Metabolic Signatures of Youth Exposure to Mixtures of Per- and Polyfluoroalkyl Substances: A Multi-Cohort Study

Abstract

Background: Exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous and has been associated with an increased risk of several cardiometabolic diseases. However, the metabolic pathways linking PFAS exposure and human disease are unclear. Objective: We examined associations of PFAS mixtures with alterations in metabolic pathways in independent cohorts of adolescents and young adults. Methods: Three hundred twelve overweight/obese adolescents from the Study of Latino Adolescents at Risk (SOLAR) and 137 young adults from the Southern California Children’s Health Study (CHS) were included in the analysis. Plasma PFAS and the metabolome were determined using liquid-chromatography/high-resolution mass spectrometry. A metabolome-wide association study was performed on log-transformed metabolites using Bayesian regression with a g-prior specification and g-computation for modeling exposure mixtures to estimate the impact of exposure to a mixture of six ubiquitous PFAS (PFOS, PFHxS, PFHpS, PFOA, PFNA, and PFDA). Pathway enrichment analysis was performed using Mummichog and Gene Set Enrichment Analysis. Significance across cohorts was determined using weighted -tests. Results: In the SOLAR and CHS cohorts, PFAS exposure was associated with alterations in tyrosine metabolism (meta-analysis ) and de novo fatty acid biosynthesis ( ), among others. For example, when increasing all PFAS in the mixture from low ( th percentile) to high ( th percentile), thyroxine (T4), a thyroid hormone related to tyrosine metabolism, increased by 0.72 standard deviations (SDs; equivalent to a standardized mean difference) in the SOLAR cohort (95% Bayesian credible interval (BCI): 0.00, 1.20) and 1.60 SD in the CHS cohort (95% BCI: 0.39, 2.80). Similarly, when going from low to high PFAS exposure, arachidonic acid increased by 0.81 SD in the SOLAR cohort (95% BCI: 0.37, 1.30) and 0.67 SD in the CHS cohort (95% BCI: 0.00, 1.50). In general, no individual PFAS appeared to drive the observed associations. Discussion: Exposure to PFAS is associated with alterations in amino acid metabolism and lipid metabolism in adolescents and young adults. https://doi.org/10.1289/EHP11372

Metabolic Perturbations Associated with an Exposure Mixture of Per- and Polyfluoroalkyl Substances in the Atlanta African American Maternal-Child Cohort

“…In previous work, we reported on the maternal and fetal metabolomic associations with prenatal exposure to single PFAS chemicals and adverse birth outcomes. , The present analysis builds on this work by examining the effects of a PFAS mixture. Similar to our approach, a 2023 study also examined the impact of a PFAS mixture on the plasma metabolome of adolescents and young adults enrolled in the Study of Latino Adolescents at Risk (SOLAR) and Southern California Children’s Health Study (CHS) . Across our study and the study conducted within SOLAR and CHS, amino acids and fatty acids critical to energy production and endocrine signaling for healthy growth and development in early life were consistently perturbed.…”

“…Our work has also demonstrated that short-chain PFAS, such as perfluorohexanesulfonic acid (PFHxS), perturb the maternal metabolome through biosynthetic and bioenergetic pathways while legacy long-chain PFAS, such as PFOS and PFOA, tend to dysregulate signaling pathways . Despite awareness that individuals are exposed to multiple PFAS chemicals, the cumulative effects of PFAS on the human metabolome remain largely unknown due to the complexity of integrating high-dimensional data across statistical approaches . The assessment of biological responses to PFAS exposures and resulting health outcomes is further complicated by the lack of sensitive and specific biomarkers, interindividual heterogeneity in toxicokinetics, and involvement of numerous endogenous pathways.…”

IDSL.GOA: Gene Ontology Analysis for Interpreting Metabolomic datasets

“…Analysis of these metabolic genes, their products, and endogenous metabolites using omics approaches, including genomics, transcriptomics, proteomics, and metabolomics, can identify metabolic processes that are important during different life stages in normal and adverse health conditions 3 . These molecular omics approaches are discovering new insights into how metabolic processes are altered by diseases, toxic exposures and baseline genetic variations, enabling new prevention and therapeutic strategies for human diseases [4][5][6][7] .…”

Associations of a Prenatal Serum Per- and Polyfluoroalkyl Substance Mixture with the Cord Serum Metabolome in the HOME Study

“…Untargeted metabolomics is a discovery-based technique that comprehensively assesses metabolic profiles and pathways . In tandem with statistical tools like metabolome-wide association studies (MWAS) and pathway enrichment analysis, relations between exposures to PFAS and hundreds to thousands of metabolites and their corresponding biological pathways can be investigated. − As such, untargeted metabolomics is being increasingly used to identify metabolites and pathways associated with human exposure or disease …”

“…While numerous statistical methods have been developed to quantify the potential effects of chemical mixtures, few studies have evaluated the impact of PFAS mixtures on the fetal metabolome. − Understanding the impact of PFAS exposures on the fetal metabolome is important because PFAS can cross the placenta, and the fetus may be more sensitive to environmental exposures compared to later life stages . Furthermore, the investigation of chemical mixtures is critical, given that PFAS exposure does not occur in isolation.…”