Per- and polyfluoroalkyl substance (PFAS) exposure, maternal metabolomic perturbation, and fetal growth in African American women: A meet-in-the-middle approach

• Type of Material: Article
• Authors: Che-Jung Chang, Emory University; Dana Barr, Emory University; P Ryan, Emory University; Parinya Panuwet, Emory University; Melissa Smarr, Emory University; Ken Liu, Emory University; Kurunthachalam Kannan, New York University; Volha Yakimavets, Emory University; Youran Tan, Emory University; ViLinh Ly, Emory University; Carmen Marsit, Emory University; Dean Jones, Emory University; Elizabeth Corwin, Emory University; Anne Dunlop, Emory University; Donghai Liang, Emory University
• Language: English
• Date: 2021-11-01
• Publisher: PERGAMON-ELSEVIER SCIENCE LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 The Authors. Published by Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.envint.2021.106964
• Title of Journal or Parent Work: ENVIRONMENT INTERNATIONAL
• Volume: 158
• Start Page: 106964
• End Page: 106964
• Grant/Funding Information: This work was supported by the Environmental Influences on Child Health Outcomes (ECHO) program, Office of the Director, National Institutes of Health [5U2COD023375-05/A03-3824], the National Institute of Health (NIH) research grants [R01NR014800, R01MD009064, R24ES029490, R01MD009746, R21ES032117], NIH Center Grants [P50ES02607, P30ES019776, UH3OD023318, U2CES026560, U2CES026542, U24ES026539], and Environmental Protection Agency (USEPA) center grant [83615301].
• Keywords: PFAS; INTRAHEPATIC CHOLESTASIS; Fetal growth; Environmental Sciences; PERFLUOROOCTANOIC ACID; Biomarkers; AIR-POLLUTION; EVIDENCE-BASED MEDICINE; FOR-GESTATIONAL-AGE; BILE-ACID LEVELS; HIGH-RESOLUTION METABOLOMICS; URIC-ACID; Science & Technology; PERFLUOROALKYL SUBSTANCES; OXIDATIVE STRESS; High-resolution metabolomics; Life Sciences & Biomedicine; Environmental Sciences & Ecology

Abstract

Background: Prenatal exposures to per- and polyfluoroalkyl substances (PFAS) have been linked to reduced fetal growth. However, the detailed molecular mechanisms remain largely unknown. This study aims to investigate biological pathways and intermediate biomarkers underlying the association between serum PFAS and fetal growth using high-resolution metabolomics in a cohort of pregnant African American women in the Atlanta area, Georgia. Methods: Serum perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) measurements and untargeted serum metabolomics profiling were conducted in 313 pregnant African American women at 8–14 weeks gestation. Multiple linear regression models were applied to assess the associations of PFAS with birth weight and small-for-gestational age (SGA) birth. A high-resolution metabolomics workflow including metabolome-wide association study, pathway enrichment analysis, and chemical annotation and confirmation with a meet-in-the-middle approach was performed to characterize the biological pathways and intermediate biomarkers of the PFAS-fetal growth relationship. Results: Each log2-unit increase in serum PFNA concentration was significantly associated with higher odds of SGA birth (OR = 1.32, 95% CI 1.07, 1.63); similar but borderline significant associations were found in PFOA (OR = 1.20, 95% CI 0.94, 1.49) with SGA. Among 25,516 metabolic features extracted from the serum samples, we successfully annotated and confirmed 10 overlapping metabolites associated with both PFAS and fetal growth endpoints, including glycine, taurine, uric acid, ferulic acid, 2-hexyl-3-phenyl-2-propenal, unsaturated fatty acid C18:1, androgenic hormone conjugate, parent bile acid, and bile acid-glycine conjugate. Also, we identified 21 overlapping metabolic pathways from pathway enrichment analyses. These overlapping metabolites and pathways were closely related to amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism perturbations. Conclusion: In this cohort of pregnant African American women, higher serum concentrations of PFOA and PFNA were associated with reduced fetal growth. Perturbations of biological pathways involved in amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism were associated with PFAS exposures and reduced fetal growth, and uric acid was shown to be a potential intermediate biomarker. Our results provide opportunities for future studies to develop early detection and intervention for PFAS-induced fetal growth restriction.