Synthetic musks (SMs) with pleasant odor have been extensively used in personal care products. SMs are emerging contaminants due to the wide detection in human breast milk and blood, and even caused miscarriage to pregnant women. Aiming at this, the two-dimensional quantitative structure-activity relationship (2D-QSAR) coupling with three-dimensional quantitative structure-activity relationship (3D-QSAR) methods were first used to analyze the SM-induced risk of miscarriage in pregnant women, and the above two models were used to mutually authenticate each other. It was found that the critical volume, melting point and heat of formation of SMs were the key descriptors leading to miscarriage. In addition, the adverse outcome pathway (AOP) was used to assess the miscarriage risk of selected SMs and the environment-friendly SM derivatives with desired functional properties designed in previous studies. Results showed that the miscarriage risk of musk ketone derivative (M27) was reduced by approximately three times than that of MK. The miscarriage risk of galaxolide derivatives (i.e., D6 and D24) were about six times lower than that of galaxolide, which further confirmed that the theoretically designed SMs derivatives can effectively reduce the risk of miscarriage in pregnant women. This study provides a comprehensive analysis of the mechanism of SM-induced miscarriage, and provides an accurate and rapid theoretical evaluation method for the future risk assessment of SM-induced miscarriage.
Keywords: 2D-QSAR; 3D-QSAR; Adverse outcome pathway; Miscarriage risk mechanism; Molecular docking; Molecular dynamics simulation.
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