266 results on '"Irina Lehmann"'
Search Results
2. RECAST: Study protocol for an observational study for the understanding of the increased REsilience of Children compared to Adults in SARS-CoV-2 infecTion
- Author
-
Irina Lehmann, Thomas Boeckel, Birgit Sawitzki, Anita Balázs, Valentin Schriever, Jobst Roehmel, Leif E Sander, Sebastian Stricker, Niklas Ziegahn, Martin Karsten, Heike Stich-Boeckel, Jakob Maske, Evelyn Rugo, Pamela Millar Büchner, Chantip Dang-Heine, Roland Eils, Markus Ralser, Victor M Corman, and Marcus A Mall
- Subjects
Medicine - Abstract
Introduction The SARS-CoV-2 pandemic remains a threat to public health. Soon after its outbreak, it became apparent that children are less severely affected. Indeed, opposing clinical manifestations between children and adults are observed for other infections. The SARS-CoV-2 outbreak provides the unique opportunity to study the underlying mechanisms. This protocol describes the methods of an observational study that aims to characterise age dependent differences in immune responses to primary respiratory infections using SARS-CoV-2 as a model virus and to assess age differences in clinical outcomes including lung function.Methods and analysis The study aims to recruit at least 120 children and 60 adults that are infected with SARS-CoV-2 and collect specimen for a multiomics analysis, including single cell RNA sequencing of nasal epithelial cells and peripheral blood mononuclear cells, mass cytometry of whole blood samples and nasal cells, mass spectrometry-based serum and plasma proteomics, nasal epithelial cultures with functional in vitro analyses, SARS-CoV-2 antibody testing, sequencing of the viral genome and lung function testing. Data obtained from this multiomics approach are correlated with medical history and clinical data. Recruitment started in October 2020 and is ongoing.Ethics and dissemination The study was reviewed and approved by the Ethics Committee of Charité – Universitätsmedizin Berlin (EA2/066/20). All collected specimens are stored in the central biobank of Charité – Universitätsmedizin Berlin and are made available to all participating researchers and on request.Trial registration number DRKS00025715, pre-results publication.
- Published
- 2023
- Full Text
- View/download PDF
3. A targetable ‘rogue’ neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS
- Author
-
Victoria L. M. Herrera, Allan J. Walkey, Mai Q. Nguyen, Christopher M. Gromisch, Julie Z. Mosaddhegi, Matthew S. Gromisch, Bakr Jundi, Soeren Lukassen, Saskia Carstensen, Ridiane Denis, Anna C. Belkina, Rebecca M. Baron, Mayra Pinilla-Vera, Meike Mueller, W. Taylor Kimberly, Joshua N. Goldstein, Irina Lehmann, Angela R. Shih, Roland Eils, Bruce D. Levy, and Nelson Ruiz-Opazo
- Subjects
Medicine ,Science - Abstract
Abstract Neutrophil-mediated secondary tissue injury underlies acute respiratory distress syndrome (ARDS) and progression to multi-organ-failure (MOF) and death, processes linked to COVID-19-ARDS. This secondary tissue injury arises from dysregulated neutrophils and neutrophil extracellular traps (NETs) intended to kill pathogens, but instead cause cell-injury. Insufficiency of pleiotropic therapeutic approaches delineate the need for inhibitors of dysregulated neutrophil-subset(s) that induce subset-specific apoptosis critical for neutrophil function-shutdown. We hypothesized that neutrophils expressing the pro-survival dual endothelin-1/VEGF-signal peptide receptor, DEspR, are apoptosis-resistant like DEspR+ cancer-cells, hence comprise a consequential pathogenic neutrophil-subset in ARDS and COVID-19-ARDS. Here, we report the significant association of increased peripheral DEspR+CD11b+ neutrophil-counts with severity and mortality in ARDS and COVID-19-ARDS, and intravascular NET-formation, in contrast to DEspR[-] neutrophils. We detect DEspR+ neutrophils and monocytes in lung tissue patients in ARDS and COVID-19-ARDS, and increased neutrophil RNA-levels of DEspR ligands and modulators in COVID-19-ARDS scRNA-seq data-files. Unlike DEspR[-] neutrophils, DEspR+CD11b+ neutrophils exhibit delayed apoptosis, which is blocked by humanized anti-DEspR-IgG4S228P antibody, hu6g8, in ex vivo assays. Ex vivo live-cell imaging of Rhesus-derived DEspR+CD11b+ neutrophils showed hu6g8 target-engagement, internalization, and induction of apoptosis. Altogether, data identify DEspR+CD11b+ neutrophils as a targetable ‘rogue’ neutrophil-subset associated with severity and mortality in ARDS and COVID-19-ARDS.
- Published
- 2022
- Full Text
- View/download PDF
4. Age-Related Differences in Structure and Function of Nasal Epithelial Cultures From Healthy Children and Elderly People
- Author
-
Anita Balázs, Pamela Millar-Büchner, Michael Mülleder, Vadim Farztdinov, Lukasz Szyrwiel, Annalisa Addante, Aditi Kuppe, Tihomir Rubil, Marika Drescher, Kathrin Seidel, Sebastian Stricker, Roland Eils, Irina Lehmann, Birgit Sawitzki, Jobst Röhmel, Markus Ralser, and Marcus A. Mall
- Subjects
primary nasal epithelial cultures ,aging ,airways disease ,ion transport ,proteome ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The nasal epithelium represents the first line of defense against inhaled pathogens, allergens, and irritants and plays a key role in the pathogenesis of a spectrum of acute and chronic airways diseases. Despite age-dependent clinical phenotypes triggered by these noxious stimuli, little is known about how aging affects the structure and function of the airway epithelium that is crucial for lung homeostasis and host defense. The aim of this study was therefore to determine age-related differences in structural and functional properties of primary nasal epithelial cultures from healthy children and non-smoking elderly people. To achieve this goal, highly differentiated nasal epithelial cultures were established from nasal brushes at air–liquid interface and used to study epithelial cell type composition, mucin (MUC5AC and MUC5B) expression, and ion transport properties. Furthermore, we determined age-dependent molecular signatures using global proteomic analysis. We found lower numeric densities of ciliated cells and higher levels of MUC5AC expression in cultures from children vs. elderly people. Bioelectric studies showed no differences in basal ion transport properties, ENaC-mediated sodium absorption, or CFTR-mediated chloride transport, but detected decreased calcium-activated TMEM16A-mediated chloride secretory responses in cultures from children vs. elderly people. Proteome analysis identified distinct age-dependent molecular signatures associated with ciliation and mucin biosynthesis, as well as other pathways implicated in aging. Our data identified intrinsic, age-related differences in structure and function of the nasal epithelium and provide a basis for further studies on the role of these findings in age-dependent airways disease phenotypes observed with a spectrum of respiratory infections and other noxious stimuli.
- Published
- 2022
- Full Text
- View/download PDF
5. Maternal paraben exposure triggers childhood overweight development
- Author
-
Beate Leppert, Sandra Strunz, Bettina Seiwert, Linda Schlittenbauer, Rita Schlichting, Christiane Pfeiffer, Stefan Röder, Mario Bauer, Michael Borte, Gabriele I. Stangl, Torsten Schöneberg, Angela Schulz, Isabell Karkossa, Ulrike E. Rolle-Kampczyk, Loreen Thürmann, Martin von Bergen, Beate I. Escher, Kristin M. Junge, Thorsten Reemtsma, Irina Lehmann, and Tobias Polte
- Subjects
Science - Abstract
Parabens are preservatives widely used in consumer products including cosmetics and food. Here the authors demonstrate that maternal paraben exposure may contribute to childhood overweight development by an altered neuronal appetite regulation.
- Published
- 2020
- Full Text
- View/download PDF
6. Wood emissions and asthma development: Results from an experimental mouse model and a prospective cohort study
- Author
-
Kristin M. Junge, Lisa Buchenauer, Elena Elter, Katja Butter, Tibor Kohajda, Gunda Herberth, Stefan Röder, Michael Borte, Wieland Kiess, Martin von Bergen, Jan C. Simon, Ulrike E. Rolle-Kampczyk, Irina Lehmann, Richard Gminski, Martin Ohlmeyer, and Tobias Polte
- Subjects
Wood emission ,Volatile organic compounds ,Mixture effect ,Asthma ,Wheezing ,FHA ,Environmental sciences ,GE1-350 - Abstract
Background: Increased use of renewable resources like sustainably produced wood in construction or for all sorts of long-lived products is considered to contribute to reducing society's carbon footprint. However, as a natural, biological material, wood and wood products emit specific volatile organic compounds (VOCs). Therefore, the evaluation of possible health effects due to wood emissions is of major interest. Objectives: We investigated the effects of an exposure to multiple wood-related VOCs on asthma development. Methods: A murine asthma model was used to evaluate possible allergic and inflammatory effects on the lung after short- or long-term and perinatal exposure to pinewood or oriented strand board (OSB). In addition, wood-related VOCs were measured within the German prospective mother–child cohort LINA and their joint effect on early wheezing or asthma development in children until the age of 10 was estimated by Bayesian kernel machine regression (BKMR) stratifying also for family history of atopy (FHA). Results: Our experimental data show that neither pinewood nor OSB emissions even at high total VOC levels and a long-lasting exposure period induce significant inflammatory or asthma-promoting effects in sensitized or non-sensitized mice. Moreover, an exposure during the vulnerable time window around birth was also without effect. Consistently, in our mother–child cohort LINA, an exposure to multiple wood-related VOCs during pregnancy or the first year of life was not associated with early wheezing or asthma development in children independent from their FHA. Conclusion: Our findings indicate that emissions from wood and wood products at levels commonly occurring in the living environment do not exert adverse effects concerning wheezing or asthma development.
- Published
- 2021
- Full Text
- View/download PDF
7. An individual participant data meta-analysis on metabolomics profiles for obesity and insulin resistance in European children
- Author
-
Christian Hellmuth, Franca F. Kirchberg, Stephanie Brandt, Anja Moß, Viola Walter, Dietrich Rothenbacher, Hermann Brenner, Veit Grote, Dariusz Gruszfeld, Piotr Socha, Ricardo Closa-Monasterolo, Joaquin Escribano, Veronica Luque, Elvira Verduci, Benedetta Mariani, Jean-Paul Langhendries, Pascale Poncelet, Joachim Heinrich, Irina Lehmann, Marie Standl, Olaf Uhl, Berthold Koletzko, Elisabeth Thiering, and Martin Wabitsch
- Subjects
Medicine ,Science - Abstract
Abstract Childhood obesity prevalence is rising in countries worldwide. A variety of etiologic factors contribute to childhood obesity but little is known about underlying biochemical mechanisms. We performed an individual participant meta-analysis including 1,020 pre-pubertal children from three European studies and investigated the associations of 285 metabolites measured by LC/MS-MS with BMI z-score, height, weight, HOMA, and lipoprotein concentrations. Seventeen metabolites were significantly associated with BMI z-score. Sphingomyelin (SM) 32:2 showed the strongest association with BMI z-score (P = 4.68 × 10−23) and was also closely related to weight, and less strongly to height and LDL, but not to HOMA. Mass spectrometric analyses identified SM 32:2 as myristic acid containing SM d18:2/14:0. Thirty-five metabolites were significantly associated to HOMA index. Alanine showed the strongest positive association with HOMA (P = 9.77 × 10−16), while acylcarnitines and non-esterified fatty acids were negatively associated with HOMA. SM d18:2/14:0 is a powerful marker for molecular changes in childhood obesity. Tracing back the origin of SM 32:2 to dietary source in combination with genetic predisposition will path the way for early intervention programs. Metabolic profiling might facilitate risk prediction and personalized interventions in overweight children.
