Elucidating Key Characteristics of PFAS Binding to Human Peroxisome Proliferator-Activated Receptor Alpha: An Explainable Machine Learning Approach

Per- and polyfluoroalkyl substances (PFAS) are widely employed anthropogenic fluorinated chemicals known to disrupt hepatic lipid metabolism by binding to human peroxisome proliferator-activated receptor alpha (PPARα). Therefore, screening for PFAS that bind to PPARα is of critical importance. Machi...

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Bibliographic Details
Published in:Environmental science & technology 2024-01, Vol.58 (1), p.488-497
Main Authors: Maeda, Kazuhiro, Hirano, Masashi, Hayashi, Taka, Iida, Midori, Kurata, Hiroyuki, Ishibashi, Hiroshi
Format: Article
Language:English
Subjects:
Anthropogenic factors
Binding
Data Science
Electrostatic properties
Learning algorithms
Lipid metabolism
Lipids
Machine learning
Perfluoroalkyl & polyfluoroalkyl substances
Perfluorochemicals
Performance prediction
Peroxisome proliferator-activated receptors
Receptors
Screening
Toxicity
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Summary:Per- and polyfluoroalkyl substances (PFAS) are widely employed anthropogenic fluorinated chemicals known to disrupt hepatic lipid metabolism by binding to human peroxisome proliferator-activated receptor alpha (PPARα). Therefore, screening for PFAS that bind to PPARα is of critical importance. Machine learning approaches are promising techniques for rapid screening of PFAS. However, traditional machine learning approaches lack interpretability, posing challenges in investigating the relationship between molecular descriptors and PPARα binding. In this study, we aimed to develop a novel, explainable machine learning approach to rapidly screen for PFAS that bind to PPARα. We calculated the PPARα–PFAS binding score and 206 molecular descriptors for PFAS. Through systematic and objective selection of important molecular descriptors, we developed a machine learning model with good predictive performance using only three descriptors. The molecular size (b_single) and electrostatic properties (BCUT_PEOE_3 and PEOE_VSA_PPOS) are important for PPARα-PFAS binding. Alternative PFAS are considered safer than their legacy predecessors. However, we found that alternative PFAS with many carbon atoms and ether groups exhibited a higher affinity for PPARα. Therefore, confirming the toxicity of these alternative PFAS compounds with such characteristics through biological experiments is important.
ISSN:0013-936X
1520-5851
DOI:10.1021/acs.est.3c06561