA Grant Number: R833293C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R833293
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Southern Center on Environmentally Driven Disparities in Birth Outcomes
Center Director: Miranda , Marie Lynn
Title: Research Project C: Perinatal Environmental Exposure Disparity and Neonatal Respiratory Health
Investigators: Auten, Richard , Foster, W. Michael
Institution: Duke University
EPA Project Officer: Callan, Richard
Project Period: May 1, 2007 through April 30, 2012 (Extended to April 30, 2014)
Project Period Covered by this Report: May 1, 2010 through April 30,2011
RFA: Centers for Children’s Environmental Health and Disease Prevention Research (2005) RFA Text | Recipients Lists
Research Category: Health Effects , Children's Health , Health
- To develop and operate an interdisciplinary children’s health research center with a focus on understanding how biological, physiological, environmental, and social aspects of vulnerability contribute to health disparities;
- To enhance research in children’s health at Duke by promoting research interactions among programs in biomedicine, pediatric and obstetric care, environmental health, and the social sciences and establishing an infrastructure to support and extend interdisciplinary research;
- To develop new methodologies for incorporating innovative statistical analysis into children’s environmental health research and policy practice, with a particular emphasis on spatial, genetic and proteomic analysis;
- To serve as a technical and educational resource to the local community, region, the nation, and to international agencies in the area of children’s health and health disparities; and
- To translate the results of the Center into direct interventions in clinical care and practice.
- To determine whether maternal exposure to airborne particulates (PM) and/or ozone (1st hit) restricts fetal growth and/or postnatal growth, and impairs lung development/function in newborn mice;
- To determine whether PM and/or ozone exposure ‘re-programs’ maternal inflammatory responses;
- To determine whether postnatal (2nd hit) ozone exposure further impairs postnatal somatic and lung development/function following maternal PM and/or ozone exposures; and
- To determine whether genetic or developmental susceptibility to airway hyperreactivity exacerbates maternal and/or postnatal exposure effects on postnatal somatic and lung development/function.
- Aim 4 was focused on genetic susceptibility. To determine which pathways are important to transducing maternal air pollutant exposures to adverse effects on fetuses and newborns, we have conducted studies in mice lacking the Tlr4 gene, a key innate immune response receptor previously shown to be important to acute ozone induced airway hyperreactivity in adult mice. Our studies have shown that the placental, fetal lung, and fetal brain cytokines that were induced by maternal diesel inhalation are in many cases dependent on maternal+fetal Tlr4 signaling. In particular, we have found that the maternal diesel inhalation/instillation effects on IL-1b, IL-6, KC, TNFα, and eotaxin responses in the placenta, and IL-b, TNFα, and MIP-1, and RANTES in the lung are dependent on Tlr4.
- Increasing evidence points to epigenetically mediated heritable effects of environmental pollutant exposures on health outcomes. We have conducted studies using the diesel particle described in the prior Progress Report to test this concept. Maternal diesel exposure increases the vulnerability of offspring to inflammatory airway challenge with nebulized endotoxin, a ligand for Tlr4. Studies done in collaboration with J. Hollingsworth and D. Brass suggest these increased susceptibilities are epigenetically mediated, with inheritance of the diesel exposure effect to the F3 generation. Current studies are aimed at identifying specific molecular pathways that may be responsible.
- Since the last reporting period, we have conducted additional studies on the effects of resource deprivation (nest/housing restriction) in combination with maternal pollutant (diesel) exposure and found that the combination impairs postnatal weight gain and worsens the response to inflammatory endotoxin challenge. We did not observe effects on airway hyperresponsiveness, but do not expect this without the contribution of post-natal ozone exposure. These studies suggest that the combination of sub-clinical chemical and non-chemical stressor exposures have important effects on lung susceptibility to inflammatory challenge in offspring at a juvenile stage of development. The extension of our studies to include these components is funded by a Duke Integrative Brain Sciences incubator award that was competitively renewed for FY11-12.
- We are finishing our studies on the neural contributions towards ozone induced airway hyperresponsiveness and a manuscript is in preparation.
- Because oxidative stress is an important pathway implicated in ozone induced asthma in children, we sought to determine whether an asthma susceptibility gene, NQO1 (NAD(P)H quinone oxidoreductase-1) also was important in conferring airway hyperresponsiveness in our animal model. We have completed studies showing that Nqo1 null mice are completely protected from the effects of neonatal ozone exposure on prolonged airway hyperreactivity that persists to adulthood. This strongly implicates the oxidative stress responses during early life in the development of later airway hyperreactivity. We are repeating some of the pivotal experiments to confirm this. In contrast with our studies of combined maternal diesel and postnatal ozone exposure, we did not find substantial effects of ozone, with or without Nqo1 knockout, on alveolar development.
- We are continuing to determine the contribution of combined chemical and non-chemical perinatal stressors on respiratory and neurocognitive development of offspring. We are extending our studies using the Tlr4 null mice to determine the contribution of either maternal innate immune responses or fetal/neonatal immune responses to the adverse effects of the combined stressors on lung and brain development.
- The epigenetic contributions will be studied in more detail by evaluating particular molecular pathways in pulmonary macrophages that appear to be critical to the effects on airway hyperreactivity in mice born to dams exposed to diesel inhalation.
Journal Articles on this Report : 1 Displayed | Download in RIS Format
|Other subproject views:||All 18 publications||6 publications in selected types||All 6 journal articles|
|Other center views:||All 162 publications||76 publications in selected types||All 75 journal articles|
||Auten RL, Foster WM. Biochemical effects of ozone on asthma during postnatal development. Biochimica et Biophysica Acta 2011;1810(11):1114-1119.||
Supplemental Keywords:epigenetic, innate immunity, Nqo1
Progress and Final Reports:Original Abstract
Main Center Abstract and Reports:R833293 Southern Center on Environmentally Driven Disparities in Birth Outcomes
Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R833293C001 Research Project A: Mapping Disparities in Birth Outcomes
R833293C002 Research Project B: Healthy Pregnancy, Healthy Baby: Studying Racial Disparities in Birth Outcomes
R833293C003 Research Project C: Perinatal Environmental Exposure Disparity and Neonatal Respiratory Health
R833293C004 Community Outreach and Translation Core
R833293C005 Geographic Information System and Statistical Analysis Core