New QSAR Models to Predict Human Transthyretin Disruption by Per- and Polyfluoroalkyl Substances (PFAS): Development and Application
Per- and polyfluoroalkyl substances (PFAS) are of concern because of their potential thyroid hormone system disruption by binding to human transthyretin (hTTR). However, the amount of experimental data is scarce. In this work, new classification and regression QSARs were developed to predict the hTT...
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MDPI AG
2025-07-01
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| Series: | Toxics |
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| author | Marco Evangelista Nicola Chirico Ester Papa |
| author_facet | Marco Evangelista Nicola Chirico Ester Papa |
| author_sort | Marco Evangelista |
| collection | DOAJ |
| description | Per- and polyfluoroalkyl substances (PFAS) are of concern because of their potential thyroid hormone system disruption by binding to human transthyretin (hTTR). However, the amount of experimental data is scarce. In this work, new classification and regression QSARs were developed to predict the hTTR disruption based on experimental data measured for 134 PFAS. Bootstrapping, randomization procedures, and external validation were used to check for overfitting, to avoid random correlations, and to evaluate the predictivity of the QSARs, respectively. The best QSARs were characterized by good performances (e.g., training and test accuracies in classification of 0.89 and 0.85, respectively; R<sup>2</sup>, Q<sup>2</sup><sub>loo</sub>, and Q<sup>2</sup><sub>F3</sub> in regression of 0.81, 0.77, and 0.82, respectively) and significantly broader domains compared to the few existing similar models. The application of QSARs application to the OECD List of PFAS allowed for the identification of structural categories of major concern, such as per- and polyfluoroalkyl ether-based, perfluoroalkyl carbonyl, and perfluoroalkane sulfonyl compounds. Forty-nine PFAS showed a stronger binding affinity to hTTR than the natural ligand T4. Uncertainty quantification for each model and prediction further enhanced the reliability assessment of predictions. The implementation of the new QSARs in non-commercial software facilitates their application to support future research efforts and regulatory actions. |
| format | Article |
| id | doaj-art-b50ff68c98764b72b2732063edb8b7a3 |
| institution | DOAJ |
| issn | 2305-6304 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
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| series | Toxics |
| spelling | doaj-art-b50ff68c98764b72b2732063edb8b7a32025-08-20T02:47:07ZengMDPI AGToxics2305-63042025-07-0113759010.3390/toxics13070590New QSAR Models to Predict Human Transthyretin Disruption by Per- and Polyfluoroalkyl Substances (PFAS): Development and ApplicationMarco Evangelista0Nicola Chirico1Ester Papa2QSAR Research Unit in Environmental Chemistry and Ecotoxicology, Department of Theoretical and Applied Sciences, University of Insubria, via J.H. Dunant 3, 21100 Varese, ItalyQSAR Research Unit in Environmental Chemistry and Ecotoxicology, Department of Theoretical and Applied Sciences, University of Insubria, via J.H. Dunant 3, 21100 Varese, ItalyQSAR Research Unit in Environmental Chemistry and Ecotoxicology, Department of Theoretical and Applied Sciences, University of Insubria, via J.H. Dunant 3, 21100 Varese, ItalyPer- and polyfluoroalkyl substances (PFAS) are of concern because of their potential thyroid hormone system disruption by binding to human transthyretin (hTTR). However, the amount of experimental data is scarce. In this work, new classification and regression QSARs were developed to predict the hTTR disruption based on experimental data measured for 134 PFAS. Bootstrapping, randomization procedures, and external validation were used to check for overfitting, to avoid random correlations, and to evaluate the predictivity of the QSARs, respectively. The best QSARs were characterized by good performances (e.g., training and test accuracies in classification of 0.89 and 0.85, respectively; R<sup>2</sup>, Q<sup>2</sup><sub>loo</sub>, and Q<sup>2</sup><sub>F3</sub> in regression of 0.81, 0.77, and 0.82, respectively) and significantly broader domains compared to the few existing similar models. The application of QSARs application to the OECD List of PFAS allowed for the identification of structural categories of major concern, such as per- and polyfluoroalkyl ether-based, perfluoroalkyl carbonyl, and perfluoroalkane sulfonyl compounds. Forty-nine PFAS showed a stronger binding affinity to hTTR than the natural ligand T4. Uncertainty quantification for each model and prediction further enhanced the reliability assessment of predictions. The implementation of the new QSARs in non-commercial software facilitates their application to support future research efforts and regulatory actions.https://www.mdpi.com/2305-6304/13/7/590endocrine disruptionhuman transthyretin disruptionnew approach methodologiesPFASQSAR |
| spellingShingle | Marco Evangelista Nicola Chirico Ester Papa New QSAR Models to Predict Human Transthyretin Disruption by Per- and Polyfluoroalkyl Substances (PFAS): Development and Application Toxics endocrine disruption human transthyretin disruption new approach methodologies PFAS QSAR |
| title | New QSAR Models to Predict Human Transthyretin Disruption by Per- and Polyfluoroalkyl Substances (PFAS): Development and Application |
| title_full | New QSAR Models to Predict Human Transthyretin Disruption by Per- and Polyfluoroalkyl Substances (PFAS): Development and Application |
| title_fullStr | New QSAR Models to Predict Human Transthyretin Disruption by Per- and Polyfluoroalkyl Substances (PFAS): Development and Application |
| title_full_unstemmed | New QSAR Models to Predict Human Transthyretin Disruption by Per- and Polyfluoroalkyl Substances (PFAS): Development and Application |
| title_short | New QSAR Models to Predict Human Transthyretin Disruption by Per- and Polyfluoroalkyl Substances (PFAS): Development and Application |
| title_sort | new qsar models to predict human transthyretin disruption by per and polyfluoroalkyl substances pfas development and application |
| topic | endocrine disruption human transthyretin disruption new approach methodologies PFAS QSAR |
| url | https://www.mdpi.com/2305-6304/13/7/590 |
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