PFAS (per- and polyfluorinated alkyl substances) as EDCs (endocrine-disrupting chemicals) - Identification of compounds with high potential to bind to selected terpenoids NHRs (nuclear hormone receptors).

Chemosphere Pub Date : 2025-02-01 Epub Date: 2024-12-20 DOI:10.1016/j.chemosphere.2024.143967
Natalia Bulawska, Anita Sosnowska, Dominika Kowalska, Maciej Stępnik, Tomasz Puzyn
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Abstract

The objective of the subsequent study was to examine the probability of PFAS (per- and polyfluorinated alkyl substances) binding to various NHRs (nuclear hormone receptors) and to identify their structural features that contribute most to the binding score (BS). We evaluated the BS for PFAS in relation to 7 selected NHRs - 4 with additional antagonist forms (Retinoid X receptor alpha - RXRα, Liver X receptor alpha - LXRα, Liver X receptor beta - LXRβ, Estrogen receptor alpha - ERα, Estrogen receptor alpha antagonist - anti-ERα, Estrogen receptor beta - ERβ, Estrogen receptor beta antagonist - anti-ERβ, Glucocorticoid receptor - GR, Glucocorticoid receptor antagonist - anti-GR, Androgen receptor - AR, Androgen receptor antagonist - anti-AR). We based our study on the results of molecular docking, which we used to develop MLR-QSAR (Multiple Linear Regression - Quantitative Structure-Activity Relationship) models. The models we developed allowed us to predict the BS for an extensive set of PFAS compounds from the NORMAN database (more than 4000) - virtual screening. The probability of PFAS binding to selected receptors was determined by structural features such as particle size, branching, and fluorine content. These variables were also identified in the literature reports of experimental studies as the most important for this group of compounds. The research focused on receptors from the terpenoid group. The RXRα, LXRα and β, GR, and anti-GR receptors were shown to be the group less likely to be affected by PFAS. Sex hormones such as AR, anti-AR, ERα and ERβ with their antagonist forms are the most affected.

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作为内分泌干扰化学品的PFAS(全氟和多氟烷基物质)。与选定的萜类化合物nhr(核激素受体)结合的高潜力化合物的鉴定
后续研究的目的是检查PFAS(全氟和多氟烷基物质)与各种核激素受体(nhr)结合的概率,并确定它们的结构特征对结合评分(BS)贡献最大。我们对选定的7种具有额外拮抗剂形式(类视黄醇X受体α - RXRα、肝X受体α - LXRα、肝X受体β - LXRβ、雌激素受体α -ERα、雌激素受体α拮抗剂-抗ERα、雌激素受体β拮抗剂-抗ERβ、糖皮质激素受体-GR、糖皮质激素受体拮抗剂-抗GR、雄激素受体-AR、雄激素受体拮抗剂-抗AR)的nhr - 4进行了PFAS的BS评估。基于分子对接的研究结果,我们建立了MLR-QSAR(多元线性回归-定量构效关系)模型。我们开发的模型使我们能够从NORMAN数据库(超过4000个)中预测广泛的PFAS化合物的BS -虚拟筛选。PFAS与选定受体结合的概率由结构特征(如粒度、分支和氟含量)决定。这些变量在实验研究的文献报告中也被确定为这组化合物最重要的变量。这项研究的重点是萜类化合物的受体。RXRα、LXRα和β、GR和抗GR受体是受PFAS影响较小的组。性激素如AR、抗AR、ERα和ERβ及其拮抗剂受影响最大。
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