In utero exposure to bisphenols and asthma, wheeze, and lung function in school-age children: a prospective meta-analysis of 8 European birth cohorts

Abstract

Background: In utero exposure to bisphenols, widely used in consumer products, may alter lung development and increase the risk of respiratory morbidity in the offspring. However, evidence is scarce and mostly focused on bisphenol A (BPA) only. Objective: To examine the associations of in utero exposure to BPA, bisphenol F (BPF), and bisphenol S (BPS) with asthma, wheeze, and lung function in school-age children, and whether these associations differ by sex. Methods: We included 3,007 mother-child pairs from eight European birth cohorts. Bisphenol concentrations were determined in maternal urine samples collected during pregnancy (1999-2010). Between 7 and 11 years of age, current asthma and wheeze were assessed from questionnaires and lung function by spirometry. Wheezing patterns were constructed from questionnaires from early to mid-childhood. We performed adjusted random-effects meta-analysis on individual participant data. Results: Exposure to BPA was prevalent with 90% of maternal samples containing concentrations above detection limits. BPF and BPS were found in 27% and 49% of samples. In utero exposure to BPA was associated with higher odds of current asthma (OR = 1.13, 95% CI = 1.01, 1.27) and wheeze (OR = 1.14, 95% CI = 1.01, 1.30) (p-interaction sex = 0.01) among girls, but not with wheezing patterns nor lung function neither in overall nor among boys. We observed inconsistent associations of BPF and BPS with the respiratory outcomes assessed in overall and sex-stratified analyses. Conclusion: This study suggests that in utero BPA exposure may be associated with higher odds of asthma and wheeze among school-age girls. ; The research leading to these results has received funding from Instituto de Salud Carlos III and European Union's FEDER funds (CP16/00128 – the ENDOLUNG project, and PI17/01194 – the INMA-Ado-Respi Project), the European Community's Seventh Framework Programme (FP7/2007–206) under grant agreement no 308,333 - the HELIX project –, and from the EC's Horizon 2020 research and innovation programme under grant agreement No 874,583 – the ATHLETE project. Generation R: This study was funded by The Erasmus MC, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development. The project received funding from the European Union's Horizon 2020 research and innovation programme (LIFECYCLE, grant agreement No 733206, 2016; EUCAN-Connect grant agreement No 824989; ATHLETE, grant agreement No 874583). Dr. Vincent Jaddoe received a grant from the European Research Council (ERC-2014-CoG-648916). This study was supported by grant R01-ES022972 and R01-ES029779 from the National Institutes of Health, USA. The researchers are independent from the funders. The study sponsors had no role in the study design, data analysis, interpretation of data, or writing of this report. INMA Gipuzkoa: This study was funded by grants from Instituto de Salud Carlos III (FIS-PI13/02187 and FIS-PI18/01142 incl. FEDER funds), CIBERESP, Department of Health of the Basque Government (2015111065), and the Provincial Government of Gipuzkoa (DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). INMA Sabadell: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; PI12/01890 incl. FEDER funds; CP13/00054 incl. FEDER funds), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR (2009 SGR 501, 2014 SGR 822), Fundació La marató de TV3 (090430), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), Agence Nationale de Securite Sanitaire de l'Alimentation de l'Environnement et du Travail (1262C0010), European Commission (261357, 308333, 603,794 and 634453). Alicia Abellan holds a LifeCycle fellowship, funded from the European Union's Horizon 2020 research and innovation programme under grant agreement No 733206. Maribel Casas holds a Miguel Servet fellowship (CP16/00128) funded by Instituto de Salud Carlos III and co-funded by European Social Fund "Investing in your future". We acknowledge support from the Spanish Ministry of Science and Innovation through the "Centro de Excelencia Severo Ochoa 2019–2023" Program (2018–000806-S), and support from the Generalitat de Catalunya through the CERCA Program. INMA Valencia: INMA Valencia was funded by Grants from UE (FP7-ENV-2011 cod 282,957 and HEALTH.2010.2.4.5–1), Spain: ISCIII (G03/176; FIS-FEDER: PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663, and PI19/1338; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051), Alicia Koplowitz Foundation, and Generalitat Valenciana: FISABIO (UGP 15–230, UGP-15–244, UGP-15–249, and AICO/2020/285). BiB: This report is independent research funded by the National Institute for Health Research Yorkshire and Humber ARC (NIHR200166) and BiB receives core infrastructure funding from the Wellcome Trust (WT101597MA). The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. EDEN: The EDEN study was supported by Foundation for medical research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR cohorte santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A), and Human Nutrition National Research Programs, Paris-Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the European Union FP7 programmes (FP7/2007–2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients (AFD)), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l'Education Nationale a complementary health insurance (MGEN), French national agency for food security, French-speaking association for the study of diabetes and metabolism (ALFEDIAM). MoBa: The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. RHEA: The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211,250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226,285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308,333 HELIX, H2020 LIFECYCLE, grant agreement No 733206, H2020 ATHLETE, grant agreement No 874583), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011–2014; "Rhea Plus": Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–15). Additional funding from NIEHS supported Dr Chatzi (R01ES030691, R01ES029944, R01ES030364, R21ES029681, R21ES028903, and P30ES007048). The funding sources had no involvement in the study design, the collection, analysis and interpretation of data or in the writing of the report and in the decision to submit the article for publication.