Metabolomic Responses to External and Internal Environmental Exposures: Evidence of Lipid and Energy Metabolism Disruption in the Estonian Biobank

Metabolomic Responses to External and Internal Environmental Exposures: Evidence of Lipid and Energy Metabolism Disruption in the Estonian Biobank | medRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Metabolomic Responses to External and Internal Environmental Exposures: Evidence of Lipid and Energy Metabolism Disruption in the Estonian Biobank View ORCID Profile Max J. Oosterwegel , View ORCID Profile Roel Vermeulen , Estonian Biobank research team , View ORCID Profile Kees de Hoogh , View ORCID Profile Liis Hiie , View ORCID Profile Tõnu Esko , View ORCID Profile Jelle Vlaanderen , View ORCID Profile Jaanika Kronberg doi: https://doi.org/10.64898/2026.03.17.26347937 Max J. Oosterwegel a Institute for Risk Assessment Sciences, Utrecht University , Utrecht, 3584 CM, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Max J. Oosterwegel Roel Vermeulen a Institute for Risk Assessment Sciences, Utrecht University , Utrecht, 3584 CM, The Netherlands b Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht , Utrecht, 3508 GA, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Roel Vermeulen c Estonian Genome Centre, Institute of Genomics, University of Tartu , Tartu, Estonia Kees de Hoogh a Institute for Risk Assessment Sciences, Utrecht University , Utrecht, 3584 CM, The Netherlands d Swiss Tropical and Public Health Institute , Allschwil, 4123, Switzerland e University of Basel , Basel, 4001, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kees de Hoogh Liis Hiie c Estonian Genome Centre, Institute of Genomics, University of Tartu , Tartu, Estonia g Institute of Mathematics and Statistics, University of Tartu , Tartu, Estonia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Liis Hiie Tõnu Esko c Estonian Genome Centre, Institute of Genomics, University of Tartu , Tartu, Estonia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Tõnu Esko Jelle Vlaanderen a Institute for Risk Assessment Sciences, Utrecht University , Utrecht, 3584 CM, The Netherlands f Centre for Safety of Substances and Products, Dutch National Institute for Public Health and the Environment , Bilthoven, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jelle Vlaanderen Jaanika Kronberg c Estonian Genome Centre, Institute of Genomics, University of Tartu , Tartu, Estonia g Institute of Mathematics and Statistics, University of Tartu , Tartu, Estonia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jaanika Kronberg For correspondence: jaanika.kronberg{at}ut.ee Abstract Full Text Info/History Metrics Data/Code Preview PDF ABSTRACT Objective To investigate associations between long-term environmental exposures, both external (ambient air pollution and built environment) and internal (circulating anthropogenic chemicals), and the human plasma metabolome, with the aim of generating biologically plausible hypotheses about affected metabolic pathways. Methods We analyzed plasma from 989 Estonian Biobank participants using untargeted LC-HRMS (Metabolon HD4). External exposures ( PM 2.5 , PM 10 , NO 2 , ozone and built-environment metrics) were assigned using spatiotemporally resolved models developed in the EXPANSE project. Internal exposures were defined as ubiquitous anthropogenic compounds detected in the same metabolomics dataset. Associations between exposures and individual metabolites were quantified using left-censored regression models and then mapped to metabolite classes (Metabolon) and KEGG pathways. For enrichment analyses, one-sided Kolmogorov-Smirnov tests were applied to external exposures and Fisher’s exact tests to internal exposures. False discovery rate was controlled at 1% per exposure and database. Results External air pollutants exhibited distinct metabolic patterns: Higher NO 2 exposure was associated with enrichment of metabolites involved in tyrosine metabolism; higher ozone with monohydroxy and dicarboxylate fatty acids (consistent with lipid peroxidation); and higher PM 2.5 with acyl-carnitine subclasses and carbohydrate metabolism (glycolysis / gluconeogenesis / pyruvate). Built-environment associations were heterogeneous across metabolites and pathways. Internal anthropogenic chemicals showed broader metabolic associations than external exposures, involving a larger number of metabolites and metabolic classes. PFAS (PFOA, PFOS) were associated with long-chain polyunsaturated fatty acids (n3/n6) and lysophospho-lipids. Associations with 4-hydroxychlorothalonil, a fungicide, pointed to androgenic steroid metabolites and alpha-linolenic acid metabolism. The phenolic 2,4-di-tert-butylphenol, a plastic associated chemical, showed widespread associations with lipid classes, suggesting disruption of membrane remodeling and fatty acid handling. Conclusion Long-term environmental exposures, both external and internal, are measurably reflected in the human plasma metabolome. Across exposure domains, recurrent signals involved lipid metabolism, membrane composition, and oxidative stress–related pathways, highlighting these as common biological targets of environmental exposures. The findings generate testable hypotheses, including nitrosative stress–related alterations for NO 2 , lipid peroxidation for ozone, energy-metabolism perturbations for PM 2.5 , potential endocrine activity for chlorothalonil metabolites, and possible obesogenic effects of 2,4-di-tert-butylphenol. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by the EXPANSE and EXPOSOME-NL projects. The EXPANSE project is funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No 874627. The EXPOSOME-NL project is funded through the Gravitation program of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant number 024.004.017). J.K, L.H and T.E were supported by the Estonian Research Council grant PRG1291. J.K and L.H were supported by the Estonian Research Council grant PRG3105. The research was conducted using the Estonian Center of Genomics/Roadmap II funded by the Estonian Research Council (project number TT17). Data analysis was carried out in part in the High-Performance Computing Center of University of Tartu. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Individual level data analysis in the Estonian Biobank participants was carried out under ethical approval 1.1-12/1468 from the Estonian Committee on Bioethics and Human Research (Estonian Ministry of Social Affairs), using data according to release application 3-10/GI/31961 from the Estonian Biobank. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes ↵ + Estonian Biobank research team: Andres Metspalu, Lili Milani, Tõnu Esko, Mait Metspalu DATA AVAILABILITY Data used is person-level data of Estonian Biobank participants, which cannot be published by the Estonian law. All data access to the Estonian Biobank’s data must adhere to the informed consent regulations established by the Estonian Committee on Bioethics and Human Research. Access to the datasets analysed in the current study can be arranged on a reasonable request to the Estonian Biobank. To initiate a request for phenotype data, it is necessary to submit a preliminary request to the Estonian Biobank releases{at}ut.ee . Information about data access, including necessary steps required to access data on the University of Tartu servers can be found at https://genomics.ut.ee/en/content/estonian-biobank . Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted March 19, 2026. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Oosterwegel , Roel Vermeulen , Estonian Biobank research team , Kees de Hoogh , Liis Hiie , Tõnu Esko , Jelle Vlaanderen , Jaanika Kronberg medRxiv 2026.03.17.26347937; doi: https://doi.org/10.64898/2026.03.17.26347937 Share This Article: Copy Citation Tools Metabolomic Responses to External and Internal Environmental Exposures: Evidence of Lipid and Energy Metabolism Disruption in the Estonian Biobank Max J. Oosterwegel , Roel Vermeulen , Estonian Biobank research team , Kees de Hoogh , Liis Hiie , Tõnu Esko , Jelle Vlaanderen , Jaanika Kronberg medRxiv 2026.03.17.26347937; doi: https://doi.org/10.64898/2026.03.17.26347937 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Occupational and Environmental Health Subject Areas All Articles Addiction Medicine (638) Allergy and Immunology (917) Anesthesia (350) Cardiovascular Medicine (5005) Dentistry and Oral Medicine (496) Dermatology (428) Emergency Medicine (676) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1691) Epidemiology (16263) Forensic Medicine (36) Gastroenterology (1241) Genetic and Genomic Medicine (7278) Geriatric Medicine (751) Health Economics (1093) Health Informatics (5289) Health Policy (1467) Health Systems and Quality Improvement (1832) Hematology (599) HIV/AIDS (1381) Infectious Diseases (except HIV/AIDS) (16490) Intensive Care and Critical Care Medicine (1203) Medical Education (700) Medical Ethics (156) Nephrology (752) Neurology (7596) Nursing (377) Nutrition (1130) Obstetrics and Gynecology (1296) Occupational and Environmental Health (1040) Oncology (3746) Ophthalmology (1093) Orthopedics (409) Otolaryngology (465) Pain Medicine (501) Palliative Medicine (143) Pathology (721) Pediatrics (1858) Pharmacology and Therapeutics (755) Primary Care Research (786) Psychiatry and Clinical Psychology (6130) Public and Global Health (9992) Radiology and Imaging (2531) Rehabilitation Medicine and Physical Therapy (1519) Respiratory Medicine (1269) Rheumatology (661) Sexual and Reproductive Health (804) Sports Medicine (597) Surgery (803) Toxicology (109) Transplantation (319) Urology (308)

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