- Published
- 2019
- Full Text
- View/download PDF
8. Gestational weight gain charts for different body mass index groups for women in Europe, North America, and Oceania
- Author
-
Susana Santos, Iris Eekhout, Ellis Voerman, Romy Gaillard, Henrique Barros, Marie-Aline Charles, Leda Chatzi, Cécile Chevrier, George P. Chrousos, Eva Corpeleijn, Nathalie Costet, Sarah Crozier, Myriam Doyon, Merete Eggesbø, Maria Pia Fantini, Sara Farchi, Francesco Forastiere, Luigi Gagliardi, Vagelis Georgiu, Keith M. Godfrey, Davide Gori, Veit Grote, Wojciech Hanke, Irva Hertz-Picciotto, Barbara Heude, Marie-France Hivert, Daniel Hryhorczuk, Rae-Chi Huang, Hazel Inskip, Todd A. Jusko, Anne M. Karvonen, Berthold Koletzko, Leanne K. Küpers, Hanna Lagström, Debbie A. Lawlor, Irina Lehmann, Maria-Jose Lopez-Espinosa, Per Magnus, Renata Majewska, Johanna Mäkelä, Yannis Manios, Sheila W. McDonald, Monique Mommers, Camilla S. Morgen, George Moschonis, Ľubica Murínová, John Newnham, Ellen A. Nohr, Anne-Marie Nybo Andersen, Emily Oken, Adriëtte J. J. M. Oostvogels, Agnieszka Pac, Eleni Papadopoulou, Juha Pekkanen, Costanza Pizzi, Kinga Polanska, Daniela Porta, Lorenzo Richiardi, Sheryl L. Rifas-Shiman, Nel Roeleveld, Loreto Santa-Marina, Ana C. Santos, Henriette A. Smit, Thorkild I. A. Sørensen, Marie Standl, Maggie Stanislawski, Camilla Stoltenberg, Elisabeth Thiering, Carel Thijs, Maties Torrent, Suzanne C. Tough, Tomas Trnovec, Marleen M. H. J. van Gelder, Lenie van Rossem, Andrea von Berg, Martine Vrijheid, Tanja G. M. Vrijkotte, Oleksandr Zvinchuk, Stef van Buuren, and Vincent W. V. Jaddoe
- Subjects
Weight gain ,Pregnancy ,Charts ,References ,Medicine - Abstract
Abstract Background Gestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies. Methods We used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape. Results We observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4–17.4) for underweight women, 14.5 kg (11.5–17.7) for normal weight women, 13.9 kg (10.1–17.9) for overweight women, and 11.2 kg (7.0–15.7), 8.7 kg (4.3–13.4) and 6.3 kg (1.9–11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications. Conclusions Gestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice.
- Published
- 2018
- Full Text
- View/download PDF
9. Early maternal perceived stress and children’s BMI: longitudinal impact and influencing factors
- Author
-
Beate Leppert, Kristin M. Junge, Stefan Röder, Michael Borte, Gabriele I. Stangl, Rosalind J. Wright, Anja Hilbert, Irina Lehmann, and Saskia Trump
- Subjects
Stress dimensions ,Perceived stress ,Weight development ,Stressor ,Infant ,Preschool children ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background Maternal perceived stress has been discussed to contribute to the development of childhood overweight. Our aim was to investigate the longitudinal relationship of early maternal perceived stress and BMI z-scores in preschool children (≤ five years). Methods A longitudinal analysis was conducted in 498 mother-child pairs of the German prospective birth cohort LINA with information on maternal perceived stress during pregnancy, one and two years after birth. BMI z-scores were based on annual measurements of children’s weight/height and calculated based on WHO reference data. General estimation equations were applied to evaluate the impact of maternal stress on children’s longitudinal BMI z-scores. Potential stressors contributing to the perceived stress of the mother were assessed by linear regression models. Using mediation analyses we evaluated the relationship between stressors, maternal perceived stress, and children’s BMI z-score development. Results Postnatal maternal stress during the first year after birth had a positive longitudinal relationship with children’s BMI z-scores up to the age of five years. Gender-stratified analyses revealed that only girls showed this positive association while boy’s BMI z-scores were unaffected by maternal stress. We identified three neighborhood strains and two socio-demographic factors, which contributed to the maternal perceived stress level. Stressors themselves did not directly affect girl’s BMI z-scores but rather mediated their effect through the perceived stress level. Conclusions While different stressors contribute to maternal stress, the perceived stress level - rather than the stressors themselves - is strongly positively associated with BMI z-score development in girls.
- Published
- 2018
- Full Text
- View/download PDF
10. Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births.
- Author
-
Elise M Philips, Susana Santos, Leonardo Trasande, Juan J Aurrekoetxea, Henrique Barros, Andrea von Berg, Anna Bergström, Philippa K Bird, Sonia Brescianini, Carol Ní Chaoimh, Marie-Aline Charles, Leda Chatzi, Cécile Chevrier, George P Chrousos, Nathalie Costet, Rachel Criswell, Sarah Crozier, Merete Eggesbø, Maria Pia Fantini, Sara Farchi, Francesco Forastiere, Marleen M H J van Gelder, Vagelis Georgiu, Keith M Godfrey, Davide Gori, Wojciech Hanke, Barbara Heude, Daniel Hryhorczuk, Carmen Iñiguez, Hazel Inskip, Anne M Karvonen, Louise C Kenny, Inger Kull, Debbie A Lawlor, Irina Lehmann, Per Magnus, Yannis Manios, Erik Melén, Monique Mommers, Camilla S Morgen, George Moschonis, Deirdre Murray, Ellen A Nohr, Anne-Marie Nybo Andersen, Emily Oken, Adriëtte J J M Oostvogels, Eleni Papadopoulou, Juha Pekkanen, Costanza Pizzi, Kinga Polanska, Daniela Porta, Lorenzo Richiardi, Sheryl L Rifas-Shiman, Nel Roeleveld, Franca Rusconi, Ana C Santos, Thorkild I A Sørensen, Marie Standl, Camilla Stoltenberg, Jordi Sunyer, Elisabeth Thiering, Carel Thijs, Maties Torrent, Tanja G M Vrijkotte, John Wright, Oleksandr Zvinchuk, Romy Gaillard, and Vincent W V Jaddoe
- Subjects
Medicine - Abstract
BackgroundFetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight.Methods and findingsWe performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations.ConclusionsWe observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.
- Published
- 2020
- Full Text
- View/download PDF
11. We are what we experienced before birth: Lessons from epigenetics
- Author
-
Saskia Trump, Loreen Thürmann, Matthias Klös, Tobias Polte, Roland Eils, and Irina Lehmann
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2020
- Full Text
- View/download PDF
12. MEST mediates the impact of prenatal bisphenol A exposure on long-term body weight development
- Author
-
Kristin M. Junge, Beate Leppert, Susanne Jahreis, Dirk K. Wissenbach, Ralph Feltens, Konrad Grützmann, Loreen Thürmann, Tobias Bauer, Naveed Ishaque, Matthias Schick, Melanie Bewerunge-Hudler, Stefan Röder, Mario Bauer, Angela Schulz, Michael Borte, Kathrin Landgraf, Antje Körner, Wieland Kiess, Martin von Bergen, Gabriele I. Stangl, Saskia Trump, Roland Eils, Tobias Polte, and Irina Lehmann
- Subjects
EDC ,Prenatal exposure ,Infants ,Obesity ,LINA ,Mice ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Exposure to endocrine-disrupting chemicals can alter normal physiology and increase susceptibility to non-communicable diseases like obesity. Especially the prenatal and early postnatal period is highly vulnerable to adverse effects by environmental exposure, promoting developmental reprogramming by epigenetic alterations. To obtain a deeper insight into the role of prenatal bisphenol A (BPA) exposure in children’s overweight development, we combine epidemiological data with experimental models and BPA-dependent DNA methylation changes. Methods BPA concentrations were measured in maternal urine samples of the LINA mother-child-study obtained during pregnancy (n = 552), and BPA-associated changes in cord blood DNA methylation were analyzed by Illumina Infinium HumanMethylation450 BeadChip arrays (n = 472). Methylation changes were verified by targeted MassARRAY analyses, assessed for their functional translation by qPCR and correlated with children’s body mass index (BMI) z scores at the age of 1 and 6 years. Further, female BALB/c mice were exposed to BPA from 1 week before mating until delivery, and weight development of their pups was monitored (n ≥ 8/group). Additionally, human adipose-derived mesenchymal stem cells were treated with BPA during the adipocyte differentiation period and assessed for exposure-related epigenetic, transcriptional and morphological changes (n = 4). Results In prenatally BPA-exposed children two CpG sites with deviating cord blood DNA-methylation profiles were identified, among them a hypo-methylated CpG in the promoter of the obesity-associated mesoderm-specific transcript (MEST). A mediator analysis suggested that prenatal BPA exposure was connected to cord blood MEST promoter methylation and MEST expression as well as BMI z scores in early infancy. This effect could be confirmed in mice in which prenatal BPA exposure altered Mest promoter methylation and transcription with a concomitant increase in the body weight of the juvenile offspring. An experimental model of in vitro differentiated human mesenchymal stem cells also revealed an epigenetically induced MEST expression and enhanced adipogenesis following BPA exposure. Conclusions Our study provides evidence that MEST mediates the impact of prenatal BPA exposure on long-term body weight development in offspring by triggering adipocyte differentiation.
- Published
- 2018
- Full Text
- View/download PDF
13. Prices of over-the-counter drugs used by 15-year-old adolescents in Germany and their association with socioeconomic background
- Author
-
Salvatore Italia, Silke B. Wolfenstetter, Irene Brüske, Joachim Heinrich, Dietrich Berdel, Andrea von Berg, Irina Lehmann, Marie Standl, and Christina M. Teuner
- Subjects
Adolescent ,Drug utilization ,Drug prices ,Socioeconomic factors ,Over-the-counter drugs ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background In Germany, over-the-counter (OTC) drugs are normally reimbursed up to the age of 12 years only. The aim of this study was to analyse prices of over-the-counter drugs used by adolescents in Germany and their association with socioeconomic factors. Methods Based on the German GINIplus and LISAplus birth cohorts, data on drug utilization among 15-year-old adolescents (n = 4677) were collected using a self-administered questionnaire. The reported drugs were subdivided into prescription drugs and OTC drugs. The drugs’ prices were tracked by the pharmaceutical identification numbers. Results Overall, 1499 OTC drugs with clearly identifiable prices were eligible for analysis. Their mean price was €9.75 (95% confidence interval: €9.27–10.22). About 75% of the OTC drugs cost less than €10. Higher mean prices were associated with residing in Munich (€10.74; 95% confidence interval: €9.97–11.52) and with higher paternal education (e.g. highest education level: €10.17; 95% confidence interval: €9.47–10.86). Adolescents residing in Munich (in comparison with the less wealthy region of Wesel) and adolescents with higher educated fathers were also significantly more likely to use OTC drugs costing ≥ €10 or ≥ €25, respectively. Conclusions The price of €10 for non-reimbursable OTC drugs may represent a (psychological) threshold. Higher prices could discourage especially adolescents from a lower socioeconomic background from taking medically advisable but non-reimbursable OTC drugs.
