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Mechanism-based toxicity screening of organophosphate flame retardants using Tox21 assays and molecular docking
Donghyeon Kim1, Kimoon Na1, Jinhee Choi1
1School of Environmental Engineering, University of Seoul, 163 Seoulsiripdae-ro, Dongdaemun-gu, Seoul, 02504, Republic of Korea.
Abstract:
As brominated flame retardants are phased out and regulations on their use become stricter, concerns over organophosphate flame retardants (OPFRs) have increased due to their high production. In response, this study aimed to screen the potential toxicity of emerging OPFRs using in vitro Tox21 assays and in silico molecular docking analysis. For 48 OPFRs collected from the literature, we investigated their bioactivity with human nuclear receptors using Tox21 data, focusing on pathways related to endocrine disruption (ERs, AR), stress response (GR), energy homeostasis (PPARs, FXR), and detoxification (PXR, CAR). For OPFRs not tested in Tox21 assays, molecular docking simulations were performed to predict binding potential. Results showed that CAR/PXR and FXR had relatively high reactivity with diverse OPFRs, indicating potential molecular initiating events (MIEs). Among the 48 OPFRs, 28 interacted with one or more receptors, suggesting they may act as potential stressors of adverse outcome pathways (AOPs) leading to various human diseases. Aryl- and halogenated-OPFRs displayed higher bioactivity compared to alkyl-OPFRs. Additionally, as the logKow value and carbon number of OPFRs increased, their interaction with nuclear receptors also increased. These structure- and physicochemistry-dependent bioactivities provide insights for designing safer OPFRs to avoid regrettable substitutions. Of these prioritized OPFRs, 13 showed low oral points-of-departure (POD) values under 100 mg/kg/day. In contrast, the other 15 OPFRs lacked sufficient data or exhibited less severe toxicity, despite being predicted to be of high concern in our analysis. Since several OPFRs are commonly used in consumer products that can lead to daily human exposure, we suggest that these OPFRs have the potential to reveal undisclosed effects and should therefore undergo further assessment.
Insights
Concerns over organophosphate flame retardants (OPFRs) are rising. This study screened 48 OPFRs for toxicity using Tox21 assays and molecular docking, identifying 28 interacting with human nuclear receptors, indicating potential health risks.
Area of Science:
- Environmental Toxicology
- Computational Chemistry
- Endocrinology
Background:
- Rising concerns regarding organophosphate flame retardants (OPFRs) due to the phase-out of brominated flame retardants and their widespread use.
- Need for comprehensive toxicity screening of emerging OPFRs to prevent regrettable substitutions.
- Human nuclear receptors play crucial roles in endocrine disruption, stress response, energy homeostasis, and detoxification pathways.
Purpose of the Study:
- To screen the potential toxicity of 48 emerging organophosphate flame retardants (OPFRs).
- To investigate the bioactivity of OPFRs with human nuclear receptors using in vitro Tox21 assays and in silico molecular docking.
- To identify OPFRs with potential molecular initiating events (MIEs) and adverse outcome pathways (AOPs).
Main Methods:
- Utilized Tox21 high-throughput screening data to assess the interaction of 48 OPFRs with human nuclear receptors (ERs, AR, GR, PPARs, FXR, PXR, CAR).
- Performed in silico molecular docking simulations for OPFRs not included in Tox21 assays to predict binding potential.
- Analyzed structure-activity relationships, including aryl, halogenated, and alkyl substituents, logKow, and carbon number.
Main Results:
- 28 out of 48 OPFRs interacted with one or more human nuclear receptors, indicating potential MIEs and AOPs.
- Constitutive Androstane Receptor (CAR)/Pregnane X Receptor (PXR) and Farnesoid X Receptor (FXR) showed high reactivity with various OPFRs.
- Aryl- and halogenated-OPFRs exhibited higher bioactivity than alkyl-OPFRs; increased logKow and carbon number correlated with greater receptor interaction.
Conclusions:
- Identified 13 OPFRs with low oral points-of-departure (POD) values (<100 mg/kg/day), suggesting potential human health risks from daily exposure.
- Structure- and physicochemical property-dependent bioactivities provide a basis for designing safer OPFR alternatives.
- Recommended further assessment for prioritized OPFRs due to their common presence in consumer products and potential for undisclosed health effects.
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