Prenatal Exposure to Perfluoroalkyl Substances Associated With Increased Susceptibility to Liver Injury in Children

• Type of Material: Article
• Authors: Nikos Stratakis, University of Southern California; David V. Conti, University of Southern California; Ran Jin, University of Southern California; Katerina Margetaki, University of Southern California; Damaskini Valvi, Icahn School of Medicine at Mount Sinai; Alexandros P. Siskos, Imperial College London; Lea Maitre, ISGlobal; Erika Garcia, University of Southern California; Nerea Varo, University Clinic of Navarra; Yinqi Zhao, University of Southern California; Theano Roumeliotaki, University of Crete; Marina Vafeiadi, University of Crete; Jose Urquiza, ISGlobal; Silvia Fernandez-Barres, ISGlobal; Barbara Heude, University of Paris; Xavier Basagana, ISGlobal; Maribel Casas, ISGlobal; Serena Fossati, ISGlobal; Regina Grazuleviciene, Vytauto Didžiojo Universitetas; Sandra Andrusaityte, Vytauto Didžiojo Universitetas; Karan Uppal, Emory University; Rosemary R.C. McEachan, Bradford Teaching Hospitals NHS Foundation Trust; Eleni Papadopoulou, Norwegian Institute of Public Health; Oliver Robinson, Imperial College London; Line Smastuen Haug, Norwegian Institute of Public Health; John Wright, Bradford Teaching Hospitals NHS Foundation Trust; Miriam Vos, Emory University; Hector C. Keun, Imperial College London; Martine Vrijheid, ISGlobal; Kiros T. Berhane, University of Southern California; Rob McConnell, University of Southern California; Lida Chatzi, University of Southern California
• Language: English
• Date: 2020-10-19
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2020
• Final Published Version (URL): http://dx.doi.org/10.1002/hep.31483
• Title of Journal or Parent Work: HEPATOLOGY
• Volume: 72
• Issue: 5
• Start Page: 1758
• End Page: 1770
• Grant/Funding Information: The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 308333—the HELIX project. INMA 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). For a full list of funding that supported the EDEN cohort, see the publication: Heude B et al. Cohort Profile: The EDEN mother-child cohort on the prenatal and early postnatal determinants of child health and development. Int J Epidemiol 2016;45:353-363. The Norwegian Mother, Father and Child Cohort Study (MoBa) 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 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: 2012–2015). The KANC cohort was financially supported by the Lithuanian Agency for Science Innovation and Technology on September 13, 2015, No. 31V-77. Dr. Maribel Casas received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness; MS16/00128). This work was supported by National Institute of Environmental Health Sciences (NIEHS): R21ES029681 (Chatzi, Conti, McConnell, Stratakis, and Vos), R01ES030691 (Chatzi, Conti, and McConnell), R01ES029944 (Chatzi, Conti, and Valvi), R01ES030364 (Chatzi, Conti, and McConnell), R01ES028903 (Chatzi, McConnell, and Valvi), F32ES029828 (Jin), P30ES007048 (Chatzi, Conti, McConnell, and Stratakis), and R01ES030691 (Chatzi, Conti, and McConnell). Additional funding from the National Institutes of Health (NIH) supported Dr. Conti (P01CA196569, R01CA140561, and R01ES016813) and Dr. Stratakis (P30DK048522). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech), and it is a member of the ProteoRed PRB3 consortium, which is supported by grant PT17/0019 of the PE I+D+i 2013–2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, “Centro de Excelencia Severo Ochoa 2013–2017”, SEV-2012-0208, and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595).
• Keywords: Life Sciences & Biomedicine; PFOA; PERFLUOROOCTANOIC ACID; CHEMICALS; HOMEOSTASIS; BIOMARKERS; POPULATION; SERUM; Science & Technology; METABOLISM; Gastroenterology & Hepatology; STEATOSIS; ADOLESCENTS
• Research Categories: Health Sciences, Public Health

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.