Role of bioavailability and protein binding of four anionic perfluoroalkyl substances in cell-based bioassays for quantitative in vitro to in vivo extrapolations

Qin, Weiping; Henneberger, Luise; Huchthausen, Julia; König, Maria; Escher, Beate I.

doi:10.1016/j.envint.2023.107857

Cited by 11 publications

(47 citation statements)

References 70 publications

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“…When directed against the plasma membrane of epithelial cells, this lytic activity could activate damage-associated molecular patterns (DAMPs). These are pro-inflammatory compounds such as interleukin 1α (IL-1α), heat-shock protein 70 (HSP70), and tumor necrosis factor alpha (TNFα) which are released in response to cellular damage or stress. − Damage to epithelial cells through the introduction of membrane-destabilizing agents can induce the upregulation of DAMPs, , which can be correlated with asthma and other inflammatory disorders. − The ability of BSA–PFOA complexes to permeabilize lipid bilayers could induce DAMP release in a similar manner, providing an additional avenue through which exposure to dust particles containing both PFAS and protein contaminants contributes to negative health outcomes among effected populations. − …”

Section: Resultsmentioning

confidence: 99%

Albumin Proteins as Delivery Vehicles for PFAS Contaminants into Respiratory Membranes

Pye,

Wallace,

Marangoni

et al. 2023

ACS Omega

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Poly- and perfluoroalkyl substances (PFAS) are a family of chemicals that have been used in a wide range of commercial products. While their use is declining, the prevalence of PFAS, combined with their chemical longevity, ensures that detectable levels will remain in the environment for years to come. As such, there is a pressing need to understand how PFAS contaminants interact with other elements of the human exposome and the consequences of these interactions for human health. Using serum albumin as a model system, we show that proteins can bind PFAS contaminants and facilitate their incorporation into model pulmonary surfactant systems and lipid bilayers. Protein-mediated PFAS delivery significantly altered the structure and function of both model membrane systems, potentially contributing to respiratory dysfunction and airway diseases in vivo. These results provide valuable insights into the synergistic interaction between PFAS contaminants and other elements of the human exposome and their potential consequences for human health.

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Section: Resultsmentioning

confidence: 99%

Albumin Proteins as Delivery Vehicles for PFAS Contaminants into Respiratory Membranes

Pye,

Wallace,

Marangoni

et al. 2023

ACS Omega

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“…Notably, the distribution coefficients reported in this study were determined at molar ratios of PFAS to proteins ≤0.01, which is approximately 100 times lower than the molar ratio at which saturation was observed for BSA. 16 This should be considered when applying these distribution coefficients to systems with higher PFAS-to-protein ratios, such as in vitro toxicity tests. Binding to proteins was not expected to be ratelimiting based on previous work.…”

Section: Setup Of Binding Experimentsmentioning

confidence: 99%

“…10−15 Specifically, the unbound fraction of a toxicant in blood is typically more available for transport to organs and more likely to reach molecular targets that elicit toxic effects. 15,16 PFAS bound to proteins are thought to be inaccessible to biomolecules involved in transformation and elimination processes and are recirculated in the bloodstream, thereby extending elimination half-lives. 17, 18 Two of the most abundant proteins in blood are human serum albumin (HSA) and globulins.…”

Section: Introductionmentioning

confidence: 99%

“…The utility of C18 SPME fibers for measuring PFAS serum protein binding has been demonstrated in past work that used them to measure binding of four PFAS to bovine serum albumin (BSA), human plasma, and in vitro cell homogenates. 16 The main objectives of this work were to (1) investigate competitive binding of PFAS to two major proteins (HSA and γ-globulin) in human serum using SPME techniques and (2) characterize variability in the unbound fraction of PFAS in the human body. We focused on distribution of PFAS to γglobulin because it is the most abundant protein within the class of globulins in human serum.…”

Section: Introductionmentioning

confidence: 99%

“…This approach avoids extractions of chemicals from biomolecules, thereby minimizing laboratory work and matrix effects during chemical analysis. The utility of C18 SPME fibers for measuring PFAS serum protein binding has been demonstrated in past work that used them to measure binding of four PFAS to bovine serum albumin (BSA), human plasma, and in vitro cell homogenates …”

Section: Introductionmentioning

confidence: 99%

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Binding of Per- and Polyfluoroalkyl Substances (PFAS) to Serum Proteins: Implications for Toxicokinetics in Humans

Fischer,

Ludtke,

Thackray

et al. 2024

Environ. Sci. Technol.

