PFAS Exposures and the Human Metabolome: A Systematic Review of Epidemiological Studies
Open accessAbstract
Purpose of review There is a growing interest in understanding the health effects of exposure to per- and polyfluoroalkyl substances (PFAS) through the study of the human metabolome. In this systematic review, we aimed to identify consistent findings between PFAS and metabolomic signatures. We conducted a search matching specific keywords that was independently reviewed by two authors on two databases (EMBASE and PubMed) from their inception through July 19, 2022 following PRISMA guidelines.Recent findings We identified a total of 28 eligible observational studies that evaluated the associations between 31 different PFAS exposures and metabolomics in humans. The most common exposure evaluated was legacy long-chain PFAS. Population sample sizes ranged from 40 to 1,105 participants at different stages across the lifespan. A total of 19 studies used a non-targeted metabolomics approach, 7 used targeted approaches, and 2 included both. The majority of studies were cross-sectional (n = 25), including four with prospective analyses of PFAS measured prior to metabolomics.Summary Most frequently reported associations across studies were observed between PFAS and amino acids, fatty acids, glycerophospholipids, glycerolipids, phosphosphingolipids, bile acids, ceramides, purines, and acylcarnitines. Corresponding metabolic pathways were also altered, including lipid, amino acid, carbohydrate, nucleotide, energy metabolism, glycan biosynthesis and metabolism, and metabolism of cofactors and vitamins. We found consistent evidence across studies indicating PFAS-induced alterations in lipid and amino acid metabolites, which may be involved in energy and cell membrane disruption.
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PFASs can activate PPARα, disrupt nuclear receptor signaling, and interfere with genes regulating lipid and cholesterol homeostasis.
“Mechanistically, PFASs can activate peroxisome proliferatoractivated receptor alpha (PPAR α ), disrupt nuclear receptor signaling, and interfere with genes regulating lipid and cholesterol homeostasis.”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [200]
The Discussion (Potential Dysregulated Pathways Linked with PFAS Exposures in Humans; page unavailable) reports that several PFAS activate PPARα in human cells and describes effects involving other nuclear receptors and changes in gene expression. It also links PFAS to altered lipid metabolism, but does not itself establish interference with genes regulating both lipid and cholesterol homeostasis; the more specific gene findings appear in titles in the References. (LLM, conf=0.82)
Experimental — accuracy not yet measuredPFASs cause thyroid hormone disruption by binding to thyroid hormone transport proteins, displacing T4, and interfering with thyroid peroxidase activity, leading to altered feedback in the hypothalamic-pituitary-thyroid axis.
“PFASs also cause thyroid hormone disruption by binding to thyroid hormone transport proteins, displacing thyroxine (T4), and interfering with thyroid peroxidase activity, leading to altered feedback in the hypothalamic-pituitary-thyroid axis.”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [200]
The Discussion section, “Potential Dysregulated Pathways Linked with PFAS Exposures in Humans” (page unavailable), says PFAS can compete with thyroxine for binding to thyroid hormone transport proteins or receptors, potentially causing hormone dysregulation. It does not describe interference with thyroid peroxidase or altered feedback in the hypothalamic-pituitary-thyroid axis, and it presents the thyroid effect as potential rather than established causation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPFAS exposure leads to immune suppression, with multiple studies reporting significant associations between PFAS exposure and reduced immune function, particularly in children.
“Furthermore, PFAS exposure leads to immune suppression, with multiple studies reporting significant associations between PFAS exposure and reduced immune function, particularly in children.”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [200]
The Introduction (page not provided) links PFAS exposure to altered immune function and cites reports of decreased antibody response. The Discussion (page not provided) describes an association with impaired immune responses, but the review does not establish that PFAS exposure causes immune suppression or report multiple significant associations with reduced immune function specifically in children; its child-focused findings concern metabolism. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPFAS exposure is associated with changes in thyroid hormone levels, with some evidence of sex-specific effects and non-monotonic dose responses.
“Epidemiological and experimental data indicate PFAS exposure is associated with changes in thyroid hormone levels, with some evidence of sex-specific effects and non-monotonic dose responses [200,201].”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [200]
The Introduction reports links between PFAS exposure and altered thyroid function, and the Discussion (Potential Dysregulated Pathways Linked with PFAS Exposures in Humans) describes a possible mechanism for changing circulating thyroid hormone levels. Neither passage, nor the additional passages searched for sex-specific and non-monotonic dose responses, reports those patterns for thyroid hormones. Page numbers were not provided in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPFAS exposure is robustly linked to dyslipidemia and altered lipid metabolism.
“In the realm of lipid metabolism, PFAS exposure is robustly linked to dyslipidemia and altered lipid metabolism.”
From Industrial Applications, Environmental Fate, Human Exposure, and Health Effects of PFAS (2025) · cites this paper as [200]
The Discussion (‘Potential Dysregulated Pathways Linked with PFAS Exposures in Humans’) reports generally positive PFAS–triglyceride associations in the reviewed human metabolomics studies and identifies altered lipid-metabolism pathways. But it also says associations with unhealthy lipids, including triglycerides and LDL cholesterol, have not been consistent across epidemiological studies. Thus ‘robustly linked to dyslipidemia’ overstates the evidence presented. (LLM, conf=0.88)
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References 244 · Cited by 114
Research works printed but not linked: 3
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- Authors
- India-Aldana, S., Yao, M., Midya, V., Colicino, E., Chatzi, L., Chu, J., Gennings, C., Jones, D. P., Loos, R. J. F., Setiawan, V. W., Smith, M. R., Walker, R. W., Barupal, D., Walker, D. I., & Valvi, D.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- University of Southern California (US)
- Emory University (US)
- University of Copenhagen (DK)
- Corresponding author
- Valvi, Damaskini
- ORCID
- Venue
- Current Pollution Reports
- Published
- 2023-06-29
- Volume
- 9
- Issue
- 3
- Pages
- 510-568
- ISSN
- 2198-6592 (ISSN-L)
- PMC
- PMC10520990
- OpenAlex
- W4382560302
- Cited by
- 114
- References
- 244
- Citations by year
- 2026: 44 · 2025: 45 · 2024: 25
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Current Pollution Reports (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Funders
- NIEHS (R01ES033688, R21029328, P30ES023515)
- Topics
- Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Health, Environment, Cognitive Aging
- Keywords
- per- and polyfluoroalkyl substances, PFAS exposure, human metabolome, metabolomic signatures, amino acid metabolism, lipid metabolism, glycerophospholipids, acylcarnitines, bile acids, ceramide, energy metabolism, glycan biosynthesis
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