15 Mar Prenatal Tobacco Smoke Raises Risk of Atopic Dermatitis in Offspring
MedicalResearch.com Interview with:
Dr. Saskia Trump
Dr. Saskia Trump PhD
Helmholtz-Centre for Environmental Research – UFZ
Department of Environmental Immunology
Leipzig, Germany
MedicalResearch.com: What is the background for this study?
Response: Environmental chemicals have long been discussed to contribute to the exacerbation or even the development of allergic diseases. In our study we were particularly interested in the effect of tobacco smoke exposure, which is the main source for indoor benzene exposure, on regulatory T cell (Treg) function and its relation to the development of childhood atopic dermatitis (AD). Tregs play a critical in controlling T effector cell activity by avoiding overexpression. A deficiency in this T cell subset increases the risk for allergic inflammation.
We have previously described that exposure to tobacco smoke during pregnancy can decrease the number of regulatory T cells (Treg) in the cord blood and predispose the child to the development of AD (1). In this subsequent study we were interested in the underlying mechanism involved.
Benzene itself is not considered to be toxic, however its metabolization leads to the formation of highly reactive molecules. In humans for example the metabolite 1,4-benzochinone (1,4-BQ) can be found in the blood as a consequence of benzene exposure.
To further assess the effect of benzene on Treg and the development of AD we combined in vitro studies, evaluating the impact of 1,4-BQ on human expanded Treg, with data from our prospective mother-child cohort LINA. The LINA study, recruited in Leipzig, Germany, is a longitudinal evaluation of mother-child pairs with respect to lifestyle and environmental factors that might contribute to disease development in the child. Based on this deeply phenotyped cohort we were able to translate our in vitro findings to the in vivo scenario.
MedicalResearch.com: What are the main findings?
Response: We could show that even low concentrations of 1,4-BQ can negatively affect Treg function by impairing their ability to secret the anti-inflammatory cytokine interleukin 10 (IL-10) and decrease their suppressive function against T effector cells.
Treg suppressive function is commonly evaluated by co-culturing T effector cells with different proportions of Treg and monitoring the proliferation of fluorescently labeled T effector cells. In these assays we not only saw the already mentioned functional impairment of Treg but also observed a strong increase in interleukin 13 (IL-13) and granzyme B (GZMB). GZMB is an important mediator of cell death and its increase might point to an enhanced apoptosis rate in Treg cells, which – in addition to their diminished IL-10 secretion – could account for the relative decrease in Treg suppression by 1,4-BQ.
Similar to these in vitro results in LINA high concentrations of indoor benzene during pregnancy were associated with a decrease in the number of Treg cells in the peripheral blood of pregnant women and one-year-old children. This decrease in Treg cells was accompanied by an increase of GZMB and IL-13 in accordance to what we saw in our in vitro assays. We were able to show that this benzene-related IL-13 deregulation set the children at a higher risk for the development of atopic dermatitis up to the age of six years.
MedicalResearch.com: What should readers take away from your report?
Response: Our results support the notion that even low levels of the reactive benzene metabolite 1,4-BQ can significantly impair the suppressive function of Treg by reducing their potential to secrete the anti-inflammatory cytokine IL-10. This functional impairment most likely reduces Treg suppressive capacity resulting in higher GZMB production by effector cells and a subsequent further loss in Treg numbers presumably due to higher apoptosis rates induced by GrzB. Our study provides further mechanistic insights into
how benzene/tobacco smoke exposure can contribute to early childhood atopic dermatitis by reducing Treg activity.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: The prenatal period is a particular sensitive window to negative effects of environmental exposure, which might prime the child for disease development later in life. Although most of us are aware of the fact that smoking is bad for our health there is still a considerable number of pregnant women who report active smoking during pregnancy. According to PRAMS in 2013 (Pregnancy Risk Assessment Monitoring System) about 10% of pregnant women smoked in the last 3 month of their pregnancy (2).
Smoking during pregnancy not only puts the health of the mothers at risk but also has long-term negative consequences for the health of the child.
As we showed in our study prenatal tobacco smoke exposure is related to the development of atopic dermatitis by impairing Treg immune function. It would be interesting to see which other mechanisms mediate the effect of prenatal exposure and AD development, for example changes in epigenetic modifications, which would help to explain the latency period between exposure and disease development. Several studies addressing DNA methylation changes in cord blood of prenatally tobacco smoke exposed children have already been conducted (3), however still little is known about tobacco smoke-related DNA methylation changes, which might predispose children to the development of AD.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
References:
(1) Herberth G, Bauer M, Gasch M, Hinz D, Roder S, Olek S, et al. Maternal and cord blood miR-223 expression associates with prenatal tobacco smoke exposure and low regulatory T-cell numbers. J Allergy Clin Immunol 2014; 133:543-50
(2) https://www.cdc.gov/prams/pramstat/mch-indicators.html
(3) Bauer T, Trump S, Ishaque N, Thürmann L, Gu L, Bauer M, Bieg M, Gu Z, Weichenhan D, Mallm JP, Röder S, Herberth G, Takada E, Mücke O, Winter M, Junge KM, Grützmann K, Rolle-Kampczyk U, Wang Q, Lawerenz C, Borte M, Polte T, Schlesner M, Schanne M, Wiemann S, Geörg C, Stunnenberg HG, Plass C, Rippe K, Mizuguchi J, Herrmann C, Eils R, Lehmann I. Environment-induced epigenetic reprogramming in genomic regulatory elements in smoking mothers and their children. Mol Sys Biol 2016; 12(3):861.
Citation:
The benzene metabolite 1,4-benzoquinone reduces Tregfunction – a potential mechanism for tobacco smoke-associated atopic dermatitis
Journal of Allergy and Clinical Immunology
Available online 6 March 2017
http://dx.doi.org/10.1016/j.jaci.2017.01.034
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Last Updated on March 15, 2017 by Marie Benz MD FAAD