Novel and Legacy Per- and Polyfluoroalkyl Substances in Humans: Long-Term Temporal Variability and Metabolic Perturbations
Open accessAbstract
As legacy per- and polyfluoroalkyl substances (PFAS) are phased out, numerous substitutes have emerged, raising concerns about their potential health impacts. Using targeted and untargeted approaches, we evaluated plasma PFAS on an -omic scale, examining temporal variability and associated metabolomic disruptions. A total of 400 blood samples from 200 Sister Study participants (collected in 2007-2008 and 2013-2014) were analyzed using liquid chromatography with high-resolution mass spectrometry. Temporal variability was assessed using Spearman correlations and intraclass correlation coefficients. Network analysis, metabolome-wide association studies, and pathway analysis were used to evaluate the impacts of PFAS mixtures on the human metabolome. We detected 24 legacy PFAS via the targeted approach and 1,802 features annotated as potential PFAS via the untargeted approach (21 confirmed by reference standards). While legacy PFAS demonstrated low temporal variability, novel PFAS, especially those that have increased in abundance over time, demonstrated greater temporal variability. The legacy PFAS mixture was associated with lipid and amino acid metabolism, while other PFAS mixtures consisting of novel PFAS affected a wider range of metabolic pathways in addition to amino and lipid metabolism, such as carbohydrate, cofactor and vitamin, and endocrine metabolism. These findings underscore the need for further research on these novel PFAS and their health effects.
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Newer PFAS compounds exert broader effects across metabolic pathways, including carbohydrate processing, vitamin/cofactor utilization, and endocrine regulation.
“Legacy PFAS mixtures have been shown to primarily disrupt amino acid and lipid metabolism, while newer PFAS compounds exert broader effects across metabolic pathways, including those involved in carbohydrate processing, vitamin/cofactor utilization, and endocrine regulation [79].”
From Exposure to Per- and Polyfluoroalkyl Substances (PFASs) in Healthcare: Environmental and Clinical Insights (2025) · cites this paper as [79]
Legacy PFAS mixtures primarily disrupt amino acid and lipid metabolism.
“Legacy PFAS mixtures have been shown to primarily disrupt amino acid and lipid metabolism, while newer PFAS compounds exert broader effects across metabolic pathways, including those involved in carbohydrate processing, vitamin/cofactor utilization, and endocrine regulation [79].”
From Exposure to Per- and Polyfluoroalkyl Substances (PFASs) in Healthcare: Environmental and Clinical Insights (2025) · cites this paper as [79]
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- Authors
- Chang, C.-J., Young, A. S., Keil, A., Mullins, C. E., Liang, D., Zhao, S., Jones, D. P., Hu, X., Walker, D. I., & White, A. J.
- Affiliations
- National Institutes of Health (US)
- Emory University (US)
- National Institute of Environmental Health Sciences (US)
- Corresponding author
- White, Alexandra J.
- ORCID
- Venue
- Environment International
- Publisher
- Elsevier BV
- Published
- 2025-07
- Volume
- 201
- Pages
- 109590
- ISSN
- 0160-4120 (ISSN-L)
- PMC
- PMC12219314
- OpenAlex
- W4411081266
- Semantic Scholar
- e7d60368b80b2d15c7528411f7e41cb6680edc99
- Cited by
- 16
- References
- 67
- Citations by year
- 2026: 11 · 2025: 5
- FWCI
- 4.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Environment International (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Environmental Health Sciences (Z01-ES044005, R01ES032831, Z1AES103332)
- Topics
- Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Fluorine in Organic Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- per- and polyfluoroalkyl substances, legacy PFAS, temporal variation, human metabolome, lipid metabolism, amino acid metabolism, carbohydrate metabolism, endocrine metabolism, cofactor and vitamin metabolism, Sister Study, PFAS mixtures
- MeSH terms
- Adult, Environmental Exposure, Environmental Pollutants, Female, Fluorocarbons, Humans, Middle Aged, Metabolome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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