In the sensitivity analysis, excluding women with a history of maternal allergy or current smokers had no impact on the results (data not shown in tables). In addition, using the LUR model of NO2 exposure assessment did not materially change the ORs from the mean pregnancy exposure models. Trimester-specific values estimated from the LUR model were highly correlated. As a result, trimester-specific ORs were similar to each other (data not shown).
This study was conducted to determine the association between maternal exposure to ambient air pollutants and umbilical cord blood concentrations of IgE, TSLP, and IL-33. There is a body of literature supporting a causal association between childhood exposure to air pollutants and exacerbation of asthma and literature that is suggestive of an association between air pollution and development of asthma4 as well as recent immunological literature demonstrating the integral role of these immune system biomarkers in the mechanisms underlying childhood allergy.30
As this study is the first of its kind, it was not feasible to conduct direct comparisons with previous epidemiological studies. However, the present findings are consistent with results regarding relations among NO2, epithelial cells, and TSLP. NO2 exposure may induce epithelial cell injury29 and promote release of pro-inflammatory mediators.28 Furthermore, diesel exhaust, which may contain NO2, has been shown to upregulate epithelial cell production of TSLP.50
The present findings are also consistent with literature from animal models reporting that in utero exposure to pollutants, including diesel and particulate matter, promotes susceptibility to asthma and allergic sensitization51–53 and induces the release of pro-inflammatory mediators, such as IL-8, from lung tissue.54 Maternal air pollution exposure may also stimulate placental production of pro-inflammatory cytokines and subsequently influence fetal immune system development.55 We therefore speculate that the observed association between NO2 and IL-33 and TSLP is mediated by air pollution induced inflammatory responses in maternal airway tissue. These maternal responses, which can include release of pro-inflammatory mediators, may promote fetal epithelial cell cytokine production. Given the stronger magnitude of association in the third trimester, it is possible that later gestational NO2 exposure is the critical window for influencing TSLP and IL-33 concentrations. Experimental evidence has suggested that third trimester exposure to the heavy metal lead may be more likely to promote Th2 cytokine response than exposure earlier in pregnancy.56 However, authors of a birth cohort study in the Czech Republic reported that air pollution (PM2.5 and polycyclic aromatic hydrocarbons) exposure during the first trimester was associated with increases in T lymphocytes that may promote autoimmune responses.22 Scientific understanding regarding the critical window of gestational exposure for each pollutant and specific immunological endpoint is limited. Replication of the present findings regarding third trimester NO2 exposure and pro-inflammatory cytokine responses will help address this knowledge gap.
We hypothesize that it is unlikely that the cytokines measured in the present study are produced by maternal epithelial cells. IL-33 is a member of the IL-1 family and previous research has reported that IL-1α and IL-1β do not readily cross the placenta.57,58 TSLP has been shown to be produced by trophoblasts during early gestation.59 However, it is unlikely that maternal TSLP crosses the placenta due to its large molecular weight, which is of comparable size to IL-1, and the absence of known active transport processes.
Strengths of this study included the relatively large sample size in the MIREC study, the inclusion of many potential confounding factors, and the availability of novel immune system biomarkers. The use of spatiotemporal models for NO2 and PM2.5 enabled us to develop average exposure measures over the time span of a pregnancy that captured both detailed spatial and temporal variations in pollutant concentrations.
A primary limitation of our study is the potential exposure misclassification of the air pollutants resulting from the use of three-digit postal codes rather than full residential address. We did not have information on work location, time spent at home, or indoor pollutants. Further, the use of different exposure estimation methods for the two pollutants precluded direct comparison of results for the two pollutants. A second limitation is the lack of clinical outcome data. Although IL-33 and TSLP have been implicated in allergic disease,31 literature on the longitudinal relation from birth to childhood is lacking. Thus, it is not possible to draw definitive conclusions about the risk of developing childhood allergic disease on the basis of these findings. Determining the impacts of the observed results on childhood allergic disease requires further follow-up of the MIREC cohort. Third, considering that high NO2 concentrations are found in regions of high population density, it is possible that the observed results are subject to residual confounding due to co-occurring pollutants or characteristics unique to this subpopulation.
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