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Exploring the reproductive exposure risks of phthalates and organophosphates in atmospheric particulate matter based on quantitative structure-activity relationships and network toxicology models

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JOURNAL OF HAZARDOUS MATERIALS 2025年 488卷 137395页

作者： Gao, Ke Hua, Kai Wang, Shiyuan Chen, Xi Zhu, Tong Beijing Univ Technol Dept Environm Sci Key Lab Beijing Reg Air Pollut Control Beijing 100124 Peoples R China Peking Univ Coll Environm Sci & Engn SKL ESPC Beijing Peoples R China Peking Univ Coll Environm Sci & Engn BIC ESAT Beijing Peoples R China Shenzhen Inst Bldg Res Co Ltd Hebei Technol Innovat Ctr Human Settlement Green B Xiongan Peoples R China

Minimal study focused on the association between mixed pollutants in atmospheric particulate matter (PM2.5) and their reproductive health risks. Utilizing a novel quantitative structure-activity relationship (QSAR) integrated machine learning algorithms, we evaluated the mixed reproductive health risks associated with phthalates (PAEs) and organophosphates (OPEs) exposure by assessing the affinities of these compounds binding to estrogen receptors (ER) and androgen receptors (AR). The mixed toxicity equivalent factor (TEFmix) and mixed toxicity equivalent quantity (TEQmix) by the QSAR model were all smaller than the sum TEF and TEQ of individual PAEs and OPEs, which may be due to the antagonistic effect of PAEs and OPEs monomers on reproductive toxicity. Based on network toxicology approach, a total of 590 potential targets associated with PAEs and OPEs affecting sex hormones were initially identified, with an additional 50 core targets, including AR and ER. Di-2-ethylhexyl phthalate (DEHP), triphenyl phosphate (TPHP) and mono-(2-ethylhexyl) phthalate (MEHP) were key components to disrupt AR and ER signaling pathway, and was confirmed by molecular docking analysis. In addition to ER and AR, serine/threonine kinase 1 (AKT1) and heat shock protein 90 alpha family A member 1 (HSP90AA1) might be key targets for reproductive toxicity, which have hardly mentioned before. Our study provided precious information on the mixed reproductive exposure risk of PAEs and OPEs in PM2.5, and innovatively explored the potential mechanisms of PAEs and OPEs affecting human reproductive health using network toxicology.

关键词： Phthalates Organophosphates Atmospheric particulate matter quantitative structure-activity relationships Network toxicology

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quantitative structure-activity relationships for phenyl triazolinones of protoporphyrinogen oxidase inhibitors: A density functional theory study

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JOURNAL OF COMPUTATIONAL CHEMISTRY 2004年第15期25卷 1827-1832页

作者： Wan, J Zhang, L Yang, GF Cent China Normal Univ Coll Chem Minist Educ CCNU Wuhan 430079 Peoples R China

The equilibrium geometries, electronic structures, and electrostatic potentials of a series of substituted phenyl triazolinones of protoporphyrinogen oxidase (PPO) inhibitors have been investigated by using the density functional theory (DFT) method. The quantum chemical descriptors, highest occupied molecular orbital and lowest unoccupied molecular orbital energy gap (DeltaE), weighted electrophilic, and nucleophilic atomic frontier electron density (FA and FA), and net atomic charge (Q), were computed at the same DFT level. Based on these precise quantum chemical descriptors, a quantitative structure-activity relationships study has been carried out and shown that Q(C11), F-N5(E), F-C10(N), and DE of individual molecules are most likely to be responsible for the in vitro biological activity and greenhouse preemergence activity of phenyl triazolinones. The ability to quite accurately predict the biological activity of phenyl triazolinones by using DFT-based QSAR can be expected to help facilitate the design of additional substituted phenyl triazolinones as PPO inhibitors with good biological activity. (C) 2004 Wiley Periodicals, Inc.

关键词： density functional theory quantitative structure-activity relationships inhibitors

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quantitative structure-activity relationships for kinetic parameters of polycyclic aromatic hydrocarbon biotransformation

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ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2008年第7期27卷 1496-1504页