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Per-and polyfluoroalkyl substances (PFAS) are a diverse class of highly persistent anthropogenic chemicals that are detectable in the serum of most humans. PFAS exposure has been associated with many adverse effects on human health including immunotoxicity, increased risk of certain cancers, and metabolic disruption. PFAS binding to the most abundant blood serum proteins (human serum albumin [HSA] and globulins) is thought to affect transport to active sites, toxicity, and elimination half-lives. However, few studies have investigated the competitive binding of PFAS to these proteins in human serum. Here, we use C18 solidphase microextraction fibers to measure HSA−water and globulin− water distribution coefficients (D HSA/w , D glob/w ) for PFAS with carbon chains containing 4 to 13 perfluorinated carbons (η pfc = 4− 13) and several functional head-groups. PFAS with η pfc < 7 were highly bound to HSA relative to globulins, whereas PFAS with η pfc ≥ 7 showed a greater propensity for binding to globulins. Experimentally measured D HSA/w and D glob/w and concentrations of serum proteins successfully predicted the variability in PFAS binding in human serum. We estimated that the unbound fraction of serum PFAS varied by up to a factor of 2.5 among individuals participating in the 2017−2018 U.S. National Health and Nutrition Examination Survey. These results suggest that serum HSA and globulins are important covariates for epidemiological studies aimed at understanding the effects of PFAS exposure.

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N‐glucuronidation and Excretion of Perfluoroalkyl Sulfonamides in Mice Following Ingestion of Aqueous Film‐Forming Foam

Dukes,

McDonough

2024

Enviro Toxic and Chemistry

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Perfluoroalkyl sulfonamides (FASAs) and other FASA‐based per‐ and polyfluoroalkyl substances (PFASs) can transform into recalcitrant perfluoroalkyl sulfonates in vivo. We conducted high‐resolution mass spectrometry suspect screening of urine and tissues (kidney and liver) from mice dosed with an electrochemically fluorinated aqueous film‐forming foam (AFFF) to better understand the biological fate of AFFF‐associated precursors. The B6C3F1 mice were dosed at five levels (0, 0.05, 0.5, 1, and 5 mg kg−1 day−1) based on perfluorooctane sulfonate and perfluorooctanoate content of the AFFF mixture. Dosing continued for 10 days followed by a 6‐day depuration. Total oxidizable precursor assay of the AFFF suggested significant contributions from precursors with three to six perfluorinated carbons. We identified C4 to C6 FASAs and N‐glucuronidated FASAs (FASA‐N‐glus) excreted in urine collected throughout dosing and depuration. Based on normalized relative abundance, FASA‐N‐glus accounted for up to 33% of the total excreted FASAs in mouse urine, highlighting the importance of phase II metabolic conjugation as a route of excretion. High‐resolution mass spectrometry screening of liver and kidney tissue revealed accumulation of longer‐chain (C7 and C8) FASAs not detected in urine. Chain‐length–dependent conjugation of FASAs was also observed by incubating FASAs with mouse liver S9 fractions. Shorter‐chain (C4) FASAs conjugated to a much greater extent over a 120‐min incubation than longer‐chain (C8) FASAs. Overall, this study highlights the significance of N‐glucuronidation as an excretion mechanism for short‐chain FASAs and suggests that monitoring urine for FASA‐N‐glus could contribute to a better understanding of PFAS exposure, as FASAs and their conjugates are often overlooked by traditional biomonitoring studies. Environ Toxicol Chem 2024;00:1–11. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

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Role of bioavailability and protein binding of four anionic perfluoroalkyl substances in cell-based bioassays for quantitative in vitro to in vivo extrapolations

Cited by 11 publications

References 70 publications

Albumin Proteins as Delivery Vehicles for PFAS Contaminants into Respiratory Membranes

Albumin Proteins as Delivery Vehicles for PFAS Contaminants into Respiratory Membranes

Binding of Per- and Polyfluoroalkyl Substances (PFAS) to Serum Proteins: Implications for Toxicokinetics in Humans

N‐glucuronidation and Excretion of Perfluoroalkyl Sulfonamides in Mice Following Ingestion of Aqueous Film‐Forming Foam

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