- Published
- 2017
- Full Text
- View/download PDF
14. From the exposome to mechanistic understanding of chemical-induced adverse effects
- Author
-
Beate I. Escher, Jörg Hackermüller, Tobias Polte, Stefan Scholz, Achim Aigner, Rolf Altenburger, Alexander Böhme, Stephanie K. Bopp, Werner Brack, Wibke Busch, Marc Chadeau-Hyam, Adrian Covaci, Adolf Eisenträger, James J. Galligan, Natalia Garcia-Reyero, Thomas Hartung, Michaela Hein, Gunda Herberth, Annika Jahnke, Jos Kleinjans, Nils Klüver, Martin Krauss, Marja Lamoree, Irina Lehmann, Till Luckenbach, Gary W. Miller, Andrea Müller, David H. Phillips, Thorsten Reemtsma, Ulrike Rolle-Kampczyk, Gerrit Schüürmann, Benno Schwikowski, Yu-Mei Tan, Saskia Trump, Susanne Walter-Rohde, and John F. Wambaugh
- Subjects
Environmental sciences ,GE1-350 - Abstract
The exposome encompasses an individual's exposure to exogenous chemicals, as well as endogenous chemicals that are produced or altered in response to external stressors. While the exposome concept has been established for human health, its principles can be extended to include broader ecological issues. The assessment of exposure is tightly interlinked with hazard assessment. Here, we explore if mechanistic understanding of the causal links between exposure and adverse effects on human health and the environment can be improved by integrating the exposome approach with the adverse outcome pathway (AOP) concept that structures and organizes the sequence of biological events from an initial molecular interaction of a chemical with a biological target to an adverse outcome. Complementing exposome research with the AOP concept may facilitate a mechanistic understanding of stress-induced adverse effects, examine the relative contributions from various components of the exposome, determine the primary risk drivers in complex mixtures, and promote an integrative assessment of chemical risks for both human and environmental health. Keywords: Exposome, AOP, Systems toxicology, Systems biology, Systems chemistry, Risk assessment
- Published
- 2017
- Full Text
- View/download PDF
15. Elevated Gestational IL-13 During Fetal Development Is Associated With Hyperactivity and Inattention in Eight-Year-Old Children
- Author
-
Loreen Thürmann, Gunda Herberth, Ulrike Rolle-Kampczyk, Stefan Röder, Michael Borte, Martin von Bergen, Irina Lehmann, and Saskia Trump
- Subjects
hyperactivity ,inattention ,SDQ ,maternal ,atopic dermatitis ,inflammation ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Maternal immune activation (MIA) during fetal development leads to behavioral and psychological disorders in the offspring. Concomitantly, insufficient supply of polyunsaturated fatty acids (PUFAs) is suspected to contribute to early neuronal maldevelopment due to the immune modulatory capabilities of PUFAs. However, human data are missing considering both of these aspects and their impact on children's behavioral outcomes. In line, this study aimed to elucidate the influence of gestational cytokines and PUFA-containing lipids during late pregnancy on behavioral sequelae in childhood, particularly focusing on an immune activation shaped by a history of maternal atopic diseases instead of a pathogen-mediated immune response. Based on the prospective mother-child cohort LINA we assessed the unstimulated blood cytokine profiles and concentrations of PUFA-containing lipids of 293 mothers at the 34th week of pregnancy. Maternal history of atopic diseases was obtained from questionnaires and behavior in eight-year-old children was assessed by the standardized Strength and Difficulties Questionnaires (SDQ) generating scores for hyperactivity/inattention, emotional symptoms, conduct problems, and peer relationship problems. Elevated IL-13 increased the risk for the child to show behavioral difficulties, in particular, hyperactive/inattentive behavior [adj. OR (95% CI): 2.47 (1.51–4.02), n = 255 vs. 38] at the age of eight years. Although the presence of maternal atopic dermatitis (AD) was associated with increased gestational IL-13 concentrations [adj. MR (95% CI): 1.17 (1.04–1.32)], no effect on children's behavioral difficulties was observed. However, a decrease in the PUFA containing lipid species PC aa C38:6 was not only associated with an increased gestational IL-13 concentration but also mediated the indirect effect of low PC aa C38:6 concentrations on children's abnormal behavior independent of maternal AD. We additionally assessed whether maternal IL-13 and PC aa C38:6 concentrations translate their effect by altering children's cord blood PC aa C38:6 and IL-13. While also the children's cord blood IL-13 was related to children's behavior, no effect of children's PC aa C38:6 was observed. This is the first study demonstrating that elevated gestational IL-13 increases the risk for children to develop behavioral difficulties. Analyses suggest that a reduced supply of gestational PC aa C38:6 contributes to elevated gestational IL-13 leading to behavioral sequelae in the offspring.
- Published
- 2019
- Full Text
- View/download PDF
16. Vaccinations and Infections Are Associated With Unrelated Antibody Titers: An Analysis From the German Birth Cohort Study LISA
- Author
-
Mahrrouz Caputo, Heike Raupach-Rosin, André Karch, Michael Borte, Irina Lehmann, Uwe Gerd Liebert, Marie Standl, Joachim Heinrich, and Rafael T. Mikolajczyk
- Subjects
humoral response ,vaccinations ,infectious diseases ,non-specific effects ,immune response ,Pediatrics ,RJ1-570 - Abstract
The evidence for non-specific effects (NSE) of vaccinations on all-cause morbidity and mortality among children is growing. However, our understanding of the underlying mechanisms is still limited. One hypothesis is that NSE are mediated by antibody titers. We used data of 2,123 children from the population-based birth cohort study LISA conducted in Germany to explore whether routine childhood vaccinations and the individual infection history in the first 2 years of life are associated with unrelated antibody titers. We selected 19 exposures (infections and vaccinations) and investigated their association with levels of 12 IgG antibody titers at the age of 2 years. Based on univariable analyses (ANOVA), we identified 21 crude associations between exposures and titers (p < 0.05), while 11 (95%-CI: 6, 17) spurious associations were expected due to multiple testing. In exploratory multivariable analyses, we observed associations between seven investigated IgG titers and 10 exposures; either administered vaccines [e.g., higher anti-hRSV IgG titer in BCG-vaccinated children (regression-coefficient in standard-deviation-units: 0.38; 95%-CI: 0.12, 0.65)] or infections [e.g., higher anti-measles IgG titer in children with reported chickenpox (0.44; 95%-CI: 0.08, 0.80)]. Our results indicate the existence of associations between immunogenic exposures and unrelated antibody titers. Further studies investigating the underlying immunological mechanisms are required.
- Published
- 2019
- Full Text
- View/download PDF
17. Maternal body mass index, gestational weight gain, and the risk of overweight and obesity across childhood: An individual participant data meta-analysis.
- Author
-
Ellis Voerman, Susana Santos, Bernadeta Patro Golab, Pilar Amiano, Ferran Ballester, Henrique Barros, Anna Bergström, Marie-Aline Charles, Leda Chatzi, Cécile Chevrier, George P Chrousos, Eva Corpeleijn, Nathalie Costet, Sarah Crozier, Graham Devereux, Merete Eggesbø, Sandra Ekström, Maria Pia Fantini, Sara Farchi, Francesco Forastiere, Vagelis Georgiu, Keith M Godfrey, Davide Gori, Veit Grote, Wojciech Hanke, Irva Hertz-Picciotto, Barbara Heude, Daniel Hryhorczuk, Rae-Chi Huang, Hazel Inskip, Nina Iszatt, Anne M Karvonen, Louise C Kenny, Berthold Koletzko, Leanne K Küpers, Hanna Lagström, Irina Lehmann, Per Magnus, Renata Majewska, Johanna Mäkelä, Yannis Manios, Fionnuala M McAuliffe, Sheila W McDonald, John Mehegan, Monique Mommers, Camilla S Morgen, Trevor A Mori, George Moschonis, Deirdre Murray, Carol Ní Chaoimh, Ellen A Nohr, Anne-Marie Nybo Andersen, Emily Oken, Adriëtte J J M Oostvogels, Agnieszka Pac, Eleni Papadopoulou, Juha Pekkanen, Costanza Pizzi, Kinga Polanska, Daniela Porta, Lorenzo Richiardi, Sheryl L Rifas-Shiman, Luca Ronfani, Ana C Santos, Marie Standl, Camilla Stoltenberg, Elisabeth Thiering, Carel Thijs, Maties Torrent, Suzanne C Tough, Tomas Trnovec, Steve Turner, Lenie van Rossem, Andrea von Berg, Martine Vrijheid, Tanja G M Vrijkotte, Jane West, Alet Wijga, John Wright, Oleksandr Zvinchuk, Thorkild I A Sørensen, Debbie A Lawlor, Romy Gaillard, and Vincent W V Jaddoe
- Subjects
Medicine - Abstract
BackgroundMaternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact.Methods and findingsWe conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0-5.0 years), mid (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations.ConclusionsIn this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.
- Published
- 2019
- Full Text
- View/download PDF
18. Handgrip strength is associated with improved spirometry in adolescents.
- Author
-
Maia Phillips Smith, Marie Standl, Dietrich Berdel, Andrea von Berg, Carl-Peter Bauer, Tamara Schikowski, Sibylle Koletzko, Irina Lehmann, Ursula Krämer, Joachim Heinrich, and Holger Schulz
- Subjects
Medicine ,Science - Abstract
Pulmonary rehabilitation, including aerobic exercise and strength training, improves function, such as spirometric indices, in lung disease. However, we found spirometry did not correlate with physical activity (PA) in healthy adolescents (Smith ERJ: 42(4), 2016). To address whether muscle strength did, we measured these adolescents' handgrip strength and correlated it with spirometry.In 1846 non-smoking, non-asthmatic Germans (age 15.2 years, 47% male), we modeled spirometric indices as functions of handgrip strength by linear regression in each sex, corrected for factors including age, height, and lean body mass.Handgrip averaged 35.4 (SD 7.3) kg in boys, 26.6 (4.2) in girls. Spirometric volumes and flows increased linearly with handgrip. In boys each kg handgrip was associated with about 28 mL greater FEV1 and FVC; 60 mL/sec faster PEF; and 38 mL/sec faster FEF2575. Effects were 10-30% smaller in girls (all p
- Published
- 2018
- Full Text
- View/download PDF
19. Prenatal VOC exposure and redecoration are related to wheezing in early infancy
- Author
-
Ulrich Franck, Annegret Weller, Stefan W. Röder, Gunda Herberth, Kristin M. Junge, Tibor Kohajda, Martin von Bergen, Ulrike Rolle-Kampczyk, Ulrike Diez, Michael Borte, and Irina Lehmann
- Subjects
Environmental sciences ,GE1-350 - Abstract
Redecoration of dwellings is a common behavior of expecting parents. Former studies gave evidence that early childhood exposure to volatile organic compounds (VOC) resulting from renovation activities may increase the risk for wheeze in infants. Objectives: The aim of the present study was to evaluate the impact of prenatal exposure on early wheeze and to identify sensitive time windows.Within the LINA birth cohort study data on renovation activities and respiratory outcomes were assessed via questionnaires during pregnancy and at children's age of one. At both timepoints, also indoor VOC concentrations were measured. The associations were studied by logistic regression analysis.Floor covering during pregnancy contributed to an increased risk for physician treated wheeze (adjusted odds ratio OR = 5.20, 95% confidence interval 1.8–15.2) during the first 12 months after birth in particular in children with an atopic predisposition. Thereby, wall-to-wall-carpets, PVC material, and laminate were the flooring materials which showed the strongest adverse associations. Floor covering was associated with enhanced concentrations of VOCs in the apartments. For the VOCs styrene, ethylbenzene, octane, 1-butanol, tridecane, and o-xylene, a significant association was found to the occurrence of wheezing symptoms. In contrast to pregnancy, exposure during the first 12 months after birth showed less detrimental associations. Only the association between wheezing and styrene as well as between wheezing and PVC flooring remained significant for exposure after birth.Redecoration during pregnancy, especially changing floor materials, increases the risk for respiratory diseases in early childhood and should therefore be avoided at least in families with a history of atopic diseases. Keywords: Childhood, Prenatal exposure, Wheezing, Volatile organic compounds, Redecoration
- Published
- 2014
- Full Text
- View/download PDF
20. Dietary Acid Load and Mental Health Outcomes in Children and Adolescents: Results from the GINIplus and LISA Birth Cohort Studies
- Author
-
Judith Bühlmeier, Carla Harris, Sibylle Koletzko, Irina Lehmann, Carl-Peter Bauer, Tamara Schikowski, Andrea von Berg, Dietrich Berdel, Joachim Heinrich, Johannes Hebebrand, Manuel Föcker, Marie Standl, and Lars Libuda
- Subjects
PRAL ,acid base balance ,low grade metabolic acidosis ,SDQ ,emotional problems ,hyperactivity ,Nutrition. Foods and food supply ,TX341-641 - Abstract
High dietary acid load may have detrimental effects on mental health during childhood and adolescence. We examined cross-sectional and prospective associations of dietary acid load and mental health problems in a population-based sample, using data from the German birth cohort studies GINIplus (German Infant Nutritional Intervention plus environmental and genetic influences on allergy development) and LISA (Influences of lifestyle-related factors on the immune system and the development of allergies in childhood). These studies included detailed assessments of dietary intake through a food frequency questionnaire (FFQ), mental health outcomes measured through the Strengths and Difficulties Questionnaire (SDQ), and covariates. Using logistic regression, cross-sectional associations between dietary acid load measured as potential renal acid load (PRAL) and SDQ subscales were assessed at age 10 years (N = 2350) and 15 years (N = 2061). Prospective associations were assessed, considering PRAL at 10 years as exposure and SDQ subscales at 15 years as outcome (N = 1685). Results indicate that children with a diet higher in PRAL have more emotional problems (OR = 1.33 (95% CI = 1.15; 1.54); p < 0.001), and show hyperactivity more often (1.22 (1.04; 1.43); p = 0.014) at 10 years. No significant associations were present either cross-sectionally at age 15 years, nor prospectively. Results were confirmed in sensitivity analyses. These findings reveal first evidence for potential relationships between PRAL and mental health in childhood, although we cannot exclude reverse causality, i.e., that dietary behavior and PRAL are influenced by mental status. Future studies should address confirmation and identify biological mechanisms.