作者： Dimitriou-Christidis, Petros Autenrierh, Robin L. Abraham, Michael H. Texas A&M Univ Dept Civil Engn Environm Engn Div College Stn TX 77843 USA UCL Dept Chem Christopher Ingold Labs London WC1H 0AJ England

quantitative structure-activity relationships (QSARs) were developed for three Monod-type parameters-q(max), K-S, and q(max)/K-S-that express the kinetics of polycyclic aromatic hydrocarbon (PAH) biotransformation by Sphingomonas paucimobilis strain EPA505. The training sets contained high-quality experimental values of the kinetic parameters for 20 unsubstituted and methylated PAHs as well as values of 41 meaningful molecular descriptors. A genetic function approximation algorithm was used to develop the QSARs. Statistical evaluation of the developed QSARs showed that the relationships are statistically significant and satisfy the assumptions of linear-regression analysis. The Organization for Economic Co-operation and Development principles for (Q)SAR validation were followed to evaluate the developed QSARs, which showed that the QSARs are valid. The QSARs contain spatial, spatial and electronic, topological, and thermodynamic molecular descriptors. Whereas spatial descriptors were essential in explaining biotransformation kinetics, electronic descriptors were not. Mechanistic interpretation of the QSARs resulted in evidence that is consistent with the hypothesis of membrane transport as being the rate-limiting process in PAH biotransformation by strain EPA505. The present study demonstrates the value of QSAR not only as a predictive tool but also as a framework for understanding the mechanisms governing biodegradation at the molecular level.

关键词： quantitative structure-activity relationships polycyclic aromatic hydrocarbons Monod kinetics Sphingomonas paucimobilis strain EPA505 biotransformation

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quantitative structure-activity relationships studies with micellar electrokinetic chromatography - Influence of surfactant type and mixed micelles on estimation of hydrophobicity and bioavailability

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JOURNAL OF CHROMATOGRAPHY A 1996年第2期721卷 323-335页

作者： Yang, SY Bumgarner, JG Kruk, LFR Khaledi, MG N CAROLINA STATE UNIV DEPT CHEMRALEIGHNC 27695

Applications of micellar electrokinetic chromatography (MEKC) in quantitative structure-activity relationships (QSAR) were studied. First, quantitative structure-retention relationships (QSRR), which describe the correlation between logarithm of capacity factor (log k') in MEKC and logarithm of distribution coefficient between 1-octanol and water (log P-ow), were investigated for 60 aromatic compounds and 9 corticosteroids using three different anionic surfactants [e.g., sodium dodecyl sulfate (SDS), sodium cholate (SC), and lithium perfluorooctane sulfonate (LiPFOS)], one cationic surfactant (C(14)TAB), and mixed anionic micellar systems. Linear solvation energy relationships (LSER) and solvatochromic parameters were used to shed light on the different log k' vs. log P-ow relationships for the various surfactants. It was concluded that hydrogen bonding interactions have a great influence on retention behavior in MEKC and its relationship with hydrophobicity. Interestingly, bile salt surfactants (e.g., SC) and mixed bile salt micellar systems provide better correlations for log k' vs. log P-ow than SDS and/or SDS with buffer additives (e.g., beta-cyclodextrin, urea, and acetonitrile). Using SC micelles, only one line was adequate to describe the relationship between retention in MEKC and hydrophobicity for a group of 60 aromatic compounds. The existence of higher correlation for the SC system was attributed to a similar hydrogen bonding pattern between SC micelles and 1-octanol. In the SDS system, however, three lines were recognized for the congeneric subgroups of compounds. This is due to the hydrogen bond donor (HBD) characteristic of SDS micelles that selectively differentiate between the solutes with different hydrogen bond acceptor (HBA) strength, thus demonstrating that retention is not solely based on hydrophobicity. A similar result was observed for a C(14)TAB-MEKC system, however, the HBA characteristic of C(14)TAB selectively differentiates between the so

关键词： micellar electrokinetic chromatography quantitative structure-activity relationships hydrophobicity partition coefficients micelles protein binding surfactants sodium dodecyl sulfate bile salts tetradecyltrimethylammonium bromide

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quantitative structure-activity relationships (QSAR) with the MolNet Molecular Graph Machine

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CURRENT BIOINFORMATICS 2011年第2期6卷 261-268页

作者： Ivanciuc, Ovidiu Univ Texas Med Branch Dept Biochem & Mol Biol Galveston TX 77555 USA

quantitative structure-activity relationships (QSAR) are statistical models that may predict various physicochemical and biological properties of chemical compounds. Typical QSAR models use as input molecular descriptors computed from the chemical structure of the compounds in the dataset. QSAR models are based on algorithms or mathematical functions that correlate these molecular descriptors with the experimental property that is modeled. A different approach is explored in molecular graph machines (MGM) which represent a class of QSAR models that actively consider the molecular topology in the process of generating a structure-property model. After a review of the major MGM models, we present a detailed overview of the artificial neural network MolNet, which is a multilayer perceptron that encodes the molecular topology of each chemical presented to the network during learning or prediction. Each non-hydrogen atom in a molecule has a corresponding neuron in the input and hidden layers, whereas the output layer has only one neuron which provides the computed molecular property. The connections between the input and hidden layers encode the topological distance matrix of a molecule, whereas the connections between the hidden and output layers are classified according to atom types. Connection weights corresponding to the same topological distance or to the same atom type have a constant value for all chemicals in the training set. A MolNet application is presented for the glycogen synthase kinase-beta (GSK-3 beta) inhibition by aloisines.

