Environmental Perfluoroalkyl Acid Exposures Are Associated with Liver Disease Characterized by Apoptosis and Altered Serum Adipocytokines
Open accessAbstract
Exposures to perfluoroalkyl substances (PFAS) including perfluoroalkyl acids (PFAAs) are associated with increased liver enzymes in cohort studies including the C8 Health Study. In animal models, PFAAs disrupt hepatic lipid metabolism and induce apoptosis to cause nonalcoholic fatty liver disease (NAFLD). PFAAs are immunotoxic and inhibit pro-inflammatory cytokine release from stimulated leukocytes in vitro. This cross-sectional study tests the hypothesis that environmental PFAAs are associated with increased hepatocyte apoptosis and decreased pro-inflammatory cytokines in serum. Biomarkers previously associated with PFAS exposures and/or NAFLD were evaluated as secondary endpoints. Two hundred adult C8 Health Study participants were included. Measured serum biomarkers included: perfluorohexane sulfonate (PFHxS); perfluorooctanoic acid (PFOA); perfluorooctane sulfonate (PFOS); perfluorononanoic acid (PFNA); cytokeratin 18 M30 (CK18 M30, hepatocyte apoptosis); adipocytokines; insulin; and cleaved complement 3 (C3a). Confounder-adjusted linear regression models determined associations between PFAS and disease biomarkers with cut-offs determined by classification and regression tree analysis. CK18 M30 was positively associated with PFHxS (β = 0.889, p = 0.042); PFOA (β = 2.1, p = 0.005); and PFNA (β = 0.567, p = 0.03). Tumor necrosis factor α (TNFα) was inversely associated with PFHxS (β = -0.799, p = 0.001); PFOA (β = - 1.242, p = 0.001); and PFOS (β = -0.704, p < 0.001). Interleukin 8 was inversely associated with PFOS and PFNA. PFAAs were also associated with sexually dimorphic adipocytokine and C3a responses. Overall, PFAA exposures were associated with the novel combination of increased biomarkers of hepatocyte apoptosis and decreased serum TNFα. These data support previous findings from cohorts and experimental systems that PFAAs may cause liver injury while downregulated some aspects of the immune response. Further studies of PFAAs in NAFLD are warranted and should evaluate sex differences.
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PFAS exposure has been associated with dysfunction and genesis of kidney and liver disease, including increased risk for carcinogenesis in these tissues.
“PFAS exposure has been associated with dysfunction and genesis of kidney and liver disease, including increased risk for carcinogenesis in these tissues”
From A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior (2022) · cites this paper as Bassler et al., 2019
The Introduction reports associations between PFAS exposure and liver-enzyme levels, and the Discussion considers a possible role in initiating fatty liver disease. The passages do not support the claim about kidney disease or increased cancer risk in either organ; searches for kidney disease and carcinogenesis found no such finding in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHuman cohorts have shown positive associations between serological biomarkers of hepatocyte death/apoptosis and serum PFAS concentrations.
“Human cohorts have shown positive associations between serological biomarkers of hepatocyte death/apoptosis and serum PFAS concentrations (Bassler et al., 2019).”
From A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior (2022) · cites this paper as Bassler et al., 2019
Animal studies have demonstrated PFAS-associated disruption of hepatic lipid metabolism, which may be mediated in part through interactions with PPARs and contribute to increased risk of NAFLD associated with PFAS exposure.
“animal studies have demonstrated PFAS associated disruption of hepatic lipid metabolism, which may be mediated, in part, through interactions with PPARs and contribute to increased risk of NAFLD associated with PFAS exposure”
From A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior (2022) · cites this paper as Bassler et al., 2019
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References 56 · Cited by 206
- Authors
- Bassler, J., Ducatman, A., Elliott, M., Wen, S., Wahlang, B., Barnett, J., & Cave, M. C.
- Affiliations
- West Virginia University (US)
- University of Louisville (US)
- Corresponding author
- Cave, Matthew C.
- ORCID
- Venue
- Environmental Pollution
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 247
- Pages
- 1055-1063
- ISSN
- 0269-7491 (ISSN-L)
- PMC
- PMC6404528
- OpenAlex
- W2910596005
- Cited by
- 206
- References
- 56
- Citations by year
- 2026: 14 · 2025: 33 · 2024: 33 · 2023: 31 · 2022: 39 · 2021: 27 · 2020: 22 · 2019: 7
- FWCI
- 10.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Environmental Pollution (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (P50AA024337)
- National Institute of General Medical Sciences (P20GM113226)
- National Institute of Environmental Health Sciences (P42ES023716, T32ES0011564, R35ES028373)
- Topics
- Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Fluorine in Organic Chemistry
- Keywords
- perfluoroalkyl acids, PFAS exposure, non-alcoholic fatty liver disease, hepatocyte apoptosis, adipokines, TNF-α, interleukin-8, complement C3a, perfluorooctanoic acid, PFOS, PFHxS, perfluorononanoic acid, sex differences, liver injury, immunotoxicity, biomarkers
- MeSH terms
- Adult, Aged, Animals, Cross-Sectional Studies, Environmental Exposure, Female, Fluorocarbons, Humans, Male, Middle Aged, Biomarkers, Apoptosis, Lipid Metabolism, Adipokines, Chemical and Drug Induced Liver Injury
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