Final Report: Research Project C: Perinatal Environmental Exposure Disparity and Neonatal Respiratory Health

EPA 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)
RFA: Centers for Children’s Environmental Health and Disease Prevention Research (2005) RFA Text |  Recipients Lists
Research Category: Health Effects , Children's Health , Health

Objective:

  1. 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;
  2. To determine whether PM and/or ozone exposure ‘re-programs’ maternal inflammatory responses;
  3. To determine whether postnatal (2nd hit) ozone exposure further impairs postnatal somatic and lung development/function following maternal PM and/or ozone exposures;
  4. To determine whether genetic or developmental susceptibility to airway hyperreactivity exacerbates maternal and/or postnatal exposure effects on postnatal somatic and lung development/function.

Summary/Accomplishments (Outputs/Outcomes):

Significant progress was made in Project 3. We determined that postnatal ozone (1 ppm x 3h/d, 3 d/week x 4 weeks) significantly impairs postnatal weight gain in C56BL/6 mice. Air pollutant exposure at a vulnerable window of postnatal development impairs growth. We also saw that postnatal ozone increases nebulized methacholine induced airway hyperreactivity (AHR) in C57BL/6 mice measured at 4 weeks but not 3 weeks. Ozone induced AHR is developmentally regulated.
 
We have found that prenatal instillation of particulate matter (St. Louis particle, NIST#1648) twice weekly in time mated pregnant mice augments postnatal ozone-induced AHR in mice, measured at 4 weeks postnatal. Prenatal air pollutant exposure reprograms postnatal air pollutant responses that result in AHR (Auten et al., Am J Resp Crit Care Med 2009).
 
In studies in collaboration with M. Ian Gilmour, EPA , we exposed time-mated C56BL/6 pregnant mice to internal combustion engine diesel exhaust (0.5, 1, and 2 mg/m3 x 6h/d, 5d/week, from gestation day 6-17) v. air control. Pups delivered to exposed dams were exposed postnatally to ozone as described above. Prenatal diesel exposure dose-dependently impaired lung compliance and pressure-volume loop hysteresis v. air or prenatal air postnatal ozone controls. There were parallel effects on nebulized methacholine challenge induced AHR. Prenatal ambient exposures to diesel particulates at doses relevant to human environmental exposure worsened postnatal ozone-induced lung function and AHR.
 
We published a manuscript that reported the effect of prenatal diesel particulate pulmonary exposure on postnatal ozone induced airway hyperreactivity (Auten et al., Am J Resp Cell Mol Biol., 2012). The report showed dose-dependent effects of particulate matter inhalation on maternal inflammatory responses; synergistic effects of prenatal diesel exposure and postnatal ozone exposure on lung inflammatory cytokine responses, and synergistic effects of prenatal diesel and postnatal ozone on postnatal airway hyperresponsiveness to inhaled methacholine challenge.
 
Because increasing evidence links non-chemical stressor effects on mothers and offspring to both AHR and cognitive development, we sought to determine if other stressors that would be typical co-exposures in human experience would potentially exacerbate effects of air pollution exposure. In impoverished environments in the United States, this would include resource/housing deprivation and uncertainty, as well as poor diet. Therefore, we sought collaboration with investigators with expertise in behavioral/cognitive development and neuroinflammation, because that mechanism was likely common to the inflammatory mechanisms that underpin pollution effects on AHR.
 
We developed a mouse model of nest-restriction during pregnancy that had no effects on maternal licking and grooming in the first postnatal week, but which apparently unmasked adverse effects of diesel inhalation during pregnancy. Combined prenatal diesel aspiration and pre-natal nest restriction of pregnant mice induced increased anxiety in offspring of both sexes and impaired cognition in male offspring. This sexually dimorphic response was parallel to changes in brain IL-1 and IL-10. Findings were reported in Bolton et al., Environmental Health Perspectives (2013;121(9):1075-1082). Only the combination of diesel inhalation and resource deprivation produced this finding. This suggests the importance of studying exposures in combination. However, our preliminary studies showed that these combined stressors did not affect AHR.
 
