Wang, CongrongSunyer Deu, JordiBorràs, EvaSabidó Aguadé, Eduard, 1981-González, Juan RamónVives Usano, Marta, 1990-Estivill, Xavier, 1955-Casas Sanahuja, MaribelNieuwenhuijsen, Mark J.Bustamante Pineda, MarionaMaitre, LéaVrijheid, MartineAlfano, Rossella2025-09-182025-09-182025Wang C, Reimann B, Nawrot TS, Martens DS, Wright J, McEachan R, et al. Meet-in-the-middle meets multi-omics identifying molecular signatures of environmental drivers of childhood overweight. Environ Int. 2025 Aug;202:109630. DOI: 10.1016/j.envint.2025.1096300160-4120http://hdl.handle.net/10230/71219Background: Obesity is a multi-cause chronic disease recognized across the lifespan, with childhood obesity prevalence rising over the past decades. Although exposome-wide association studies have identified early-life environmental drivers of child obesity, and explored the multi-omics signatures of the exposome of children, it is understudied whether the combined effects of multiple exposures are potentially mediated by multi-omics. Methods: Within the Human Early Life Exposome (HELIX) project, 1041 mother-child pairs were surveyed for a wide range of environmental exposures including over 354 prenatal and childhood exposures. Multi-omics molecular features were measured during childhood, encompassing the blood methylome and transcriptome, plasma proteins and urinary and serum metabolites. Exposome and multi-omics features were integrated into latent factors by Multi-omics Factor Analysis, based on which structural equation modelling was used to assess whether multi-omics mediated associations between exposome and child body mass index (BMI). Results: Key findings included: (i) prenatal nutrition, exercise, and passive smoking influencing BMI via DNA methylation of HOXA5 and Tenascin XB; (ii) childhood exposure to PCBs and phenols linked with BMI through inflammation and coagulation pathways; and (iii) childhood PCB and dietary exposures associated with BMI via immune pathways. Conclusions: This novel untargeted workflow elucidated biological mechanisms linking environmental exposures to child obesity, potentially supporting targeted public health interventions.application/pdfeng© 2025 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.envint.2025.109630Childhood obesityExposomeHELIXMOFAMeet-in-the-middleMulti-omicsinfo:eu-repo/semantics/openAccess