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. 2022 Jan:158:106964.
doi: 10.1016/j.envint.2021.106964. Epub 2021 Nov 1.

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

Affiliations

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

Che-Jung Chang et al. Environ Int. 2022 Jan.

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.

Keywords: Biomarkers; Fetal growth; High-resolution metabolomics; PFAS.

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Conflict of interest statement

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.. Workflow of the meet-in-the-middle (MITM) approach and the number of extracted or significant metabolic features in each analytical step.
Overlapping significant features are the metabolic features associated with both PFAS and fetal growth endpoints. Validated features are the overlapping features exhibiting clear gaussian peak shapes and signal-to-noise ratio above 3:1 from their extracted ion chromatographs. Confirmed metabolites are the validated features successfully annotated and confirmed with chemical identities. (HILIC = hydrophilic interaction liquid chromatography column; C18 = C18 column; PFAS = per- and polyfluorinated alkyl substance; MWAS = metabolome-wide association study)
Figure 2.
Figure 2.. The enriched metabolic pathways significantly associated with ≥ 2 PFAS serum concentrations and fetal growth in pregnant African American women in the Atlanta area, 2014-2018 (n=313).
(a) Heat map of p-values. Each cell was colored by the p-value of the association of each metabolic pathway and with either serum PFAS or fetal growth endpoints. Overlap size represents the average number of significant putative metabolites (p-value < 0.05) that were associated with either serum PFAS or fetal growth endpoints among each metabolic pathway. Pathway size represents the number of metabolites within each metabolic pathway. % is the percentage of overlap size to pathway size. These pathways were ordered by the number of significance results. (b) The percentages of each class among all enriched metabolic pathways. (c) The class of enriched metabolic pathways. (Note: HILIC = hydrophilic interaction liquid chromatography column; C18 = C18 column; PFHxS = perfluorohexane sulfonic acid; PFOS = perfluorooctane sulfonic acid; PFOA = perfluorooctanoic acid; PFNA = perfluorononanoic acid; BW = birth weight [the analyses were restricted to term births]; SGA = small-for-gestational age; KEGG = Kyoto Encyclopedia of Genes and Genomes)

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