- Published
- 2018
- Full Text
- View/download PDF
21. Lifetime-dependent effects of bisphenol A on asthma development in an experimental mouse model.
- Author
-
Susanne Petzold, Marco Averbeck, Jan C Simon, Irina Lehmann, and Tobias Polte
- Subjects
Medicine ,Science - Abstract
BACKGROUND: Environmental factors are thought to contribute significantly to the increase of asthma prevalence in the last two decades. Bisphenol A (BPA) is a xenoestrogen commonly used in consumer products and the plastic industry. There is evidence and an ongoing discussion that endocrine disruptors like BPA may affect human health and also exert alterations on in the immune system. The aim of this study was to investigate age-dependent effects of BPA on the asthma risk using a murine model to explain the controversial results reported till date. METHODS: BALB/c mice were exposed to BPA via the drinking water for different time periods including pregnancy and breastfeeding. To induce an asthma phenotype, mice were sensitized to ovalbumin (OVA), followed by an intrapulmonary allergen challenge. RESULTS: BPA exposure during pregnancy and breastfeeding had no significant effect on asthma development in the offspring. In contrast, lifelong exposure from birth until the last antigen challenge clearly increased eosinophilic inflammation in the lung, airway hyperreactivity and antigen-specific serum IgE levels in OVA-sensitized adult mice compared to mice without BPA exposure. Surprisingly, BPA intake during the sensitization period significantly reduced the development of allergic asthma. This effect was reversed in the presence of a glucocorticoid receptor antagonist. CONCLUSIONS: Our results demonstrate that the impact of BPA on asthma risk is strongly age-dependent and ranges from asthma-promoting to asthma-reducing effects. This could explain the diversity of results from previous studies regarding the observed health impact of BPA.
- Published
- 2014
- Full Text
- View/download PDF
22. Generation of IL-8 and IL-9 Producing CD4+ T Cells Is Affected by Th17 Polarizing Conditions and AHR Ligands
- Author
-
Michaela Gasch, Tina Goroll, Mario Bauer, Denise Hinz, Nicole Schütze, Tobias Polte, Dörthe Kesper, Jan C. Simon, Jörg Hackermüller, Irina Lehmann, and Gunda Herberth
- Subjects
Pathology ,RB1-214 - Abstract
The T helper cell subsets Th1, Th2, Th17, and Treg play an important role in immune cell homeostasis, in host defense, and in immunological disorders. Recently, much attention has been paid to Th17 cells which seem to play an important role in the early phase of the adoptive immune response and autoimmune disease. When generating Th17 cells under in vitro conditions the amount of IL-17A producing cells hardly exceeds 20% while the nature of the remaining T cells is poorly characterized. As engagement of the aryl hydrocarbon receptor (AHR) has also been postulated to modulate the differentiation of T helper cells into Th17 cells with regard to the IL-17A expression we ask how far do Th17 polarizing conditions in combination with ligand induced AHR activation have an effect on the production of other T helper cell cytokines. We found that a high proportion of T helper cells cultured under Th17 polarizing conditions are IL-8 and IL-9 single producing cells and that AHR activation results in an upregulation of IL-8 and a downregulation of IL-9 production. Thus, we have identified IL-8 and IL-9 producing T helper cells which are subject to regulation by the engagement of the AHR.
- Published
- 2014
- Full Text
- View/download PDF
23. A longitudinal analysis of associations between traffic-related air pollution with asthma, allergies and sensitization in the GINIplus and LISAplus birth cohorts
- Author
-
Elaine Fuertes, Marie Standl, Josef Cyrys, Dietrich Berdel, Andrea von Berg, Carl-Peter Bauer, Ursula Krämer, Dorothea Sugiri, Irina Lehmann, Sibylle Koletzko, Chris Carlsten, Michael Brauer, and Joachim Heinrich
- Subjects
Asthma ,Allergies ,Air pollution ,Birth cohort ,Children ,Long-term exposure ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Background. There is a need to study whether the adverse effects of traffic-related air pollution (TRAP) on childhood asthma and allergic diseases documented during early-life persist into later childhood. This longitudinal study examined whether TRAP is associated with the prevalence of asthma, allergic rhinitis and aeroallergen sensitization in two German cohorts followed from birth to 10 years.Materials. Questionnaire-derived annual reports of doctor diagnosed asthma and allergic rhinitis, as well as eye and nose symptoms, were collected from 6,604 children. Aeroallergen sensitization was assessed for 3,655 children who provided blood samples. Associations between these health outcomes and nitrogen dioxide (NO2), particles with aerodynamic diameters less than 2.5 µg/m3 (PM2.5) mass, PM2.5 absorbance and ozone, individually estimated for each child at the birth, six and 10 year home addresses, were assessed using generalized estimation equations including adjustments for relevant covariates. Odds ratios [95% confidence intervals] per increase in interquartile range of pollutant are presented for the total population and per geographical area (GINI/LISA South, GINI/LISA North and LISA East, Germany).Results. The risk estimates for the total population were generally null across outcomes and pollutants. The area-specific results were heterogeneous. In GINI/LISA North, all associations were null. In LISA East, associations with ozone were elevated for all outcomes, and those for allergic rhinitis and eyes and nose symptom prevalence reached statistical significance (1.30 [1.02, 1.64] and 1.35 [1.16, 1.59], respectively). For GINI/LISA South, two associations with aeroallergen sensitization were significant (0.84 [0.73, 0.97] for NO2 and 0.87 [0.78, 0.97] for PM2.5 absorbance), as well as the association between allergic rhinitis and PM2.5 absorbance (0.83 [0.72, 0.96]).Conclusions. This study did not find consistent evidence that TRAP increases the prevalence of childhood asthma, allergic rhinitis or aeroallergen sensitization in later childhood using data from birth cohort participants followed for 10 years in three locations in Germany. Results were heterogeneous across the three areas investigated.
- Published
- 2013
- Full Text
- View/download PDF
24. Children with ADHD symptoms have a higher risk for reading, spelling and math difficulties in the GINIplus and LISAplus cohort studies.
- Author
-
Darina Czamara, Carla M T Tiesler, Gabriele Kohlböck, Dietrich Berdel, Barbara Hoffmann, Carl-Peter Bauer, Sibylle Koletzko, Beate Schaaf, Irina Lehmann, Olf Herbarth, Andrea von Berg, Bertram Müller-Myhsok, Gerd Schulte-Körne, and Joachim Heinrich
- Subjects
Medicine ,Science - Abstract
Attention-deficit/hyperactivity disorder (ADHD) and dyslexia belong to the most common neuro-behavioral childhood disorders with prevalences of around 5% in school-aged children. It is estimated that 20-60% of individuals affected with ADHD also present with learning disorders. We investigated the comorbidity between ADHD symptoms and reading/spelling and math difficulties in two on-going population-based birth cohort studies. Children with ADHD symptoms were at significantly higher risk of also showing reading/spelling difficulties or disorder (Odds Ratio (OR) = 2.80, p = 6.59×10⁻¹³) as compared to children without ADHD symptoms. For math difficulties the association was similar (OR = 2.55, p = 3.63×10⁻⁰⁴). Our results strengthen the hypothesis that ADHD and learning disorders are comorbid and share, at least partially, the same underlying process. Up to date, it is not clear, on which exact functional processes this comorbidity is based.
- Published
- 2013
- Full Text
- View/download PDF
25. Volatile organic compounds enhance allergic airway inflammation in an experimental mouse model.
- Author
-
Ulrike Bönisch, Alexander Böhme, Tibor Kohajda, Iljana Mögel, Nicole Schütze, Martin von Bergen, Jan C Simon, Irina Lehmann, and Tobias Polte
- Subjects
Medicine ,Science - Abstract
Epidemiological studies suggest an association between exposure to volatile organic compounds (VOCs) and adverse allergic and respiratory symptoms. However, whether VOCs exhibit a causal role as adjuvants in asthma development remains unclear.To investigate the effect of VOC exposure on the development of allergic airway inflammation Balb/c mice were exposed to VOCs emitted by new polyvinylchloride (PVC) flooring, sensitized with ovalbumin (OVA) and characterized in acute and chronic murine asthma models. Furthermore, prevalent evaporated VOCs were analyzed and mice were exposed to selected single VOCs.Exposure of mice to PVC flooring increased eosinophilic lung inflammation and OVA-specific IgE serum levels compared to un-exposed control mice. The increased inflammation was associated with elevated levels of Th2-cytokines. Long-term exposure to PVC flooring exacerbated chronic airway inflammation. VOCs with the highest concentrations emitted by new PVC flooring were N-methyl-2-pyrrolidone (NMP) and 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB). Exposure to NMP or TXIB also increased the allergic immune response in OVA-sensitized mice. In vitro or in vivo exposure to NMP or TXIB reduced IL-12 production in maturing dendritic cells (DCs) and enhanced airway inflammation after adoptive DC transfer into Balb/c mice. At higher concentrations both VOCs induced oxidative stress demonstrated by increased isoprostane and glutathione-S-transferase-pi1 protein levels in the lung of non-sensitized mice. Treatment of PVC flooring-exposed mice with N-acetylcysteine prevented the VOC-induced increase of airway inflammation.Our results demonstrate that exposure to VOCs may increase the allergic immune response by interfering with DC function and by inducing oxidative stress and has therefore to be considerate as risk factor for the development of allergic diseases.
