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A molecular and cellular understanding of PFDA-exposure-associated outcomes on biological assemblies.

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Title: A molecular and cellular understanding of PFDA-exposure-associated outcomes on biological assemblies.
Authors: Wilson, Daisy L.1 (AUTHOR), Chakraborty, Sayantani1,2 (AUTHOR), Sweety, Ummy Habiba1 (AUTHOR), Sharifan, Hamidreza2 (AUTHOR), Hernandez, Jose A.2 (AUTHOR), White, Jason C.3 (AUTHOR), Vukovic, Lela1,2,4,5 (AUTHOR) Lvukovic@utep.edu, Narayan, Mahesh1,2 (AUTHOR) mnarayan@utep.edu
Source: Environmental Research. May2026, Vol. 297, pN.PAG-N.PAG. 1p.
Subjects: Protein structure, Retinol-binding proteins, Poisons, Caenorhabditis elegans, Molecular dynamics, Immune response, Dopaminergic neurons, Toxic substance exposure
Abstract: Human exposure to the fluorosurfactant perfluorodecanoic acid (PFDA) is associated with toxic health outcomes in part arising compromised immune responses. However, the molecular mechanisms leading to adverse physiological outputs have remained elusive. Here, the interactions between PFDA and the milk protein β-lactoglobulin (BLG) was extensively investigated. Our results reveal that PFDA perturbs protein structure in a dose-dependent manner. Furthermore, by binding to BLG (Kd ≈ 3.2 μM; ΔG = −7.5 kcal/mol) PFDA compromises the ability of the protein to recruit and bind to retinol (Vitamin A), which is otherwise transported by lipocalin. This feature was experimentally verified by measuring the kinetics of retinol binding to BLG which was attenuated in the presence of PFDA. Docking and molecular dynamics (MD) simulations expose several intermolecular interactions between the protein-side chain and both the fluoroalkyl tail and polar head group of PFDA providing an understanding of the mechanism(s) by which PFDA competes with retinol binding and also interferes with protein structure. These interactions include salt-bridge formation between the -COO- headgroup of the PFDA molecule with Lys60 and Lys69. To investigate the effects of PFDA exposure in more complex biological systems, the nematode Caenorhabditis elegans (C. elegans) was exposed to fluoro-alkanoic acid. This exposure resulted in the ablation of dopaminergic (DA) neurons and impaired locomotion. The findings provide important insight into the mechanisms by which this PFAS impacts protein structure and function, exerts toxicity in humans, develops a mechanism to expose upstream targets, informs intervention and assists in the development of risk mitigation. [Display omitted] • PFDA alters structure and function in the key milk protein, β-lactoglobulin. • The "forever chemical" competes with physiological retinol binding. • PFDA ablates dopaminergic neurons and initiates locomotory deficits in nematodes. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
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Abstract:Human exposure to the fluorosurfactant perfluorodecanoic acid (PFDA) is associated with toxic health outcomes in part arising compromised immune responses. However, the molecular mechanisms leading to adverse physiological outputs have remained elusive. Here, the interactions between PFDA and the milk protein β-lactoglobulin (BLG) was extensively investigated. Our results reveal that PFDA perturbs protein structure in a dose-dependent manner. Furthermore, by binding to BLG (Kd ≈ 3.2 μM; ΔG = −7.5 kcal/mol) PFDA compromises the ability of the protein to recruit and bind to retinol (Vitamin A), which is otherwise transported by lipocalin. This feature was experimentally verified by measuring the kinetics of retinol binding to BLG which was attenuated in the presence of PFDA. Docking and molecular dynamics (MD) simulations expose several intermolecular interactions between the protein-side chain and both the fluoroalkyl tail and polar head group of PFDA providing an understanding of the mechanism(s) by which PFDA competes with retinol binding and also interferes with protein structure. These interactions include salt-bridge formation between the -COO- headgroup of the PFDA molecule with Lys60 and Lys69. To investigate the effects of PFDA exposure in more complex biological systems, the nematode Caenorhabditis elegans (C. elegans) was exposed to fluoro-alkanoic acid. This exposure resulted in the ablation of dopaminergic (DA) neurons and impaired locomotion. The findings provide important insight into the mechanisms by which this PFAS impacts protein structure and function, exerts toxicity in humans, develops a mechanism to expose upstream targets, informs intervention and assists in the development of risk mitigation. [Display omitted] • PFDA alters structure and function in the key milk protein, β-lactoglobulin. • The "forever chemical" competes with physiological retinol binding. • PFDA ablates dopaminergic neurons and initiates locomotory deficits in nematodes. [ABSTRACT FROM AUTHOR]
ISSN:00139351
DOI:10.1016/j.envres.2026.124118