Prenatal environmental exposures associated with sex differences in childhood obesity and neurodevelopment

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  • dc.contributor.author Cáceres, Alejandro
  • dc.contributor.author Carreras Gallo, Natàlia
  • dc.contributor.author Bustamante Pineda, Mariona
  • dc.contributor.author Maitre, Léa
  • dc.contributor.author Nieuwenhuijsen, Mark J.
  • dc.contributor.author Stratakis, Nikos
  • dc.contributor.author Urquiza, José M.
  • dc.contributor.author Casas Sanahuja, Maribel
  • dc.contributor.author Vrijheid, Martine
  • dc.contributor.author González, Juan Ramón
  • dc.date.accessioned 2023-06-15T06:00:19Z
  • dc.date.available 2023-06-15T06:00:19Z
  • dc.date.issued 2023
  • dc.description.abstract Background: Obesity and neurodevelopmental delay are complex traits that often co-occur and differ between boys and girls. Prenatal exposures are believed to influence children's obesity, but it is unknown whether exposures of pregnant mothers can confer a different risk of obesity between sexes, and whether they can affect neurodevelopment. Methods: We analyzed data from 1044 children from the HELIX project, comprising 93 exposures during pregnancy, and clinical, neuropsychological, and methylation data during childhood (5-11 years). Using exposome-wide interaction analyses, we identified prenatal exposures with the highest sexual dimorphism in obesity risk, which were used to create a multiexposure profile. We applied causal random forest to classify individuals into two environments: E1 and E0. E1 consists of a combination of exposure levels where girls have significantly less risk of obesity than boys, as compared to E0, which consists of the remaining combination of exposure levels. We investigated whether the association between sex and neurodevelopmental delay also differed between E0 and E1. We used methylation data to perform an epigenome-wide association study between the environments to see the effect of belonging to E1 or E0 at the molecular level. Results: We observed that E1 was defined by the combination of low dairy consumption, non-smokers' cotinine levels in blood, low facility richness, and the presence of green spaces during pregnancy (ORinteraction = 0.070, P = 2.59 × 10-5). E1 was also associated with a lower risk of neurodevelopmental delay in girls, based on neuropsychological tests of non-verbal intelligence (ORinteraction = 0.42, P = 0.047) and working memory (ORinteraction = 0.31, P = 0.02). In line with this, several neurodevelopmental functions were enriched in significant differentially methylated probes between E1 and E0. Conclusions: The risk of obesity can be different for boys and girls in certain prenatal environments. We identified an environment combining four exposure levels that protect girls from obesity and neurodevelopment delay. The combination of single exposures into multiexposure profiles using causal inference can help determine populations at risk.
  • dc.description.sponsorship The study has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no 308333 (HELIX project); and the H2020-EU.3.1.2.—Preventing Disease Programme under grant agreement no 874583 (ATHLETE project). BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA-SAB data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6–04-2014_31V-66). 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. 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 211250 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 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), 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). This research has received funding from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023 (CEX2018-000,806-S) program, and support from the Generalitat de Catalunya through the CERCA Program. NC and JU are supported by Spanish regional program PERIS (Ref.: SLT017/20/000061 and SLT017/20/000119, respectively), granted by Departament de Salut de la Generalitat de Catalunya. TruDiagnostics also provided funding for data analysis.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Cáceres A, Carreras-Gallo N, Andrusaityte S, Bustamante M, Carracedo Á, Chatzi L, et al. Prenatal environmental exposures associated with sex differences in childhood obesity and neurodevelopment. BMC Med. 2023 Apr 12;21(1):142. DOI: 10.1186/s12916-023-02815-9
  • dc.identifier.doi http://dx.doi.org/10.1186/s12916-023-02815-9
  • dc.identifier.issn 1741-7015
  • dc.identifier.uri http://hdl.handle.net/10230/57169
  • dc.language.iso eng
  • dc.publisher BioMed Central
  • dc.relation.ispartof BMC Med. 2023 Apr 12;21(1):142
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/308333
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/874583
  • dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Causal inference
  • dc.subject.keyword Childhood obesity
  • dc.subject.keyword DNA methylation
  • dc.subject.keyword Multiexposure profile
  • dc.subject.keyword Neurodevelopment
  • dc.subject.keyword Prenatal environment
  • dc.subject.keyword Sexual dimorphism
  • dc.title Prenatal environmental exposures associated with sex differences in childhood obesity and neurodevelopment
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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