In utero ultrafine particulate matter exposure causes offspring pulmonary immunosuppression
Contributed by Mario J. Molina, December 6, 2018 (sent for review September 19, 2018; reviewed by Alexandra Noel and Tong Zhu)
Significance
Particulate matter exposure causes infant respiratory morbidity and mortality, but the role of ultrafine particles (UFPs) with an aerodynamic diameter of less than 0.1 μm in asthma and respiratory tract infections is unclear. Limited mechanistic information is available concerning UFP influence on the etiology of childhood asthma or susceptibility to respiratory infections. Here we exposed two strains of mice (sensitive to oxidative stress or allergen exposure) to UFPs throughout gestation at concentrations relevant to human exposures. Our results reveal a window of pulmonary immunosuppression in offspring following in utero UFP exposure. A dampened host immune response during early development underlies increased childhood susceptibility to respiratory infections, highlighting the necessity to develop strategies to protect the fetus during this vulnerable period.
Abstract
Early life exposure to fine particulate matter (PM) in air is associated with infant respiratory disease and childhood asthma, but limited epidemiological data exist concerning the impacts of ultrafine particles (UFPs) on the etiology of childhood respiratory disease. Specifically, the role of UFPs in amplifying Th2- and/or Th17-driven inflammation (asthma promotion) or suppressing effector T cells (increased susceptibility to respiratory infection) remains unclear. Using a mouse model of in utero UFP exposure, we determined early immunological responses to house dust mite (HDM) allergen in offspring challenged from 0 to 4 wk of age. Two mice strains were exposed throughout gestation: C57BL/6 (sensitive to oxidative stress) and BALB/C (sensitive to allergen exposure). Offspring exposed to UFPs in utero exhibited reduced inflammatory response to HDM. Compared with filtered air (FA)-exposed/HDM-challenged mice, UFP-exposed offspring had lower white blood cell counts in bronchoalveolar lavage fluid and less pronounced peribronchiolar inflammation in both strains, albeit more apparent in C57BL/6 mice. In the C57BL/6 strain, offspring exposed in utero to FA and challenged with HDM exhibited a robust response in inflammatory cytokines IL-13 and Il-17. In contrast, this response was lost in offspring exposed in utero to UFPs. Circulating IL-10 was significantly up-regulated in C57BL/6 offspring exposed to UFPs, suggesting increased regulatory T cell expression and suppressed Th2/Th17 response. Our results reveal that in utero UFP exposure at a level close to the WHO recommended PM guideline suppresses an early immune response to HDM allergen, likely predisposing neonates to respiratory infection and altering long-term pulmonary health.
Acknowledgments
We thank Ms. Valery Roman and Ms. Ana Cardenas for assistance with mouse experiments. This research was supported by a grant from the National Institute of Environmental Health Sciences, National Institutes of Health (R01 ES028866); a Research Enhancement Development Initiative grant from the Texas A&M School of Public Health; and a Tier One Program grant from Texas A&M University. R.Z. acknowledges additional support from Robert A. Welch Foundation Grant A-1417.
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Copyright © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
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Published online: February 11, 2019
Published in issue: February 26, 2019
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Acknowledgments
We thank Ms. Valery Roman and Ms. Ana Cardenas for assistance with mouse experiments. This research was supported by a grant from the National Institute of Environmental Health Sciences, National Institutes of Health (R01 ES028866); a Research Enhancement Development Initiative grant from the Texas A&M School of Public Health; and a Tier One Program grant from Texas A&M University. R.Z. acknowledges additional support from Robert A. Welch Foundation Grant A-1417.
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The authors declare no conflict of interest.
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