Prediction of the endocrine-disrupting ability of 49 per- and polyfluoroalkyl substances: In silico and epidemiological evidence

Yu, Shuling; Ren, Jing; Lv, Zhenxia; Li, Rui; Zhong, Yuan; Yao, Wu; Yuan, Jiaqing

doi:10.1016/j.chemosphere.2021.133366

Cited by 15 publications

(3 citation statements)

References 80 publications

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“…This suggests that these long-chain PFAS may enact similar mechanisms of toxicity in C. elegans. We did however see variation among strains in their responses between PFNA and PFOS (Figure 6A), which are more similar in structure than PFOA and PFOS (barring functional group), which is supported by other studies that functional group contributes to PFAS mechanisms of action via variation in nuclear receptor activation (Yu et al 2022;Zhao et al 2023). Indeed, PFOS was significantly more potent than PFOA, which has also been observed in two recent C. elegans studies (Breton et al 2023;Lin et al 2022).…”

Section: Discussionsupporting

confidence: 87%

Structure-specific variation in per- and polyfluoroalkyl substances toxicity among genetically diverseCaenorhabditis elegansstrains

Leuthner,

Zhang,

Kohrn

et al. 2024

Preprint

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BackgroundThere are >14,500 structurally diverse per- and polyfluoroalkyl substances (PFAS). Despite knowledge that these “forever chemicals” are in 99% of humans, mechanisms of toxicity and adverse health effects are incompletely known. Furthermore, the contribution of genetic variation to PFAS susceptibility and health consequences is unknown.ObjectivesWe determined the toxicity of a structurally distinct set of PFAS in twelve genetically diverse strains of the genetic model systemCaenorhabditis elegans.MethodsDose-response curves for four perfluoroalkyl carboxylic acids (PFNA, PFOA, PFPeA, and PFBA), two perfluoroalkyl sulfonic acids (PFOS and PFBS), two perfluoroalkyl sulfonamides (PFOSA and PFBSA), two fluoroether carboxylic acids (GenX and PFMOAA), one fluoroether sulfonic acid (PFEESA), and two fluorotelomers (6:2 FCA and 6:2 FTS) were determined in theC. eleganslaboratory reference strain, N2, and eleven genetically diverse wild strains. Body length was quantified by image analysis at each dose after 48 hr of developmental exposure of L1 arrest-synchronized larvae to estimate effective concentration values (EC50).ResultsThere was a significant range in toxicity among PFAS: PFOSA > PFBSA ≈ PFOS ≈ PFNA > PFOA > GenX ≈ PFEESA > PFBS ≈ PFPeA ≈ PFBA. Long-chain PFAS had greater toxicity than short-chain, and fluorosulfonamides were more toxic than carboxylic and sulfonic acids. Genetic variation explained variation in susceptibility to PFBSA, PFOS, PFBA, PFOA, GenX, PFEESA, PFPeA, and PFBA. There was significant variation in toxicity amongC. elegansstrains due to chain length, functional group, and between legacy and emerging PFAS.ConclusionC. elegansrespond to legacy and emerging PFAS of diverse structures, and this depends on specific structures and genetic variation. Harnessing the natural genetic diversity ofC. elegansand the structural complexity of PFAS is a powerful New Approach Methodology (NAM) to investigate structure-activity relationships and mechanisms of toxicity which may inform regulation of other PFAS to improve human and environmental health.

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Section: Discussionsupporting

confidence: 87%

Structure-specific variation in per- and polyfluoroalkyl substances toxicity among genetically diverseCaenorhabditis elegansstrains

Leuthner,

Zhang,

Kohrn

et al. 2024

Preprint

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“…Dataset for the development QSAR models. The commonly used 43 PFAS encompassing perfluorinated carboxylic acids (PFCAs), fluorotelomer alcohols (FTOHs), perfluorinated sulfonic acids (PFSAs), and other related PFAS, were selected [19]. Names, acronyms, CAS numbers, and SMILES of PFAS examined in this study are listed in Supplementary Materials S1.…”

Section: Datasetmentioning

confidence: 99%

“…Recently, studies indicated that some perfluoroalkyl substances may have been endocrine disrupting chemicals (EDCs) by interfering with hormone action [ 19 , 20 ]. These substances may act as agonists or antagonists of nuclear hormone receptors (NHRs).…”

Section: Introductionmentioning

confidence: 99%

How the Structure of Per- and Polyfluoroalkyl Substances (PFAS) Influences Their Binding Potency to the Peroxisome Proliferator-Activated and Thyroid Hormone Receptors—An In Silico Screening Study

Kowalska¹,

Sosnowska²,

Buławska³

et al. 2023

Molecules

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In this study, we investigated PFAS (per- and polyfluoroalkyl substances) binding potencies to nuclear hormone receptors (NHRs): peroxisome proliferator-activated receptors (PPARs) α, β, and γ and thyroid hormone receptors (TRs) α and β. We have simulated the docking scores of 43 perfluoroalkyl compounds and based on these data developed QSAR (Quantitative Structure-Activity Relationship) models for predicting the binding probability to five receptors. In the next step, we implemented the developed QSAR models for the screening approach of a large group of compounds (4464) from the NORMAN Database. The in silico analyses indicated that the probability of PFAS binding to the receptors depends on the chain length, the number of fluorine atoms, and the number of branches in the molecule. According to the findings, the considered PFAS group bind to the PPARα, β, and γ only with low or moderate probability, while in the case of TR α and β it is similar except that those chemicals with longer chains show a moderately high probability of binding.

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HNF4A as a potential target of PFOA and PFOS leading to hepatic steatosis: Integrated molecular docking, molecular dynamic and transcriptomic analyses

Li,

Zhang,

Xuan

et al. 2024

Chemico-Biological Interactions

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Prediction of the endocrine-disrupting ability of 49 per- and polyfluoroalkyl substances: In silico and epidemiological evidence

Cited by 15 publications

References 80 publications

Structure-specific variation in per- and polyfluoroalkyl substances toxicity among genetically diverseCaenorhabditis elegansstrains

Structure-specific variation in per- and polyfluoroalkyl substances toxicity among genetically diverseCaenorhabditis elegansstrains

How the Structure of Per- and Polyfluoroalkyl Substances (PFAS) Influences Their Binding Potency to the Peroxisome Proliferator-Activated and Thyroid Hormone Receptors—An In Silico Screening Study

HNF4A as a potential target of PFOA and PFOS leading to hepatic steatosis: Integrated molecular docking, molecular dynamic and transcriptomic analyses

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