Investigation of the Interaction between Human Serum Albumin and Branched Short-Chain Perfluoroalkyl Compounds

Moro, Giulia; Liberi, S.; Vascon, Filippo; Linciano, Sara; Felice, Sofia De; Fasolato, S.; Toni, Luca De; Nisio, Andrea Di; Cendron, Laura; Angelini, Alessandro

doi:10.1021/acs.chemrestox.2c00211

Cited by 25 publications

(8 citation statements)

References 59 publications

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“…The molar ratio of PFAS to proteins was kept below 0.004 (HSA, BSA) and 0.009 (γ-globulin) in all binding experiments (i.e., 261 and 111 mol of protein per mol of PFAS, respectively), which is well below where saturation of serum proteins was observed in previous studies that measured binding isotherms for PFAS ,,− and other chemicals. ,, For example, nonlinearity of BSA binding has been observed for PFBA, PFOA, PFHxS, and PFOS at molar ratios of ≥0.39, emphasizing that our experiments were conducted at concentrations within the linear binding range. Low molar ratios were selected to mimic binding in serum at PFAS concentrations relevant to human exposure, based on ratios of ≤0.0005 that were estimated from PFAS concentrations reported in human sera…”

Section: Materials and Methodsmentioning

confidence: 87%

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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Section: Materials and Methodsmentioning

confidence: 87%

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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“…In the recent past, there have been efforts to identify the molecular underpinnings driving PFAS-associated cellular and organismal outcomes. For example, PFAS binds to human serum albumin (HSA), which helps explain its systemic distribution and agency for toxicity. − Furthermore, crystallographic studies implicated a number of amino acids in HSA interacting with PFOA through −H···F–C, C–F···π, and C–F···X bonds . A single high-affinity binding site, along with three other weaker binding sites, was disclosed in the report.…”

Section: Introductionmentioning

confidence: 93%

An Atomic and Molecular Insight into How PFOA Reduces α-Helicity, Compromises Substrate Binding, and Creates Binding Pockets in a Model Globular Protein

Yadav,

Vuković,

Narayan

2024

J. Am. Chem. Soc.

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Per-and polyfluoroalkyl substances (PFAS) pose significant health risks due to their widespread presence in various environmental and biological matrices. However, the molecular-level mechanisms underlying the interactions between PFAS and biological constituents, including proteins, carbohydrates, lipids, and DNA, remain poorly understood. Here, we investigate the interactions between a legacy PFAS, viz. perfluorooctanoic acid (PFOA), and the milk protein β-lactoglobulin (BLG) obtained using a combination of experimental and computational techniques. Circular dichroism studies reveal that PFOA perturbs the secondary structure of BLG, by driving a dose-dependent loss of α-helicity and alterations in its β-sheet content. Furthermore, exposure of the protein to PFOA attenuates the on-rate constant for the binding of the hydrophobic probe 8anilino-1-naphthalene sulfonic acid (ANS), suggesting potential functional impairment of BLG by PFOA. Steered molecular dynamics and umbrella sampling calculations reveal that PFOA binding leads to the formation of an energetically favorable novel binding pocket within the protein, when residues 129−142 are steered to unfold from their initial α-helical structure, wherein a host of intermolecular interactions between PFOA and BLG's residues serve to insert the PFOA into the region between the unfolded helix and beta-sheets. Together, the data provide a novel understanding of the atomic and molecular mechanism(s) by which PFAS modulates structure and function in a globular protein, leading to a beginning of our understanding of altered biological outcomes.

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“…106 Hexafluoropropylene-oxide-dimer-acid (GenX) and perfluoro ([5-methoxy-1,3-dioxolan-4-yl]oxy) acetic acid (C6O4) as common substitutes are shown to have the ability to form stable complexes with human serum albumin (hSA), though the affinity is weaker compared to those of the long-chain ones. 107,108 Short-chain PFASs in the bloodstream can also distribute throughout the body and ultimately accumulate and cause detrimental health effects in the body. GenX has been proven to have similar adverse effects on human health to those of PFOA and PFOS.…”

Section: Environmental Fate and Potential Hazards Of Soil Pfassmentioning

confidence: 99%

“…Considerable concentrations of 6:2 FTS (fluorotelomer sulfonate) (which had been considered unlikely to bioaccumulate in aquatic systems) have been found in marine invertebrates . Hexafluoropropylene-oxide-dimer-acid (GenX) and perfluoro ([5-methoxy-1,3-dioxolan-4-yl]oxy) acetic acid (C6O4) as common substitutes are shown to have the ability to form stable complexes with human serum albumin (hSA), though the affinity is weaker compared to those of the long-chain ones. , Short-chain PFASs in the bloodstream can also distribute throughout the body and ultimately accumulate and cause detrimental health effects in the body. GenX has been proven to have similar adverse effects on human health to those of PFOA and PFOS. , Reports about the adverse effects of C6O4 on organisms started to appear. , There is an association between thyroid hormone (involved in the early development of the fetus) levels and short-chain PFASs concentrations in pregnant women .…”

Section: Environmental Fate and Potential Hazards Of Soil Pfassmentioning

confidence: 99%

PFASs in Soil: How They Threaten Human Health through Multiple Pathways and Whether They Are Receiving Adequate Concern

Xing

Chen

et al. 2023

J. Agric. Food Chem.

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Per-and polyfluoroalkyl substances (PFASs) have been mass-produced and widely applied in consumer and industrial products, resulting in their widespread presence in the environment. Features such as environmental persistence, bioaccumulation, and high toxicity even at low doses have made PFASs an increasing concern. This brief review focuses on soil PFASs, especially the effect of soil PFASs on other environmental media and their potential threats to human health through daily diet. Specifically, soil PFASs contamination caused by different pathways was first investigated. Soil pollution from application of aqueous film-forming foams (AFFFs) is generally more severe than that from fluorochemical manufacturing plants, followed by biosolid land use, landfill, and irrigation. Factors, such as carbon chain length of PFASs, wastewater treatment technology, geographical conditions, and regional development level, are related to soil PFASs' pollution. Then, the migration, bioaccumulation, and toxicity characteristics of soil PFASs were analyzed. Short-chain PFASs have higher solubility, mobility, and bioavailability, while long-chain PFASs have higher bioaccumulation potential and are more toxic to organisms. Factors such as soil texture, solution chemistry conditions, enzymes, and fertilization conditions also influence the environmental behavior of PFASs. The risk of human exposure to PFASs through agricultural and animal products is difficult to control and varies depending on living region, age, eating habits, lifestyle, ethnicity, etc. Soil PFASs threaten drinking water safety, affect soil function, and enter food webs, threatening human health. Knowledge gaps and perspectives in these research fields are also included in current work to assist future research to effectively investigate and understand the environmental risks of soil PFASs, thereby reducing human exposure.

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Investigation of the Interaction between Human Serum Albumin and Branched Short-Chain Perfluoroalkyl Compounds

Cited by 25 publications

References 59 publications

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

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

An Atomic and Molecular Insight into How PFOA Reduces α-Helicity, Compromises Substrate Binding, and Creates Binding Pockets in a Model Globular Protein

PFASs in Soil: How They Threaten Human Health through Multiple Pathways and Whether They Are Receiving Adequate Concern

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