- Published
- 2012
- Full Text
- View/download PDF
26. Membership Inference Against DNA Methylation Databases.
- Author
-
Inken Hagestedt, Mathias Humbert, Pascal Berrang, Irina Lehmann, Roland Eils, Michael Backes 0001, and Yang Zhang 0016
- Published
- 2020
- Full Text
- View/download PDF
27. Dissecting Privacy Risks in Biomedical Data.
- Author
-
Pascal Berrang, Mathias Humbert, Yang Zhang 0016, Irina Lehmann, Roland Eils, and Michael Backes 0001
- Published
- 2018
- Full Text
- View/download PDF
28. Leveraging implicit knowledge in neural networks for functional dissection and engineering of proteins.
- Author
-
Julius Upmeier zu Belzen, Thore Bürgel, Stefan Holderbach, Felix Bubeck, Lukás Adam, Catharina Gandor, Marita Klein, Jan Mathony, Pauline Pfuderer, Lukas Platz, Moritz Przybilla, Max Schwendemann, Daniel Heid, Mareike Daniela Hoffmann, Michael Jendrusch, Carolin Schmelas, Max Waldhauer, Irina Lehmann, Dominik Niopek, and Roland Eils
- Published
- 2019
- Full Text
- View/download PDF
29. Identifying Personal DNA Methylation Profiles by Genotype Inference.
- Author
-
Michael Backes 0001, Pascal Berrang, Matthias Bieg, Roland Eils, Carl Herrmann, Mathias Humbert, and Irina Lehmann
- Published
- 2017
- Full Text
- View/download PDF
30. Enhanced Airway Epithelial Response to SARS-CoV-2 Infection in Children is Critically Tuned by the Cross-Talk Between Immune and Epithelial Cells
- Author
-
Vladimir G. Magalhães, Sören Lukassen, Maike Drechsler, Jennifer Loske, Sandy S. Burkart, Sandra Wüst, Eva-Maria Jacobsen, Jobst Röhmel, Marcus A. Mall, Klaus-Michael Debatin, Roland Eils, Stella Autenrieth, Aleš Janda, Irina Lehmann, and Marco Binder
- Abstract
To cope with novel virus infections to which no prior adaptive immunity exists, the body strongly relies on the innate immune system. In such cases, including infections with SARS-CoV-2, children tend to fair better than adults. In the context of COVID-19, it became evident that a rapid interferon response at the site of primary infection is key for successful control of the virus and prevention of severe disease. The airway epithelium of children was shown to exhibit a primed state already at homeostasis and to respond particularly well to SARS-CoV-2 infection. However, the underlying mechanism for this priming remained elusive. Here we show that interactions between airway mucosal immune cells and epithelial cells are stronger in children, and via cytokine-mediated signaling lead to IRF-1-dependent upregulation of the viral sensors RIG-I and MDA5. Based on a cellularin vitromodel we show that stimulated human peripheral blood mononuclear cells (PBMC) can induce a robust interferon-beta response towards SARS-CoV-2 in a lung epithelial cell line otherwise unresponsive to this virus. This is mediated by type I interferon, interferon-gamma and TNF, and requires induction of both, RIG-I and MDA5. In single cell-analysis of nasal swab samples the same cytokines are found to be elevated in mucosal immune cells of children, correlating with elevated epithelial expression of viral sensors.In vitroanalysis of PBMC derived from healthy adolescents and adults confirm that immune cells of younger individuals show increased cytokine production and potential to prime epithelial cells. In co-culture with SARS-CoV-2-infected A549 cells, PBMC from adolescents significantly enhance the antiviral response. Taken together, our study suggests that higher numbers and a more vigorous activity of innate immune cells in the airway mucosa of children tune the set-point of the epithelial antiviral system. This likely is a major contributor to the robust immune response to SARS-CoV-2 in children. Our findings shed light on the molecular underpinnings of the stunning resilience of children towards severe COVID-19, and may propose a novel concept for immunoprophylactic treatments.
- Published
- 2023
31. Klinisches Bild von COVID-19 bei Kindern und Jugendlichen mit primärer SARS-CoV-2-Infektion im Verlauf der Pandemie
- Author
-
Sebastian Stricker, Niklas Ziegahn, Martin Karsten, Thomas Böckel, Heike Stich-Böckel, Jakob Maske, Evelyn Rugo, Anita Balázs, PamelaMillar Büchner, Chantip Dang-Heine, Mirjam Stahl, Roland Eils, Irina Lehmann, Leif E. Sander, Markus Ralser, Victor M. Corman, Marcus A. Mall, Birgit Sawitzki, and Jobst Röhmel
- Published
- 2023
32. Global hypomethylation in childhood asthma identified by genome‐wide DNA‐methylation sequencing preferentially affects enhancer regions
- Author
-
Loreen Thürmann, Matthias Klös, Sebastian D. Mackowiak, Matthias Bieg, Tobias Bauer, Naveed Ishaque, Marey Messingschlager, Carl Herrmann, Stefan Röder, Mario Bauer, Sascha Schäuble, Erik Faessler, Udo Hahn, Dieter Weichenhan, Oliver Mücke, Christoph Plass, Michael Borte, Erika von Mutius, Gabriele I. Stangl, Roger Lauener, Anne M. Karvonen, Amandine Divaret‐Chauveau, Josef Riedler, Joachim Heinrich, Marie Standl, Andrea von Berg, Beate Schaaf, Gunda Herberth, Michael Kabesch, Roland Eils, Saskia Trump, and Irina Lehmann
- Subjects
Immunology ,Immunology and Allergy - Published
- 2023
33. RECAST: Study protocol for an observational study for the understanding of the increased resilience of children compared to adults in SARS-CoV-2 infection
- Author
-
Sebastian Stricker, Niklas Ziegahn, Martin Karsten, Thomas Boeckel, Heike Stich-Boeckel, Jakob Maske, Evelyn Rugo, Anita Balazs, Pamela Millar Büchner, Chantip Dang-Heine, Valentin Schriever, Roland Eils, Irina Lehmann, Leif E Sander, Markus Ralser, Victor M Corman, Marcus A Mall, Birgit Sawitzki, and Jobst Roehmel
- Subjects
Chemical Biology & High Throughput ,Metabolism ,Ecology,Evolution & Ethology ,Synthetic Biology ,General Medicine ,Computational & Systems Biology - Abstract
IntroductionThe SARS-CoV-2 pandemic remains a threat to public health. Soon after its outbreak, it became apparent that children are less severely affected. Indeed, opposing clinical manifestations between children and adults are observed for other infections. The SARS-CoV-2 outbreak provides the unique opportunity to study the underlying mechanisms. This protocol describes the methods of an observational study that aims to characterise age dependent differences in immune responses to primary respiratory infections using SARS-CoV-2 as a model virus and to assess age differences in clinical outcomes including lung function.Methods and analysisThe study aims to recruit at least 120 children and 60 adults that are infected with SARS-CoV-2 and collect specimen for a multiomics analysis, including single cell RNA sequencing of nasal epithelial cells and peripheral blood mononuclear cells, mass cytometry of whole blood samples and nasal cells, mass spectrometry-based serum and plasma proteomics, nasal epithelial cultures with functional in vitro analyses, SARS-CoV-2 antibody testing, sequencing of the viral genome and lung function testing. Data obtained from this multiomics approach are correlated with medical history and clinical data. Recruitment started in October 2020 and is ongoing.Ethics and disseminationThe study was reviewed and approved by the Ethics Committee of Charité – Universitätsmedizin Berlin (EA2/066/20). All collected specimens are stored in the central biobank of Charité – Universitätsmedizin Berlin and are made available to all participating researchers and on request.Trial registration numberDRKS00025715, pre-results publication.
- Published
- 2023
- Full Text
- View/download PDF
34. Publisher Correction: Leveraging implicit knowledge in neural networks for functional dissection and engineering of proteins.
- Author
-
Julius Upmeier zu Belzen, Thore Bürgel, Stefan Holderbach, Felix Bubeck, Lukás Adam, Catharina Gandor, Marita Klein, Jan Mathony, Pauline Pfuderer, Lukas Platz, Moritz Przybilla, Max Schwendemann, Daniel Heid, Mareike Daniela Hoffmann, Michael Jendrusch, Carolin Schmelas, Max Waldhauer, Irina Lehmann, Dominik Niopek, and Roland Eils
- Published
- 2019
- Full Text
- View/download PDF
35. Maternal paraben exposure triggers childhood overweight development
- Author
-
Bettina Seiwert, Loreen Thürmann, Michael Borte, Thorsten Reemtsma, Stefan Röder, Rita Schlichting, Sandra Strunz, Beate I. Escher, Tobias Polte, Christiane Pfeiffer, Kristin M. Junge, Torsten Schöneberg, Isabell Karkossa, Irina Lehmann, Martin von Bergen, Beate Leppert, Gabriele I. Stangl, Linda Schlittenbauer, Ulrike Rolle-Kampczyk, Mario Bauer, and Angela Schulz
- Subjects
0301 basic medicine ,Male ,Pro-Opiomelanocortin ,General Physics and Astronomy ,Physiology ,010501 environmental sciences ,Overweight ,Urine ,Weight Gain ,01 natural sciences ,chemistry.chemical_compound ,Eating ,Mice ,Pregnancy ,Epidemiology ,Child ,lcsh:Science ,Multidisciplinary ,Paraben ,Maternal Exposure ,Child, Preschool ,Prenatal Exposure Delayed Effects ,Cohort ,Female ,medicine.symptom ,medicine.medical_specialty ,Offspring ,Urinary system ,Science ,Hypothalamus ,Parabens ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,medicine ,Animals ,Humans ,0105 earth and related environmental sciences ,business.industry ,Preservatives, Pharmaceutical ,General Chemistry ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,lcsh:Q ,business ,Weight gain - Abstract
Parabens are preservatives widely used in consumer products including cosmetics and food. Whether low-dose paraben exposure may cause adverse health effects has been discussed controversially in recent years. Here we investigate the effect of prenatal paraben exposure on childhood overweight by combining epidemiological data from a mother–child cohort with experimental approaches. Mothers reporting the use of paraben-containing cosmetic products have elevated urinary paraben concentrations. For butyl paraben (BuP) a positive association is observed to overweight within the first eight years of life with a stronger trend in girls. Consistently, maternal BuP exposure of mice induces a higher food intake and weight gain in female offspring. The effect is accompanied by an epigenetic modification in the neuronal Pro-opiomelanocortin (POMC) enhancer 1 leading to a reduced hypothalamic POMC expression. Here we report that maternal paraben exposure may contribute to childhood overweight development by altered POMC-mediated neuronal appetite regulation.
- Published
- 2020
36. Pre-activated anti-viral innate immunity in the upper airways controls early SARS-CoV-2 infection in children
- Author
-
Leif E. Sander, Vladimir Gonçalves Magalhães, Sebastian Stricker, Saskia Trump, Irina Lehmann, Sven Laudi, Sven Klages, Johannes Liebig, Victor M. Corman, Jennifer Loske, Roland Eils, Soeren Lukassen, Bernd Timmermann, Marcus A. Mall, Christian Conrad, Markus Ralser, Anke Seegebarth, Marey Messingschlager, Birgit Sawitzki, Marco Binder, Jobst Röhmel, Loreen Thürmann, and Robert Lorenz Chua
- Subjects
Male ,Interferon-Induced Helicase, IFIH1 ,viruses ,CD8-Positive T-Lymphocytes ,Applied Microbiology and Biotechnology ,Basal (phylogenetics) ,Cytotoxic T cell ,Receptors, Immunologic ,Child ,education.field_of_study ,Pattern recognition receptor ,Middle Aged ,medicine.anatomical_structure ,Child, Preschool ,DEAD Box Protein 58 ,Molecular Medicine ,Female ,Single-Cell Analysis ,Biotechnology ,Adult ,Adolescent ,T cell ,Population ,Biomedical Engineering ,Bronchi ,Bioengineering ,Biology ,Virus ,Young Adult ,Immune system ,Immunity ,medicine ,Humans ,education ,Aged ,Innate immune system ,SARS-CoV-2 ,business.industry ,Macrophages ,Infant, Newborn ,COVID-19 ,Infant ,Epithelial Cells ,Dendritic Cells ,Immunity, Innate ,Immunology ,business ,Airway ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults. Single-cell sequencing reveals pre-activated immunity as important for milder COVID-19 symptoms in children.