Because obesity is common to both childhood asthma and poverty, we conducted studies to determine if post-natal high fat diet also could worsen or unmask prenatal diesel effects on behavior and cognition. We exposed time-mated mice to spontaneous diesel exhaust in collaboration with Ian Gilmour at the US EPA. Offspring were randomly assigned to normal or high fat diet after weaning. The offspring that had combined prenatal exposure to inhaled diesel (dams) and post-natal high fat diet showed increased brain microglial activation, but only males demonstrated decreased spontaneous activity and increased anxiety behavior. Prenatal air pollution appeared to program offspring for increased susceptibility to diet-induced weight gain. These findings were reported by Bolton et al. (FASEB J, 2012).


Journal Articles on this Report : 6 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
Type Citation Sub Project Document Sources
Journal Article Auten RL, Foster WM. Biochemical effects of ozone on asthma during postnatal development. Biochimica et Biophysica Acta 2011;1810(11):1114-1119. R833293 (2009)
R833293 (2010)
R833293 (Final)
R833293C003 (2010)
R833293C003 (Final)
  • Full-text from PubMed
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  • Abstract: ScienceDirect-Abstract
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  • Journal Article Block ML, Elder A, Auten RL, Bilbo SD, Chen H, Chen J-C, Cory-Slechta DA, Costa D, Diaz-Sanchez D, Dorman DC, Gold DR, Gray K, Jeng HA, Kaufman JD, Kleinman MT, Kirshner A, Lawler C, Miller DS, Nadadur SS, Ritz B, Semmens EO, Tonelli LH, Veronesi B, Wright RO, Wright RJ. The outdoor air pollution and brain health workshop. NeuroToxicology 2012;33(5):972-984. R833293 (2011)
    R833293 (2012)
    R833293 (Final)
    R833293C003 (2011)
    R833293C003 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ScienceDirect-Full Text HTML
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  • Abstract: ScienceDirect-Abstract
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  • Other: ScienceDirect-Full Text PDF
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  • Journal Article Bolton JL, Smith SH, Huff NC, Gilmour MI, Foster WM, Auten RL, Bilbo SD. Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner. FASEB Journal 2012;26(11):4743-4754. R833293 (2011)
    R833293 (Final)
    R833293C003 (2011)
    R833293C003 (Final)
  • Abstract from PubMed
  • Full-text: FASEB-Full Text HTML
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  • Abstract: FASEB-Abstract
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  • Other: FASEB-Full Text PDF
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  • Journal Article Bolton JL, Huff NC, Smith SH, Mason SN, Foster WM, Auten RL, Bilbo SD. Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice. Environmental Health Perspectives 2013;121(9):1075-1082. R833293 (2012)
    R833293 (Final)
    R833293C003 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: EHP-Full Text PDF
  • Abstract: EHP-Abstract & Full Text HTML
  • Journal Article Brown JS, Graham JA, Chen LC, Postlethwait EM, Ghio AJ, Foster WM, Gordon T. Panel discussion review: session four--assessing biological plausibility of epidemiological findings in air pollution research. Journal of Exposure Science and Environmental Epidemiology 2007;17(Suppl 2):S97-S105. R833293 (2007)
    R833293 (2008)
    R833293 (Final)
    R833293C003 (Final)
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  • Full-text: Nature-Full Text HTML
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  • Other: Nature-Full Text PDF
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  • Journal Article Miranda ML, Edwards SE, Chang HH, Auten RL. Proximity to roadways and pregnancy outcomes. Journal of Exposure Science & Environmental Epidemiology 2013;23(1):32-38. R833293 (2011)
    R833293 (2012)
    R833293 (Final)
    R833293C001 (2011)
    R833293C001 (Final)
    R833293C002 (2011)
    R833293C002 (Final)
    R833293C003 (2011)
    R833293C003 (Final)
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  • Abstract: Nature-Abstract
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  • Supplemental Keywords:

    airway hyperreactivity, diesel exhaust particles, air pollution, lung function, epigenetic, innate immunity, Nqo1, neuroinflammation, maternal stress

    Progress and Final Reports:

    Original Abstract
  • 2007
  • 2008
  • 2009 Progress Report
  • 2010 Progress Report
  • 2011 Progress Report
  • 2012

  • 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