Nikos Stratakis1,2, David V Conti1, Ran Jin1, Katerina Margetaki1, Damaskini Valvi3, Alexandros P Siskos4, Léa Maitre5,6,7, Erika Garcia1, Nerea Varo8, Yinqi Zhao1, Theano Roumeliotaki9, Marina Vafeiadi9, Jose Urquiza5,6,7, Silvia Fernández-Barrés5,6,7, Barbara Heude10, Xavier Basagana5,6,7, Maribel Casas5,6,7, Serena Fossati5,6,7, Regina Gražulevičienė11, Sandra Andrušaitytė11, Karan Uppal12, Rosemary R C McEachan13, Eleni Papadopoulou14, Oliver Robinson15, Line Småstuen Haug14, John Wright13, Miriam B Vos16,17, Hector C Keun4, Martine Vrijheid5,6,7, Kiros T Berhane1, Rob McConnell1, Lida Chatzi1,2. 1. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA. 2. Department of Complex Genetics and Epidemiology, CAPHRI School for Public Health and Primary Care, University of Maastricht, Maastricht, the Netherlands. 3. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY. 4. Department of Surgery & Cancer and Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom. 5. ISGlobal, Barcelona, Spain. 6. Universitat Pompeu Fabra (UPF), Barcelona, Spain. 7. Consortium for Biomedical Research in Epidemiology & Public Health (CIBER Epidemiología y Salud Pública - CIBERESP), Madrid, Spain. 8. Laboratory of Biochemistry, University Clinic of Navarra, Pamplona, Spain. 9. Department of Social Medicine, Faculty of Medicine, University of Crete, Heraklion, Greece. 10. Center of Research in Epidemiology and Statistics, INSERM, INRAe, University of Paris, Paris, France. 11. Department of Environmental Sciences, Vytauto Didžiojo Universitetas, Kaunas, Lithuania. 12. Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, Emory University, Atlanta, GA. 13. Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom. 14. Norwegian Institute of Public Health, Oslo, Norway. 15. MRC Centre for Environment and Health, Imperial College London, London, United Kingdom. 16. Department of Pediatrics, School of Medicine and Nutrition Health Sciences, Emory University, Atlanta, GA. 17. Children's Healthcare of Atlanta, Atlanta, GA.
Abstract
BACKGROUND AND AIMS: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been shown to have hepatotoxic effects in animal models. However, human evidence is scarce. We evaluated how prenatal exposure to PFAS associates with established serum biomarkers of liver injury and alterations in serum metabolome in children. APPROACH AND RESULTS: We used data from 1,105 mothers and their children (median age, 8.2 years; interquartile range, 6.6-9.1) from the European Human Early-Life Exposome cohort (consisting of six existing population-based birth cohorts in France, Greece, Lithuania, Norway, Spain, and the United Kingdom). We measured concentrations of perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate, perfluorohexane sulfonate, and perfluoroundecanoate in maternal blood. We assessed concentrations of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase in child serum. Using Bayesian kernel machine regression, we found that higher exposure to PFAS during pregnancy was associated with higher liver enzyme levels in children. We also measured child serum metabolomics through a targeted assay and found significant perturbations in amino acid and glycerophospholipid metabolism associated with prenatal PFAS. A latent variable analysis identified a profile of children at high risk of liver injury (odds ratio, 1.56; 95% confidence interval, 1.21-1.92) that was characterized by high prenatal exposure to PFAS and increased serum levels of branched-chain amino acids (valine, leucine, and isoleucine), aromatic amino acids (tryptophan and phenylalanine), and glycerophospholipids (phosphatidylcholine [PC] aa C36:1 and Lyso-PC a C18:1). CONCLUSIONS: Developmental exposure to PFAS can contribute to pediatric liver injury.
BACKGROUND AND AIMS: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been shown to have hepatotoxic effects in animal models. However, human evidence is scarce. We evaluated how prenatal exposure to PFAS associates with established serum biomarkers of liver injury and alterations in serum metabolome in children. APPROACH AND RESULTS: We used data from 1,105 mothers and their children (median age, 8.2 years; interquartile range, 6.6-9.1) from the European Human Early-Life Exposome cohort (consisting of six existing population-based birth cohorts in France, Greece, Lithuania, Norway, Spain, and the United Kingdom). We measured concentrations of perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate, perfluorohexane sulfonate, and perfluoroundecanoate in maternal blood. We assessed concentrations of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase in child serum. Using Bayesian kernel machine regression, we found that higher exposure to PFAS during pregnancy was associated with higher liver enzyme levels in children. We also measured child serum metabolomics through a targeted assay and found significant perturbations in amino acid and glycerophospholipid metabolism associated with prenatal PFAS. A latent variable analysis identified a profile of children at high risk of liver injury (odds ratio, 1.56; 95% confidence interval, 1.21-1.92) that was characterized by high prenatal exposure to PFAS and increased serum levels of branched-chain amino acids (valine, leucine, and isoleucine), aromatic amino acids (tryptophan and phenylalanine), and glycerophospholipids (phosphatidylcholine [PC] aa C36:1 and Lyso-PC a C18:1). CONCLUSIONS: Developmental exposure to PFAS can contribute to pediatric liver injury.
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