A model for phthalic acid esters’ biodegradability and biotoxicity multi-effect pharmacophore and its application in molecular modification

Zhou

et al. 2022

IJERPH

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In this study, 16 PAHs were selected as the priority control pollutants to summarize their environmental metabolism and transformation processes, including photolysis, plant degradation, bacterial degradation, fungal degradation, microalgae degradation, and human metabolic transformation. Meanwhile, a total of 473 PAHs by-products generated during their transformation and degradation in different environmental media were considered. Then, a comprehensive system was established for evaluating the PAHs by-products’ neurotoxicity, immunotoxicity, phytotoxicity, developmental toxicity, genotoxicity, carcinogenicity, and endocrine-disrupting effect through molecular docking, molecular dynamics simulation, 3D-QSAR model, TOPKAT method, and VEGA platform. Finally, the potential environmental risk (phytotoxicity) and human health risks (neurotoxicity, immunotoxicity, genotoxicity, carcinogenicity, developmental toxicity, and endocrine-disrupting toxicity) during PAHs metabolism and transformation were comprehensively evaluated. Among the 473 PAH’s metabolized and transformed products, all PAHs by-products excluding ACY, CHR, and DahA had higher neurotoxicity, 152 PAHs by-products had higher immunotoxicity, and 222 PAHs by-products had higher phytotoxicity than their precursors during biological metabolism and environmental transformation. Based on the TOPKAT model, 152 PAH by-products possessed potential developmental toxicity, and 138 PAH by-products had higher genotoxicity than their precursors. VEGA predicted that 247 kinds of PAH derivatives had carcinogenic activity, and only the natural transformation products of ACY did not have carcinogenicity. In addition to ACY, 15 PAHs produced 123 endocrine-disrupting substances during metabolism and transformation. Finally, the potential environmental and human health risks of PAHs metabolism and transformation products were evaluated using metabolic and transformation pathway probability and degree of toxic risk as indicators. Accordingly, the priority control strategy for PAHs was constructed based on the risk entropy method by screening the priority control pathways. This paper assesses the potential human health and environmental risks of PAHs in different environmental media with the help of models and toxicological modules for the toxicity prediction of PAHs by-products, and thus designs a risk priority control evaluation system for PAHs.

Section: Methodsmentioning

confidence: 99%

Potential Toxicity Risk Assessment and Priority Control Strategy for PAHs Metabolism and Transformation Behaviors in the Environment

Zhou

et al. 2022

IJERPH

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“…Using the Minimize module in Sybyl-X 2.0 software, the three-dimensional structures of PAEs were optimized using the Powell conjugate gradient method to obtain the low-energy conformation of each molecule, with selected Gasterger–Hückle charge and Tripos molecular force field. The energy convergence standard and iteration number were set to 0.005 kcal mol −1 and 10,000, respectively [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

PAEs Derivatives’ Design for Insulation: Integrated In-Silico Methods, Functional Assessment and Environmentally Friendly Molecular Modification

Zhang

2022

IJERPH

As a common substance in production and life, phthalic acid esters (PAEs), the main component of plastics, have brought more and more serious problems to the environment. This study normalized the insulation, toxicity, and bioconcentration data of 13 PAEs to eliminate the dimensional coefficients of each index, and then used the comprehensive index method to calculate the comprehensive effect value of PAEs with three properties. The comprehensive effect value was used as the data source to construct the 3D-QSAR model of PAE molecular comprehensive effect. The DAP was selected as the target molecule, the distribution of each force field in the three-dimensional equipotential map was analyzed, and 30 molecular modification schemes were created. The constructed single-effect models of insulation, toxicity, and bioconcentration of PAEs and the scoring function module of DS software were used to evaluate the stability and environmental friendliness of PAE derivative molecules. Four PAE derivatives were screened for increased comprehensive effects, enhanced insulation, and reduced toxicity and bioconcentration. By calculating the binding energy of the target molecule and the derivative molecule with the degrading enzyme under different applied electric fields, it was found that the binding energy of DAP-1-NO2-2-CH2C6H5 decreases more than DAP does when there is an applied electric field, indicating that the degradation ability of degrading enzymes on PAE derivative molecules is reduced, which indirectly proves that the insulation is enhanced. The innovation of this paper lies in the insulation, toxicity, and bioenrichment data of PAEs being processed by mathematical method for the first time, and PAEs with high insulation, low toxicity, and low bioconcentration were designed by building a comprehensive model.

“…After docking, the structure of the complex was uploaded to the ATB database for data extraction. Finally, using the GROMACS software, the MD simulation of the complex was performed [60,61], the BE of the complex was calculated [62], and the BE value was used to characterize the interference intensity of PAEs on the hormone receptor proteins [25].…”

Section: Calculation Of the Be Between Paes And Hormone Receptor Prot...mentioning

confidence: 99%

“…The degree of interaction between PAEs and hormone protein receptors was expressed by BE. A smaller BE indicates a stronger binding ability and a greater hormone effect [25]. To more intuitively analyze the ED effects of PAEs and determine the main molecular characteristic values that have a greater impact on their ED effects, the CV of the BE data of the molecular docking between the 22 PAEs and the estrogen protein, androgen protein, and thyroid hormone protein was calculated using the CV method; the CVs were 0.5106, 0.4583, and 0.4458, and the weights were 0.3609, 0.3240, and 0.3151, respectively.…”

Section: Introductionmentioning

confidence: 99%

Human Endocrine-Disrupting Effects of Phthalate Esters through Adverse Outcome Pathways: A Comprehensive Mechanism Analysis

Li,

Yang,

et al. 2023

IJMS

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Phthalate esters (PAEs) are widely exposed in the environment as plasticizers in plastics, and they have been found to cause significant environmental and health hazards, especially in terms of endocrine disruption in humans. In order to investigate the processes underlying the endocrine disruption effects of PAEs, three machine learning techniques were used in this study to build an adverse outcome pathway (AOP) for those effects on people. According to the results of the three machine learning techniques, the random forest and XGBoost models performed well in terms of prediction. Subsequently, sensitivity analysis was conducted to identify the initial events, key events, and key features influencing the endocrine disruption effects of PAEs on humans. Key features, such as Mol.Wt, Q+, QH+, ELUMO, minHCsats, MEDC-33, and EG, were found to be closely related to the molecular structure. Therefore, a 3D-QSAR model for PAEs was constructed, and, based on the three-dimensional potential energy surface information, it was discovered that the hydrophobic, steric, and electrostatic fields of PAEs significantly influence their endocrine disruption effects on humans. Lastly, an analysis of the contributions of amino acid residues and binding energy (BE) was performed, identifying and confirming that hydrogen bonding, hydrophobic interactions, and van der Waals forces are important factors affecting the AOP of PAEs’ molecular endocrine disruption effects. This study defined and constructed a comprehensive AOP for the endocrine disruption effects of PAEs on humans and developed a method based on theoretical simulation to characterize the AOP, providing theoretical guidance for studying the mechanisms of toxicity caused by other pollutants.