- Published
- 2021
37. Prenatal paraben exposure and atopic dermatitis-related outcomes among children
- Author
-
Michael Borte, Stefan Röder, Gunda Herberth, Loreen Thürmann, Martin von Bergen, Saskia Trump, Linda Schlittenbauer, Ulrich Sack, Bettina Seiwert, Ulrike Rolle-Kampczyk, Irina Lehmann, and Thorsten Reemtsma
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Allergy ,Amniotic fluid ,prenatal ,paraben ,Immunology ,Eczema ,Parabens ,Persistence (computer science) ,Dermatitis, Atopic ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pregnancy ,Internal medicine ,medicine ,Genetic predisposition ,Hypersensitivity ,Immunology and Allergy ,sex ,Humans ,Child ,Asthma ,atopic dermatitis ,business.industry ,Infant ,Atopic dermatitis ,medicine.disease ,allergy ,Paraben ,030104 developmental biology ,030228 respiratory system ,chemistry ,Child, Preschool ,Gestation ,Female ,business ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit - Abstract
Background Parabens, widely used as preservatives in cosmetics, foods, and other consumer products, are suspected of contributing to allergy susceptibility. The detection of parabens in the placenta or amniotic fluid raised concerns about potential health consequences for the child. Recently, an increased asthma risk following prenatal exposure has been reported. Here, we investigated whether prenatal paraben exposure can influence the risk for atopic dermatitis (AD). Methods 261 mother-child pairs of the German mother-child study LINA were included in this analysis. Eight paraben species were quantified in maternal urine obtained at gestational week 34. According to the parental report of physician-diagnosed AD from age 1 to 8 years, disease onset, and persistence, childhood AD was classified into four different phenotypes. Results 4.6% (n = 12) and 12.3% (n = 32) of the children were classified as having very early-onset AD (until age two) either with or without remission, 11.9% (n = 31) as early-onset (after age two), and 3.1% (n = 8) as childhood-onset AD (after age six). Exposure to ethylparaben and n-butylparaben was associated with an increased risk to develop very early-onset AD without remission (EtP: adj.OR/95% CI:1.44/1.04-2.00,nBuP:adj.OR/95% CI:1.95/1.22-3.12). The effects of both parabens were predominant in children without a history of maternal AD and independent of children's sex. Conclusion Prenatal EtP or nBuP exposure may increase children's susceptibility for persistent AD with disease onset at very early age. This association was particularly pronounced in children without a history of maternal AD, indicating that children without a genetic predisposition are more susceptible to paraben exposure.
- Published
- 2021
38. Leveraging implicit knowledge in neural networks for functional dissection and engineering of proteins
- Author
-
Daniel Heid, Dominik Niopek, Max C. Waldhauer, Irina Lehmann, Moritz Jakob Przybilla, Pauline L. Pfuderer, Roland Eils, Thore Bürgel, Catharina Gandor, Marita Klein, Mareike D. Hoffmann, Carolin Schmelas, Felix Bubeck, Julius Upmeier zu Belzen, Lukas Platz, Jan Mathony, Lukas Adam, Stefan Holderbach, Max Schwendemann, and Michael Jendrusch
- Subjects
0301 basic medicine ,Artificial neural network ,Computer Networks and Communications ,Computer science ,Computational biology ,Protein engineering ,Molecular machine ,Implicit knowledge ,Human-Computer Interaction ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Protein sequencing ,Signalling ,Artificial Intelligence ,Leverage (statistics) ,Computer Vision and Pattern Recognition ,Small molecule binding ,030217 neurology & neurosurgery ,Software - Abstract
Proteins are nature’s most versatile molecular machines. Deep neural networks trained on large protein datasets have recently been used to tackle the unmet complexity of protein sequence–function relationships. The implicit knowledge contained in these networks represents a powerful, but thus far inaccessible, resource for understanding protein biology. Here, we show that occlusion-based sensitivity analysis can leverage the knowledge present in deep-neural-network-based protein sequence classifiers to identify functionally relevant parts of proteins. We first validated our approach by successfully predicting positions that mediate small molecule binding or catalytic activity across different protein classes. Next, we inferred the impact of point mutations on the activity of ERK and HRas, signalling factors frequently deregulated in cancer. Finally, we used our approach to identify engineering hotspots in CRISPR–Cas9 and anti-CRISPR protein AcrIIA4. Our work demonstrates how implicit knowledge in neural networks can be harnessed for protein functional dissection and protein engineering. Deep neural networks are a powerful tool for predicting protein function, but identifying the specific parts of a protein sequence that are relevant to its functions remains a challenge. An occlusion-based sensitivity technique helps interpret these deep neural networks, and can guide protein engineering by locating functionally relevant protein positions.
- Published
- 2019
39. Hyperinflammation as underlying mechanism predisposing patients with cardiovascular diseases for severe COVID-19
- Author
-
Roland Eils, Irina Lehmann, and Ulf Landmesser
- Subjects
Adult ,Male ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Respiratory System ,Receptors, CCR1 ,Angiotensin-Converting Enzyme Inhibitors ,Angiotensin Receptor Antagonists ,Risk Factors ,Humans ,Medicine ,AcademicSubjects/MED00200 ,RNA-Seq ,Chemokine CCL4 ,Chemokine CCL3 ,Inflammation ,SARS-CoV-2 ,business.industry ,Mechanism (biology) ,COVID-19 ,Middle Aged ,COVID-19 Drug Treatment ,CardioPulse ,Gene Expression Regulation ,Hypertension ,Immunology ,Disease Progression ,Female ,Single-Cell Analysis ,Cardiology and Cardiovascular Medicine ,business - Abstract
In coronavirus disease 2019 (COVID-19), hypertension and cardiovascular diseases are major risk factors for critical disease progression. However, the underlying causes and the effects of the main anti-hypertensive therapies-angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)-remain unclear. Combining clinical data (n = 144) and single-cell sequencing data of airway samples (n = 48) with in vitro experiments, we observed a distinct inflammatory predisposition of immune cells in patients with hypertension that correlated with critical COVID-19 progression. ACEI treatment was associated with dampened COVID-19-related hyperinflammation and with increased cell intrinsic antiviral responses, whereas ARB treatment related to enhanced epithelial-immune cell interactions. Macrophages and neutrophils of patients with hypertension, in particular under ARB treatment, exhibited higher expression of the pro-inflammatory cytokines CCL3 and CCL4 and the chemokine receptor CCR1. Although the limited size of our cohort does not allow us to establish clinical efficacy, our data suggest that the clinical benefits of ACEI treatment in patients with COVID-19 who have hypertension warrant further investigation.
- Published
- 2021
40. Delayed viral clearance and exacerbated airway hyperinflammation in hypertensive COVID-19 patients
- Author
-
Fabian Pott, Marco Binder, Martin Witzenrath, Christine Goffinet, Sven Laudi, Leif E. Sander, Irina Lehmann, Teresa G Krieger, Saskia Trump, Loreen Thürmann, Johannes Liebig, Sara Hadzibegovic, Robert Lorenz Chua, Uwe G. Liebert, Jan Philipp Albrecht, Lars Kaderali, Sven Twardziok, Christian Conrad, Bianca P Hennig, Bettina Heidecker, Jennifer Loske, Alessia Lena, Markus S. Anker, Naveed Ishaque, Soeren Lukassen, Christian Drosten, Maria Theresa Völker, Christina Klasa, Sarah Dorothea Müller, Marey Messingschlager, Roland Eils, Florian Kurth, Ulf Landmesser, Victor M. Corman, Julia Kazmierski, and Jürgen Eils
- Subjects
CCR1 ,medicine.anatomical_structure ,Immune system ,business.industry ,Immunology ,Cell ,medicine ,CCL3 ,CCL4 ,Disease ,Receptor ,business ,Pathophysiology - Abstract
In COVID-19, hypertension and cardiovascular diseases have emerged as major risk factors for critical disease progression. Concurrently, the impact of the main anti-hypertensive therapies, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), on COVID-19 severity is controversially discussed. By combining clinical data, single-cell sequencing data of airway samples andin vitroexperiments, we assessed the cellular and pathophysiological changes in COVID-19 driven by cardiovascular disease and its treatment options. Anti-hypertensive ACEi or ARB therapy, was not associated with an altered expression of SARS-CoV-2 entry receptorACE2in nasopharyngeal epithelial cells and thus presumably does not change susceptibility for SARS-CoV-2 infection. However, we observed a more critical progress in COVID-19 patients with hypertension associated with a distinct inflammatory predisposition of immune cells. While ACEi treatment was associated with dampened COVID-19-related hyperinflammation and intrinsic anti-viral responses, under ARB treatment enhanced epithelial-immune cell interactions were observed. Macrophages and neutrophils of COVID-19 patients with hypertension and cardiovascular comorbidities, in particular under ARB treatment, exhibited higher expression ofCCL3, CCL4, and its receptorCCR1, which associated with critical COVID-19 progression. Overall, these results provide a potential explanation for the adverse COVID-19 course in patients with cardiovascular disease, i.e. an augmented immune response in critical cells for the disease course, and might suggest a beneficial effect of clinical ACEi treatment in hypertensive COVID-19 patients.
