Molecular phenotyping of a per- and polyfluoroalkyl substances (PFAS) mixture during human pregnancy with high-throughput, high-resolution, high-dimensional technologies Restricted; Files Only
Taibl, Kaitlin (Spring 2025)
Abstract
Approximately 15,000 chemicals belong to the per- and polyfluoroalkyl substances (PFAS) family. However, environmental epidemiology mainly investigates single PFAS, which limits understanding about potential joint effects of exposure to multiple PFAS on human health. The advent of mixture models and exposomics now enables the discovery of molecular phenotypes (i.e., markers, mechanisms, networks) that underly such exposure-outcome associations, particularly for critical windows and vulnerable populations. Hence, three aims were conducted for molecular phenotyping of prenatal exposure to four legacy chemicals – perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) – in the Atlanta African American Maternal-Child Cohort with an innovative application of high-throughput, high-resolution, and high-dimensional technologies.
Aim 1 estimated the longitudinal association between the PFAS mixture and endogenous antioxidant bilirubin during pregnancy. Aim 2 developed and applied an approach to characterize molecular phenotypes of the PFAS mixture in the maternal metabolome. Aim 3 characterized intermediate molecular phenotypes for the association between the PFAS mixture and small-for-gestational age (SGA), an adverse pregnancy outcome, in the maternal lipidome.
In Aim 1, pregnant women with higher serum concentrations of the PFAS mixture had higher serum levels of total bilirubin. Pregnancy stage modified the association, with a stronger effect observed between 21 – 36 gestational weeks. In Aim 2, the PFAS mixture was associated with a greater suite of molecular phenotypes in the maternal metabolome than single PFAS. PFOS contributed most to the overall mixture effect on lipid-specific molecular phenotypes, including arachidonic acid metabolism (e.g., pro-oxidative lipid mechanism) and eicosapentaenoic acid (e.g., anti-inflammatory lipid marker). In Aim 3, the PFAS-SGA association had 14 molecular phenotypes in the maternal lipidome. Bioactive lipid markers and mechanisms were predominant intermediates, including arachidonic acid-containing phosphatidylinositol (PI 18:1-20:4), which PFNA contributed most to the overall mixture exposure effect, and insulin resistance, respectively.
Taken altogether, lipid peroxidation and lipid-mediated inflammation from mitochondrial dysfunction underly adverse health effects of cumulative, joint exposure to PFNA, PFOA, PFOS, and PFHxS among pregnant African Americans, including those who deliver an SGA newborn. These molecular phenotypes may be translated into actionable public health strategies, such as nutritional intervention and chemical regulation.
Table of Contents
Chapter 1: Introduction
1.1 Background
1.2 Associations of per- and polyfluoroalkyl substances (PFAS) and their mixture with oxidative stress biomarkers during pregnancy
1.3 Pregnancy-related hemodynamic biomarkers in relation to trimester-specific maternal per- and polyfluoroalkyl substances exposures and adverse birth outcomes
1.4 Newborn metabolomic signatures of maternal per- and polyfluoroalkyl substance exposure and reduced length of gestation
1.5 Dissertation Aims
Chapter 2: Association of per- and polyfluoroalkyl substances with the antioxidant bilirubin across pregnancy
Introduction
Materials and Methods
Results
Discussion
Supplemental Information
Chapter 3: Metabolic perturbations associated with an exposure mixture of per- and polyfluoroalkyl substances in the Atlanta African American Maternal-Child Cohort
Introduction
Materials and Methods
Results
Discussion
Conclusion
Supplemental Information
Chapter 4: Global analysis of the maternal lipidome in relation to prenatal per- and polyfluoroalkyl substances (PFAS) exposure and small-for-gestational age (SGA) delivery
Introduction
Materials and Methods
Results
Discussion
Supplemental Information
Chapter 5: Conclusion
Summary
Key Findings
Scientific Contributions and Future Directions
Strengths and Limitations
References
About this Dissertation
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File download under embargo until 22 May 2027 | 2025-03-19 13:21:11 -0400 | File download under embargo until 22 May 2027 |
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