Insight into the binding model of per- and polyfluoroalkyl substances to proteins and membranes

Zhao, Lihui; Teng, Miaomiao; Zhao, Xiaoli; Li, Yunxia; Sun, Jiaqi; Zhao, Wentian; Ruan, Yuefei; Leung, K. M.; Wu, Fengchang

doi:10.1016/j.envint.2023.107951

Cited by 53 publications

(19 citation statements)

References 133 publications

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“…Consistently, our previous research demonstrated that despite the structural similarity between 6:2 H-PFESA and 6:2 Cl-PFESA, with the only difference being a H atom, the chloro-analogue accumulates 1.1-fold more in rats and exhibits a 5.5-fold higher solid–water partitioning coefficient in anaerobic sludge collected from a wastewater treatment plant, compared to the hydro-analogue. This indicates that subtle structural differences could significantly impact their bioaccumulation potential, which is in essence related to the molecular size and hydrophobicity, accounting for varying binding affinities of PFAS to relevant proteins . For the same reason, the binding affinities of structure-varying PFAS to TH-related proteins should be a key factor affecting TH secretion stimulation, synthesis, distribution/transport, activation, and action processes.…”

Section: Discussionmentioning

confidence: 99%

“…This indicates that subtle structural differences could significantly impact their bioaccumulation potential, which is in essence related to the molecular size and hydrophobicity, accounting for varying binding affinities of PFAS to relevant proteins. 46 For the same reason, the binding affinities of structure-varying PFAS to TH-related proteins should be a key factor affecting TH secretion stimulation, synthesis, distribution/transport, activation, and action processes.…”

Section: Discussionmentioning

confidence: 99%

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Structure-Related Thyroid Disrupting Effect of Perfluorooctanesulfonate-like Substances in Zebrafish Larvae

Yi,

Wang,

Wang

et al. 2023

Environ. Sci. Technol.

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Chlorinated polyfluorooctane ether sulfonate (6:2 Cl-PFESA), hydrogenated polyfluorooctane ether sulfonate (6:2 H-PFESA), and chlorinated polyfluorooctanesulfonate (Cl-PFOS) share structural similarities with the regulated perfluorooctanesulfonate (PFOS), but their toxic potential is rarely known. Here, the thyroid disrupting potential of these four compounds in zebrafish larvae has been comparably investigated. PFOS, Cl-PFOS, and 6:2 Cl-PFESA were accumulated in the larvae at similar levels, approximately 1.3−1.6 times higher than 6:2 H-PFESA. Additionally, PFOS, Cl-PFOS, and 6:2 Cl-PFESA exhibited stronger disruption than 6:2 H-PFESA on genetic regulation, particularly concerning thyroid hormone (TH) activation and action and on TH homeostasis in both free and total forms of thyroxine (T4) and 3,5,3′triiodothyronine (T3). These results indicate that chlorination or oxygen insertion does not substantially alter the thyrotoxicity of PFOS, but hydrogenation mitigates it. Molecular docking analysis and the luciferase reporter gene assay provided mechanistic perspectives that the PFOSlike substances could competitively replace THs to bind with TH plasma and membrane transporters, thereby disrupting TH transport and action, respectively. Moreover, they are also potent to disrupt TH synthesis and activation through Na + /K + -dependent transport of I − or competitive binding to the sites of deiodinases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structure-Related Thyroid Disrupting Effect of Perfluorooctanesulfonate-like Substances in Zebrafish Larvae

Yi,

Wang,

Wang

et al. 2023

Environ. Sci. Technol.

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“…It is also important to note that different chain lengths and terminal groups vary in their abilities of binding to receptors and degree of cell permeability. 2 This could be, as mentioned before, a possible explanation for the diverging findings between epidemiological studies if there are different PFAS contributions in the exposure mixture.…”

Section: Molecular Mechanismsmentioning

confidence: 91%

“…1 Shared chemical similarities between PFAS and fatty acids have prompted the hypothesis of PFAS interference with lipid metabolism via binding to receptors and membranes. 2 This makes them relevant suspects to investigate in relation to cardiometabolic diseases, a group of multifactorial conditions including dyslipidemia, obesity, type 2 diabetes (T2D) and cardiovascular diseases (CVD). Lipid metabolism as well as mitochondrial function, inflammation and vasculature reactivity (such as endothelial dysfunction and hypertension) play a pivotal role in the development of these diseases.…”

Section: Introductionmentioning

confidence: 99%

Per‐ and polyfluoroalkyl substances and cardiometabolic diseases: A review

Schillemans,

Donat‐Vargas,

Åkesson

2023

Basic Clin Pharma Tox

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Per‐ and polyfluoroalkyl substances (PFAS) are a group of persistent and widespread environmental pollutants that represent a high concern for human health. They have been shown to be associated with several important physiological processes such as lipid metabolism and the immune system. Consequently, PFAS are suspected to play a role in cardiometabolic disease development. However, the evidence regarding associations between PFAS and overt cardiovascular disease and type 2 diabetes remains limited and inconsistent. To address this, we conducted a review of the epidemiological evidence. A deeper understanding of potential underlying molecular mechanisms may help to explain inconsistencies in epidemiological findings. Thus, to gain more mechanistic insight, we also summarized evidence from omics and laboratory studies into an adverse outcome pathway framework. Our observations indicate the potential for associations of PFAS with multiple molecular pathways that could have opposite associations with disease risk, which could be further modified by mixture composition, lifestyle factors or genetic polymorphisms. This identifies the need for exposome studies considering mixture effects, the use of multi‐omics data to gain insight in relevant pathways and the integration of epidemiological and laboratory studies to enhance mechanistic understanding and causal inference. Improved comprehension is essential for environmental health risk assessments.

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“…The interactions of PFASs with biological molecules such as proteins and membranes have been the subject of extensive research. − A recent review elucidated these interactions, shedding light on the molecular mechanisms through which PFASs can affect cellular processes . Previous studies have also highlighted the potential risks PFASs pose to human health, linking them to developmental toxicity, , immunotoxicity, , hepatotoxicity, and tumorigenesis .…”

Section: Introductionmentioning

confidence: 99%

Prediction of the Interactions of a Large Number of Per- and Poly-Fluoroalkyl Substances with Ten Nuclear Receptors

Azhagiya Singam,

Durkin,

La Merrill

et al. 2024

Environ. Sci. Technol.

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Per-and poly-fluoroalkyl substances (PFASs) are persistent, toxic chemicals that pose significant hazards to human health and the environment. Screening large numbers of chemicals for their ability to act as endocrine disruptors by modulating the activity of nuclear receptors (NRs) is challenging because of the time and cost of in vitro and in vivo experiments. For this reason, we need computational approaches to screen these chemicals and quickly prioritize them for further testing. Here, we utilized molecular modeling and machine-learning predictions to identify potential interactions between 4545 PFASs with ten different NRs. The results show that some PFASs can bind strongly to several receptors. Further, PFASs that bind to different receptors can have very different structures spread throughout the chemical space. Biological validation of these in silico findings should be a high priority.

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Insight into the binding model of per- and polyfluoroalkyl substances to proteins and membranes

Cited by 53 publications

References 133 publications

Structure-Related Thyroid Disrupting Effect of Perfluorooctanesulfonate-like Substances in Zebrafish Larvae

Structure-Related Thyroid Disrupting Effect of Perfluorooctanesulfonate-like Substances in Zebrafish Larvae

Per‐ and polyfluoroalkyl substances and cardiometabolic diseases: A review

Prediction of the Interactions of a Large Number of Per- and Poly-Fluoroalkyl Substances with Ten Nuclear Receptors

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