Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications Susanne Jahreis, PhD, Saskia Trump,

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Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications Susanne Jahreis, PhD, Saskia Trump, PhD, Mario Bauer, MD, Tobias Bauer, PhD, Loreen Thürmann, MSc, Ralph Feltens, PhD, Qi Wang, PhD, Lei Gu, PhD, Konrad Grützmann, PhD, Stefan Röder, PhD, Marco Averbeck, MD, Dieter Weichenhan, PhD, Christoph Plass, PhD, Ulrich Sack, MD, Michael Borte, MD, Virginie Dubourg, MSc, Gerrit Schüürmann, PhD, Jan C. Simon, MD, Martin von Bergen, PhD, Jörg Hackermüller, PhD, Roland Eils, PhD, Irina Lehmann, PhD, Tobias Polte, PhD Journal of Allergy and Clinical Immunology Volume 141, Issue 2, Pages 741-753 (February 2018) DOI: 10.1016/j.jaci.2017.03.017 Copyright © 2017 The Authors Terms and Conditions

Fig 1 Maternal phthalate exposure and children's asthma and allergic sensitization. A and C, Maternal urine MnBP concentrations (34th gestational week) for children with asthma until age 6 (Fig 1, A) and sensitization against inhalant allergens (Fig 1, C) compared with control subjects (medians and interquartile ranges). B and D, Frequency and risk (adjusted odds ratio per 100 ng/mg MnBP increase) for asthma (Fig 1, B) and sensitization against inhalant allergens (Fig 1, D) according to maternal MnBP concentrations (high = greater than median). Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig 2 Phthalate exposure and induction of an asthma-like phenotype. A, Dams were exposed to BBP during pregnancy (prenatal) or until weaning when pups were 3 weeks old (perinatal exposure). B, Exposure of adult mice to BBP started 1 week before the first allergen injection and was continued until the end of the asthma induction protocol. C, Female F1 mice from exposed or control dams were mated with unexposed male mice. i.n., Intranasal; i.p., intraperitoneal. Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig 3 Prenatal and perinatal exposure to BBP increases allergic airway inflammation in a murine asthma model. Total cell numbers in bronchoalveolar lavage (BAL) fluid (A), airway inflammation examined by lung histology (hematoxylin and eosin, magnification ×100; B) quantified by an investigator-independent computer-based analysis (C), and lung resistance (D) were examined in offspring from BBP-exposed dams and in BBP-exposed adult mice. Data are expressed as means ± SEMs (n ≥ 9 animals per group in the offspring [from ≥5 dams] and adult mice from 4 independent experiments). *P < .05. Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig 4 Prenatal and perinatal exposure to BBP enhances allergen-specific IgE levels and TH2 cytokine production. OVA-specific IgE serum levels (A) and cytokine production of restimulated splenocytes (B) and lymph node cells (C) were analyzed in OVA-immunized offspring from BBP-exposed dams and in BBP-exposed adult mice. Data are expressed as means ± SEMs (n ≥ 9 animals per group in the offspring [from ≥5 dams] and adult groups from 4 independent experiments). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig 5 Maternal BBP exposure induces global hypermethylation, which mediates the asthma-promoting effect. A, DMRs were called from dams and their offspring between the exposed (F0 or F1) and nonexposed groups. B, Numbers of DMRs in different DNA regions of the F1 generation. C-G, Total cell numbers in bronchoalveolar lavage (BAL) fluid (Fig 5, C), airway inflammation (Fig 5, D), lung resistance (Fig 5, E), OVA-specific IgE levels (Fig 5, F), and cytokine production in spleen and lymph node cells (Fig 5, G) were examined in offspring from BBP-exposed dams compared with F1 mice treated with the DNA methyltransferase inhibitor Aza. Data are expressed as means ± SEMs (n ≥ 9 animals per group in the offspring [from ≥6 dams) from 6 independent experiments). *P < .05, OVA versus OVA + BBP. #P < .05, OVA + BBP versus OVA + BBP + Aza. Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig 6 BBP-induced hypermethylation leads to downregulation of selected target genes. A, Heat map displays DEGs from pups of BBP-exposed dams versus control mice. B, Two hundred forty-two of 1338 DEGs in the offspring from BBP-exposed dams can be linked to 346 DMRs. C, RNA expression of selected genes in dams (n = 5), pups, or adult mice (n ≥ 6 from ≥4 dams) was verified by using quantitative PCR. D, Mice from BBP-exposed dams were treated with Aza, as described in the Methods section, and RNA expression was measured in mature offspring (n ≥ 6 from ≥2 dams). Data are expressed as means ± SEMs from at least 2 independent experiments. *P < .05, CON versus BBP. #P < .05, BBP versus BBP + Aza. Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig 7 Altered function of CD4+ T cells in offspring of BBP-exposed mice. A-C, Numbers of CD4+CD25+ T cells (Fig 7, A), percentages of cytokine-producing T cells (Fig 7, B), and Foxp3+CD4+CD25+ T cells (Fig 7, C) are shown. D, Efficiency of CD4+CD25+ regulatory T (Treg) cells to suppress proliferation of responder T cells. Data are expressed as means ± SEMs (n ≥ 5 from 3 independent experiments). *P < .05. Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig 8 Maternal BBP exposure affects airway inflammation in the F2 generation. Total cell numbers in bronchoalveolar lavage (BAL) fluid (A), airway inflammation (B), lung resistance (C), and OVA-specific IgE levels (D) were examined in OVA-immunized F2 generation from prenatally BBP-exposed F1 dams compared with control mice. Data are expressed as means ± SEMs (n ≥ 9 animals per group in the F2 offspring [from ≥6 dams] from 6 independent experiments). *P < .05, OVA versus OVA + BBP. #P < .05, OVA + BBP versus OVA + BBP + Aza. Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2018 141, 741-753DOI: (10.1016/j.jaci.2017.03.017) Copyright © 2017 The Authors Terms and Conditions