- Published
- 2020
41. We are what we experienced before birth: Lessons from epigenetics
- Author
-
Tobias Polte, Roland Eils, Matthias Klös, Irina Lehmann, Saskia Trump, and Loreen Thürmann
- Subjects
Pulmonary and Respiratory Medicine ,Gerontology ,lcsh:Immunologic diseases. Allergy ,business.industry ,Immunology ,Immunology and Allergy ,Medicine ,Epigenetics ,business ,lcsh:RC581-607 - Published
- 2020
42. Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America
- Author
-
Andrea von Berg, Per Magnus, Camilla Stoltenberg, George P. Chrousos, Cécile Chevrier, Costanza Pizzi, Marleen M.H.J. van Gelder, Tanja G. M. Vrijkotte, Oleksandr Zvinchuk, Elise M. Philips, Daniel O. Hryhorczuk, Vincent W. V. Jaddoe, Philippa K Bird, Deirdre M. Murray, Elisabeth Thiering, Marie Standl, Merete Eggesbø, Sara Farchi, Daniela Porta, Lorenzo Richiardi, Maria Pia Fantini, Francesco Forastiere, Carel Thijs, Vagelis Georgiu, Camilla Schmidt Morgen, Yannis Manios, Leda Chatzi, Henrique Barros, Irina Lehmann, Juan J. Aurrekoetxea, Thorkild I. A. Sørensen, Juha Pekkanen, Emily Oken, Adriette J. J. M. Oostvogels, Nel Roeleveld, Jordi Sunyer, Anne-Marie Nybo Andersen, Ellen A. Nohr, Romy Gaillard, Anna Bergström, Sheryl L. Rifas-Shiman, George Moschonis, Monique Mommers, Ana Cristina Santos, Hazel Inskip, Sonia Brescianini, Wojciech Hanke, Kinga Polańska, Louise C. Kenny, Leonardo Trasande, Debbie A Lawlor, Inger Kull, Anne M. Karvonen, Nathalie Costet, Marie-Aline Charles, Susana Santos, Sarah Crozier, John Wright, Barbara Heude, Carmen Iñiguez, Erik Melén, Maties Torrent, Davide Gori, Rachel Criswell, Eleni Papadopoulou, Franca Rusconi, Keith M. Godfrey, Carol Ní Chaoimh, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), European Commission733206United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USAR01ES022972United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS)P30ES007048R21ES029681R01ES029944R01ES030364R21ES028903UK MRC fundingMC_UU_12013/5Portuguese Foundation for Science and TechnologyEuropean CommissionIF/01060/2015Netherlands Heart Foundation2017T013Dutch Diabetes Foundation2017.81.002Netherlands Organization for Health Research and Development543003109European Research Council (ERC)European CommissionERC-2014-CoG-64891, Epidemiologie, RS: CAPHRI - R5 - Optimising Patient Care, Philips E.M., Santos S., Trasande L., Aurrekoetxea J.J., Barros H., von Berg A., Bergstrom A., Bird P.K., Brescianini S., Chaoimh C.N., Charles M.-A., Chatzi L., Chevrier C., Chrousos G.P., Costet N., Criswell R., Crozier S., Eggesbo M., Fantini M.P., Farchi S., Forastiere F., van Gelder M.M.H.J., Georgiu V., Godfrey K.M., Gori D., Hanke W., Heude B., Hryhorczuk D., Iniguez C., Inskip H., Karvonen A.M., Kenny L.C., Kull I., Lawlor D.A., Lehmann I., Magnus P., Manios Y., Melen E., Mommers M., Morgen C.S., Moschonis G., Murray D., Nohr E.A., Nybo Andersen A.-M., Oken E., Oostvogels A.J.J.M., Papadopoulou E., Pekkanen J., Pizzi C., Polanska K., Porta D., Richiardi L., Rifas-Shiman S.L., Roeleveld N., Rusconi F., Santos A.C., Sorensen T.I.A., Standl M., Stoltenberg C., Sunyer J., Thiering E., Thijs C., Torrent M., Vrijkotte T.G.M., Wright J., Zvinchuk O., Gaillard R., Jaddoe V.W.V., Department of Public Health, University of Helsinki, Instituto de Saúde Pública da Universidade do Porto, Erasmus MC other, Pediatrics, Graduate School, Public and occupational health, APH - Aging & Later Life, APH - Health Behaviors & Chronic Diseases, ARD - Amsterdam Reproduction and Development, and APH - Methodology
- Subjects
Male ,Parents ,embarazo ,Epidemiology ,Maternal Health ,Social Sciences ,CHILDREN ,0302 clinical medicine ,Pregnancy ,nacimiento prematuro ,Smoking/adverse effects ,Psychology ,MATERNAL SMOKING ,estudios de cohortes ,Body mass index ,education.field_of_study ,General Medicine ,ASSOCIATION ,16. Peace & justice ,3. Good health ,Prenatal Exposure Delayed Effects ,Medicine ,GROWTH ,efectos diferidos por exposición prenatal ,Cohort study ,Human ,PRETERM BIRTH ,Europe/epidemiology ,03 medical and health sciences ,Humans ,Smoking habits ,Risk factor ,education ,Behavior ,Biology and Life Sciences ,Infant ,Odds ratio ,hábito de fumar ,medicine.disease ,Pregnancy Complications ,CESSATION ,Demography ,Pediatric Obesity ,Physiology ,humanos ,030204 cardiovascular system & hematology ,Overweight ,North America/epidemiology ,Cohort Studies ,Habits ,Risk Factors ,Medicine and Health Sciences ,030212 general & internal medicine ,DNA METHYLATION ,Smoking ,Obstetrics and Gynecology ,Gestational age ,edad gestacional ,Prenatal Exposure Delayed Effects/diagnosis ,3142 Public health care science, environmental and occupational health ,obesidad pediátrica ,Pediatric Obesity/diagnosis ,Europe ,Physiological Parameters ,Female ,Gestational Age ,Infant, Newborn ,North America ,Premature Birth ,OBESITY ,medicine.symptom ,Research Article ,Birth weight ,Population ,Premature Birth/diagnosis ,padres ,Prenatal Exposure Delayed Effect ,Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18] ,All institutes and research themes of the Radboud University Medical Center ,medicine ,factores de riesgo ,EXPOSURE ,lactante ,business.industry ,Risk Factor ,Body Weight ,Newborn ,Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10] ,Medical risk factors ,3121 General medicine, internal medicine and other clinical medicine ,Birth ,Women's Health ,WEIGHT ,Cohort Studie ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Background Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. Methods and findings We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers’ median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02–1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02–1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07–2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35–1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52–2.34] instead of OR 2.20 [95% CI 2.02–2.42] when reducing from 5–9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39–3.25] and OR 1.93 [95% CI 1.46–2.57] instead of OR 2.95 [95% CI 2.75–3.15] when reducing from ≥10 to 5–9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16–1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. Conclusions We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy., Elise Philips and co-workers investigate parental smoking and associated birth and child outcomes., Author summary Why was this study done? Maternal smoking during pregnancy is an important risk factor for various birth complications and childhood overweight. It is not clear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy. The associations of paternal smoking with birth and childhood outcomes also remain unknown. What did the researchers do and find? We conducted an individual participant data meta-analysis using data from 229,158 families from 28 pregnancy and birth cohorts from Europe and North America to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. We observed that smoking in the first trimester only did not increase the risk of preterm birth and small size for gestational age but was associated with a higher risk of childhood overweight, as compared to nonsmoking. Reducing the number of cigarettes during pregnancy, without quitting, was still associated with higher risks of these adverse outcomes. Paternal smoking seems to be associated, independently of maternal smoking, with the risks of childhood overweight. What do these findings mean? Population strategies should focus on parental smoking prevention before or at the start of, rather than during, pregnancy. Future studies are needed to assess the specific associations of smoking in the preconception and childhood periods with offspring outcomes.
- Published
- 2020
43. COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis
- Author
-
Felix Balzer, Bernd Timmermann, Saskia Trump, Naveed Ishaque, Jürgen Eils, Olivia Debnath, Sven Twardziok, Loreen Thürmann, Christian Conrad, Jennifer Loske, Fabian Pott, Uwe G. Liebert, Alexander Krannich, Christof von Kalle, Martin Witzenrath, Sein Schmidt, Robert Lorenz Chua, Florian Kurth, Andreas C. Hocke, Sven Laudi, Christian Drosten, Maria Theresa Völker, Norbert Suttorp, Roland Eils, Stefan Schneider, Irina Lehmann, Melanie Maier, Soeren Lukassen, Daniel Wendisch, Christine Goffinet, Julia Kazmierski, Holger Müller-Redetzky, Leif E. Sander, Felix Machleidt, Bianca P Hennig, and Johannes Liebig
- Subjects
Adult ,Male ,Pneumonia, Viral ,Respiratory System ,Biomedical Engineering ,Bioengineering ,Cell Communication ,Lung injury ,Peptidyl-Dipeptidase A ,Applied Microbiology and Biotechnology ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Interferon ,Nasopharynx ,Medicine ,CXCL10 ,Humans ,Interleukin 8 ,Longitudinal Studies ,Pandemics ,030304 developmental biology ,Aged ,Inflammation ,0303 health sciences ,business.industry ,COVID-19 ,Cell Differentiation ,Epithelial Cells ,respiratory system ,Middle Aged ,3. Good health ,CCL20 ,Immune System ,Immunology ,Respiratory epithelium ,Molecular Medicine ,Tumor necrosis factor alpha ,Female ,Angiotensin-Converting Enzyme 2 ,Single-Cell Analysis ,business ,Coronavirus Infections ,Transcriptome ,Bronchoalveolar Lavage Fluid ,030217 neurology & neurosurgery ,medicine.drug ,Biotechnology - Abstract
To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls. We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand–receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF. The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19.
- Published
- 2020
44. Cross-talk between the airway epithelium and activated immune cells defines severity in COVID-19
- Author
-
Loreen Thürmann, Felix Balzer, Jennifer Loske, Bernd Timmermann, Alexander Krannich, Robert Lorenz Chua, Florian Kurth, Christof von Kalle, Sven Laudi, Andreas C. Hocke, Christian Conrad, Johannes Liebig, Martin Witzenrath, Bianca P Hennig, Olivia Debnath, Fabian Pott, Roland Eils, Irina Lehmann, Soeren Lukassen, Naveed Ishaque, Felix Machleidt, Jürgen Eils, Sein Schmidt, Christian Drosten, Julia Kazmierski, Holger Müller-Redetzky, Christine Goffinet, Daniel Wendisch, Stefan Schneider, Sven Twardziok, Saskia Trump, and Leif-Erik Sander
- Subjects
Chemokine ,biology ,business.industry ,respiratory system ,Lung injury ,CCL5 ,Immune system ,Immunology ,biology.protein ,Respiratory epithelium ,CXCL10 ,Medicine ,Tumor necrosis factor alpha ,Interleukin 8 ,business - Abstract
The clinical course of COVID-19 is highly variable, however, underlying host factors and determinants of severe disease are still unknown. Based on single-cell transcriptomes of nasopharyngeal and bronchial samples from clinically well-characterized patients presenting with moderate and critical severities, we reveal the different types and states of airway epithelial cells that are vulnerable for SARS-CoV-2 infection. In COVID-19 patients, we observed a two- to threefold increase of cells expressing the SARS-CoV-2 entry receptorACE2within the airway epithelial cell compartment.ACE2is upregulated in epithelial cells through Interferon signals by immune cells suggesting that the viral defense system may increase the number of potentially susceptible cells in the respiratory epithelium. Infected epithelial cells recruit and activate immune cells by chemokine signaling. Recruited T lymphocytes and inflammatory macrophages were hyperactivated and showed a strong interaction with epithelial cells. In critical patients, increased expression ofCCL2, CCL3, CCL5, CXCL9, CXCL10, IL8, IL1BandTNFin macrophages was identified as a likely cause of a hyperinflammatory lung pathology. Moreover, we observed exacerbated epithelial cell death, likely leading to lung injury and respiratory failure in fatal cases. Our study provides novel insights into the pathophysiology of COVID-19 and suggests an immunomodulatory therapy along the CCL2, CCL3/CCR1 axis as promising option to prevent and treat critical course of COVID-19.
- Published
- 2020
45. Membership Inference Against DNA Methylation Databases
- Author
-
Michael Backes, Roland Eils, Irina Lehmann, Yang Zhang, Pascal Berrang, Inken Hagestedt, and Mathias Humbert
- Subjects
0301 basic medicine ,Database ,Computer science ,Genomic data ,Inference ,computer.software_genre ,Genome ,Set (abstract data type) ,03 medical and health sciences ,Human health ,030104 developmental biology ,0302 clinical medicine ,DNA methylation ,Key (cryptography) ,Epigenetics ,computer ,030217 neurology & neurosurgery - Abstract
Biomedical data sharing is one of the key elements fostering the advancement of biomedical research but poses severe risks towards the privacy of individuals contributing their data, as already demonstrated for genomic data. In this paper, we study whether and to which extent DNA methylation data, one of the most important epigenetic elements regulating human health, is prone to membership inference attacks, a critical type of attack that reveals an individual's participation in a given database. We design and evaluate three different attacks exploiting published summary statistics, among which one is based on machine learning and another is exploiting the dependencies between genome and methylation data. Our extensive evaluation on six datasets containing a diverse set of tissues and diseases collected from more than 1,300 individuals in total shows that such membership inference attacks are effective, even when the target's methylation profile is not accessible. It further shows that the machine-learning approach outperforms the statistical attacks, and that learned models are transferable across different datasets.
- Published
- 2020
46. Stressful life events in childhood and allergic sensitization*
- Author
-
H. Behrendt, Gunda Herberth, S Röder, Olf Herbarth, J Heinrich, Irina Lehmann, T Schäfer, A Bockelbrink, Stefanie Sausenthaler, Ulrich Kramer, and M. Borte
- Subjects
Allergy ,stressful life events ,medicine.medical_treatment ,Vasoactive intestinal peptide ,Substance P ,allergic sensitization ,Allergic sensitization ,chemistry.chemical_compound ,Immune system ,children ,medicine ,Th1/Th2 balance ,Pathological ,General Environmental Science ,business.industry ,Incidence (epidemiology) ,General Engineering ,neuropeptides ,medicine.disease ,Cytokine ,chemistry ,Immunology ,General Earth and Planetary Sciences ,business ,Research Article - Abstract
Stressful life events evidently have an impact on development of allergic diseases, but the mechanism linking stress to pathological changes of immune system function is still not fully understood. The aim of our study was to investigate the relationship between stressful life events, neuropeptide and cytokine concentrations in children as well as the association between early stressful life events and atopic eczema (AE). Within the LISA plus (Life style - Immune system - Allergy) study, blood samples from children of 6 years of age were analyzed for concentration of the neuropeptides vasoactive intestinal peptide (VIP), somatostatin (SOM), substance P (SP) and the Th1/Th2 cytokines IFN-γ and IL-4. Life events such as severe disease or death of a family member, unemployment or divorce of the parents were assessed with a questionnaire filled in by the parents. Furthermore, lifetime prevalence of AE and incidence after the assessment period of life events were compared. Our data suggest that separation/ divorce of parents increase childrens risk of developing AE later in life. Children with separated/divorced parents showed high VIP levels and high concentrations of the Th2 cytokine IL-4 in their blood. Severe diseases and death of a family member were neither associated with neuropeptide levels nor with cytokine concentrations. Unemployment of the parents was associated with decreased IFN-γ concentrations in childrens blood but not with neuropeptide levels. Thus, the neuropeptide VIP might be a mediator between stressful life events and immune regulation contributing to the Th2-shifted immune response in children with separated/divorced parents.
