首页|In silico bioavailability triggers applied to direct and indirect thyroid hormone disruptors

In silico bioavailability triggers applied to direct and indirect thyroid hormone disruptors

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Among endocrine disruption, interference with the thyroid hormone (TH) regulation is of increasing concern.Respective compounds encode through their structural features both the potential for TH disruption, and thebioavailability mitigating the toxicological effect. The aim of this study is to provide a substructure-basedscreening-level QSAR (quantitative structure-activity relationship) that discriminates bioavailable TH disruptorsfrom not bioavailable counterparts, covering both direct and indirect (retinoid- and AhR-mediated)modes of action. The QSAR has been derived from literature data for 1642 compounds, and takes into accountLipinski’s rule-of-five and the brain/blood partition coefficient Kbrain/blood. For its validation, an externaltest set of 145 substances has been used. For 1787 compounds meeting the model application domain, the modelyields only one false negative. The discussion addresses the mechanistic meaning of the bioavailability triggersmolecular weight, H-bond donor and acceptor, hydrophobicity (log Kow), and the physicochemical properties underlying log Kbrain/blood. The model may serve as bioavailability-screening step within a decision supportsystem for the predictive assessment of chemicals regarding their potential to disrupt thyroid hormone functionin a direct or indirect manner.

In silico assessmentThyroid hormone disruptorsRetinoidBioavailabilityAbsorptionPenetrationPermeationBlood/brain partitioning

Ralph Kuehne、Klara Hilscherova、Marie Smutna、Friederike Leßmoellmann、Gerrit Schueuermann

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UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstr. 15, 04318, Leipzig, Germany

RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, 61137, Brno, Czech Republic

UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstr. 15, 04318, Leipzig, Germany,Institute of Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Str. 29, 09596, Freiberg, Germany

2024

10.1016/j.chemosphere.2023.140611

Chemosphere

Chemosphere

ISSN：0045-6535
年,卷(期)：2024.348(Jan.)