- Published
- 2018
47. MEST mediates the impact of prenatal bisphenol A exposure on long-term body weight development
- Author
-
Gabriele I. Stangl, Ralph Feltens, Stefan Röder, Kristin M. Junge, Wieland Kiess, Tobias Bauer, Susanne Jahreis, Loreen Thürmann, Melanie Bewerunge-Hudler, Saskia Trump, Konrad Grützmann, Roland Eils, Irina Lehmann, Angela Schulz, Tobias Polte, Naveed Ishaque, Matthias Schick, Dirk K. Wissenbach, Kathrin Landgraf, Beate Leppert, Mario Bauer, Michael Borte, Martin von Bergen, and Antje Körner
- Subjects
0301 basic medicine ,endocrine system ,lcsh:QH426-470 ,Offspring ,lcsh:Medicine ,010501 environmental sciences ,Biology ,LINA ,01 natural sciences ,Andrology ,03 medical and health sciences ,Mice ,Prenatal exposure ,Genetics ,Epigenetics ,Obesity ,Molecular Biology ,Genetics (clinical) ,0105 earth and related environmental sciences ,DNA methylation ,Adipogenesis ,Research ,lcsh:R ,Methylation ,Environmental exposure ,lcsh:Genetics ,030104 developmental biology ,CpG site ,Cord blood ,Mesenchymal stem cells ,Reprogramming ,Infants ,Developmental Biology ,EDC - Abstract
Background Exposure to endocrine-disrupting chemicals can alter normal physiology and increase susceptibility to non-communicable diseases like obesity. Especially the prenatal and early postnatal period is highly vulnerable to adverse effects by environmental exposure, promoting developmental reprogramming by epigenetic alterations. To obtain a deeper insight into the role of prenatal bisphenol A (BPA) exposure in children’s overweight development, we combine epidemiological data with experimental models and BPA-dependent DNA methylation changes. Methods BPA concentrations were measured in maternal urine samples of the LINA mother-child-study obtained during pregnancy (n = 552), and BPA-associated changes in cord blood DNA methylation were analyzed by Illumina Infinium HumanMethylation450 BeadChip arrays (n = 472). Methylation changes were verified by targeted MassARRAY analyses, assessed for their functional translation by qPCR and correlated with children’s body mass index (BMI) z scores at the age of 1 and 6 years. Further, female BALB/c mice were exposed to BPA from 1 week before mating until delivery, and weight development of their pups was monitored (n ≥ 8/group). Additionally, human adipose-derived mesenchymal stem cells were treated with BPA during the adipocyte differentiation period and assessed for exposure-related epigenetic, transcriptional and morphological changes (n = 4). Results In prenatally BPA-exposed children two CpG sites with deviating cord blood DNA-methylation profiles were identified, among them a hypo-methylated CpG in the promoter of the obesity-associated mesoderm-specific transcript (MEST). A mediator analysis suggested that prenatal BPA exposure was connected to cord blood MEST promoter methylation and MEST expression as well as BMI z scores in early infancy. This effect could be confirmed in mice in which prenatal BPA exposure altered Mest promoter methylation and transcription with a concomitant increase in the body weight of the juvenile offspring. An experimental model of in vitro differentiated human mesenchymal stem cells also revealed an epigenetically induced MEST expression and enhanced adipogenesis following BPA exposure. Conclusions Our study provides evidence that MEST mediates the impact of prenatal BPA exposure on long-term body weight development in offspring by triggering adipocyte differentiation. Electronic supplementary material The online version of this article (10.1186/s13148-018-0478-z) contains supplementary material, which is available to authorized users.
- Published
- 2018
48. Wood emissions and asthma development: Results from an experimental mouse model and a prospective cohort study
- Author
-
Gunda Herberth, Martin von Bergen, Stefan Röder, Wieland Kiess, Lisa Buchenauer, Michael Borte, Tibor Kohajda, Tobias Polte, Martin Ohlmeyer, Irina Lehmann, Ulrike Rolle-Kampczyk, Kristin M. Junge, Jan C. Simon, Elena Elter, Richard Gminski, and Katja Butter
- Subjects
010504 meteorology & atmospheric sciences ,First year of life ,010501 environmental sciences ,01 natural sciences ,Atopy ,Mice ,Environmental health ,Animals ,Wood emission ,Medicine ,Prospective Studies ,Volatile organic compounds ,Prospective cohort study ,Adverse effect ,lcsh:Environmental sciences ,0105 earth and related environmental sciences ,General Environmental Science ,Asthma ,lcsh:GE1-350 ,Pregnancy ,Wheezing ,Perinatal Exposure ,business.industry ,Bayes Theorem ,medicine.disease ,Wood ,Mixture effect ,FHA ,Cohort ,business - Abstract
Background Increased use of renewable resources like sustainably produced wood in construction or for all sorts of long-lived products is considered to contribute to reducing society's carbon footprint. However, as a natural, biological material, wood and wood products emit specific volatile organic compounds (VOCs). Therefore, the evaluation of possible health effects due to wood emissions is of major interest. Objectives We investigated the effects of an exposure to multiple wood-related VOCs on asthma development. Methods A murine asthma model was used to evaluate possible allergic and inflammatory effects on the lung after short- or long-term and perinatal exposure to pinewood or oriented strand board (OSB). In addition, wood-related VOCs were measured within the German prospective mother–child cohort LINA and their joint effect on early wheezing or asthma development in children until the age of 10 was estimated by Bayesian kernel machine regression (BKMR) stratifying also for family history of atopy (FHA). Results Our experimental data show that neither pinewood nor OSB emissions even at high total VOC levels and a long-lasting exposure period induce significant inflammatory or asthma-promoting effects in sensitized or non-sensitized mice. Moreover, an exposure during the vulnerable time window around birth was also without effect. Consistently, in our mother–child cohort LINA, an exposure to multiple wood-related VOCs during pregnancy or the first year of life was not associated with early wheezing or asthma development in children independent from their FHA. Conclusion Our findings indicate that emissions from wood and wood products at levels commonly occurring in the living environment do not exert adverse effects concerning wheezing or asthma development.
- Published
- 2021
49. Maternal cytokine status may prime the metabolic profile and increase risk of obesity in children
- Author
-
Gunda Herberth, M. von Bergen, B Englich, Kristin M. Junge, Michael Borte, Irina Lehmann, Stefan Röder, Saskia Trump, Gabriele I. Stangl, and Ulrike Rolle-Kampczyk
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Metabolic imprinting ,Endocrinology, Diabetes and Metabolism ,Mothers ,Medicine (miscellaneous) ,Physiology ,Adaptive Immunity ,Overweight ,Body Mass Index ,03 medical and health sciences ,Th2 Cells ,Pregnancy ,Risk Factors ,Germany ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Longitudinal Studies ,Prospective Studies ,Maternal-Fetal Exchange ,Inflammation ,Interleukin-13 ,Nutrition and Dietetics ,Tumor Necrosis Factor-alpha ,business.industry ,Infant, Newborn ,Infant ,medicine.disease ,Obesity ,Immunity, Innate ,030104 developmental biology ,Endocrinology ,Child, Preschool ,Cohort ,Metabolome ,Gestation ,Female ,Cytokine secretion ,Interleukin-4 ,Interleukin-5 ,medicine.symptom ,business ,Body mass index - Abstract
The maternal inflammation status during pregnancy has been associated with metabolic imprinting and obesity development in the child. However, the influence of the maternal Th2 cytokines, interleukin-4 (IL4), IL5 and IL13, has not been studied so far. We investigated the relationship between maternal innate (IL6, IL8, IL10 and tumor necrosis factor-α (TNFa)) and adaptive (interferon-γ, IL4, IL5 and IL13) blood cytokine levels at 34 weeks of gestation and children’s overweight development until the age of 3 years in 407 children of the German longitudinal LINA (Lifestyle and Environmental Factors and their Influence on Newborns Allergy risk) cohort. Children’s body weight and height were measured during the annual clinical visits or acquired from questionnaires. Body mass index (BMI) Z-scores were calculated according to the WHO reference data to adjust for child’s age and gender. Cytokine secretion was stimulated with phytohemagglutinin or lipopolysaccharide and measured by cytometric bead assay. Furthermore, we assessed metabolic parameter in blood of 318 children at age 1 using the AbsoluteIDQ p180 Kit (Biocrates LIFE Science AG). Applying logistic regression models, we found that an increase of maternal IL4 and IL13 was associated with a decreased risk for overweight development in 1- and 2-year-old children. This effect was consistent up to the age of 3 years for IL13 and mainly concerns children without maternal history of atopy. Children’s acylcarnitine concentrations at 1 year were positively correlated with maternal IL13 levels and inversely associated with the BMI Z-score at age 1. We were able to show for the first time that the maternal Th2 status may be linked inversely to early childhood overweight development accompanied by an altered metabolic profile of the fetus. However, our data do not support a direct mediating role of acylcarnitines on maternal IL13-induced weight development.
- Published
- 2017
50. Umweltschadstoffe als Adjuvanzien und Co-Faktoren einer immunologischen Erkrankung
- Author
-
Irina Lehmann
- Subjects
03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,Public Health, Environmental and Occupational Health ,010501 environmental sciences ,01 natural sciences ,0105 earth and related environmental sciences - Abstract
Aufgabe des Immunsystems ist es, den Korper gegen eindringende Krankheitserreger zu schutzen. Voraussetzung dafur ist die Fahigkeit, zwischen eigen und fremd zu unterscheiden, das heist korperfremde Stoffe abzuwehren und gleichzeitig korpereigene Stoffe zu tolerieren. Ein komplexes regulatorisches Netzwerk sorgt dabei fur die Aufrechterhaltung des sensiblen Gleichgewichts zwischen Eigen- und Fremderkennung. Wird dieses gestort, entwickeln sich chronische Entzundungsreaktionen, wie Allergien oder Autoimmunreaktionen, oder Infektionserkrankungen, weil das Immunsystem eindringende Erreger nicht mehr effizient eliminieren kann. Umweltschadstoffe konnen derartige Storungen auslosen, indem sie die Funktion von Zellen des Immunsystems so modifizieren, dass diese entweder ubersensibel auf Allergene oder korpereigene Strukturen reagieren oder Pathogene nicht mehr adaquat bekampfen konnen. Eine derartige indirekte Wirkung bezeichnet man auch als einen adjuvanten Effekt. Fur viele Stoffe aus unserem unmittelbaren Lebensumfeld wie z. B. Pestizide, Schwermetalle, Holzschutzmittel, oder fluchtige organische Verbindungen sind derartige adjuvante Effekte bekannt. Die Mechanismen, uber die Umweltschadstoffe zur Entstehung chronisch-entzundlicher Erkrankungen beitragen konnen, sind vielschichtig und werden hier am Beispiel von Asthma und Allergien diskutiert. Wahrend das Immunsystem eines gesunden Erwachsenen meist problemlos in der Lage ist, auch unter Umwelteinflussen zuverlassig zwischen eigen und fremd zu unterscheiden, reagieren Kinder sehr viel sensibler auf die gleiche Belastung. Um zu verhindern, dass in dieser hochsensiblen Phase der fruhen Kindheit Krankheitsrisiken unter dem Einfluss von Umweltbelastungen gepragt werden, sind Kinder deshalb besonders zu schutzen.
- Published
- 2017
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.