关键词： quantitative structure-activity relationships QSAR molecular graph machines MGM glycogen synthase kinase-3 beta GSK-3 beta graph mining topological indices artificial neural network

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quantitative structure-activity relationships for polychlorinated hydroxybiphenyl estrogen receptor binding affinity: An assessment of conformer flexibility

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ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 1996年第11期15卷 1945-1954页

作者： Bradbury, SP Mekenyan, OG Ankley, GT HIGHER INST CHEM TECHNOL BURGAS 8010 BULGARIA

A diverse group of xenobiotics has a high binding affinity to the estrogen receptor (ER), suggesting that it can accommodate large variability in ligand structure. relationships between xenobiotic structure, binding affinity, and estrogenic response have been suggested to be dependent on the conformational structures of the ligands. To explore the influence of conformational flexibility on ER binding affinity, a quantitative structure-activity relationship (QSAR) study was undertaken with estradiol, diethylstilbestrol, and a set of polychlorinated hydroxybiphenyls (PCHBs) of environmental concern. Although the low-energy minima of the PCHB congeners suggested that interconversions among conformers were likely, the electronic parameters associated with the conformer geometries for a specific PCHB congener could vary significantly. The results of the QSAR analysis suggested that among the PCHBs studied, the most polarizable conformers (lower absolute volume polarizability values) were most closely associated with ER binding affinity. Across the set of ''polarizable'' conformers, which did not include the low-energy gas-phase conformers, the electron donating properties of the hydroxy moiety and the aromatic component of the estradiol A ring analogue in the PCHBs were found to be correlated with higher ER binding affinity.

关键词： quantitative structure-activity relationships conformational searching polychlorinated hydroxybiphenyls estradiol estrogen receptor

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quantitative structure-activity relationships for predicting potential ecological hazard of organic chemicals for use in regulatory risk assessments

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ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2003年第8期22卷 1822-1828页

作者： Comber, MHI Walker, JD Watts, C Hermens, J Exxon Mobil Exxon Mobil Biomed Sci B-1831 Machelen Belgium US EPA TSCA Interagcy Testing Comm Washington DC 20460 USA Water Res Ctr NSF Natl Ctr Environm Toxicol Marlow SL7 2HD Bucks England Univ Utrecht RITOX Utrecht Netherlands

The use of quantitative structure-activity relationships (QSARs) for deriving the predicted no-effect concentration of discrete organic chemicals for the purposes of conducting a regulatory risk assessment in Europe and the United States is described. In the United States, under the Toxic Substances Control Act (TSCA), the TSCA Interagency Testing Committee and the U.S. Environmental Protection Agency (U.S. EPA) use SARs to estimate the hazards of existing and new chemicals. Within the Existing Substances Regulation in Europe, QSARs may be used for data evaluation, test strategy indications, and the identification and filling of data gaps. To illustrate where and when QSARs may be useful and when their use is more problematic, an example, methyl tertiary-butyl ether (MTBE), is given and the predicted and experimental data are compared. Improvements needed for new QSARs and tools for developing and using QSARs are discussed.

关键词： quantitative structure-activity relationships risk assessment regulatory effect

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quantitative structure-activity-relationships FOR SKIN SENSITIZATION POTENTIAL OF URUSHIOL ANALOGS

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CONTACT DERMATITIS 1993年第2期29卷 78-83页

作者： ROBERTS, DW BENEZRA, C UNIV LOUIS PASTEUR STRASBOURG DERMATOCHIM LABF-67091 STRASBOURGFRANCE

The relative alkylation index (RAI), a theoretically derived parameter intended to quantify the relative extent of carrier haptenation resulting from a given dose of a given sensitizer, has previously been successfully applied to the analysis of relative sensitization potential and dose-response data for a variety of contact allergens which are directly electrophilic. Here the RAI concept is applied to analysis of data on compounds related to urushiol (i.e., 3-substituted catechols), the naturally occurring mixture of allergens responsible for contact allergy to poison ivy and poison oak. These allergens are believed to act as pro-electrophiles, being oxidized to electrophilic orthoquinones in vivo. It is found that the various types of urushiol derivatives fit the same sort of RAI-sensitization relationships as expected theoretically and as found previously with direct acting electrophiles. There is evidence that in many cases, the test conditions were such that overload effects, whereby the degree of sensitization induced decreases with increasing carrier haptenation, applied. It is also concluded that the question as to the relative sensitization potencies of the naturally occurring urushiols remains open. The commonly held view that with these materials, sensitization potential increases with increasing unsaturation in the 3-hydrocarbyl chain of the 3-hydrocarbyl catechols, is based on evidence that is capable of alternative interpretation.

关键词： quantitative structure-activity relationships RELATIVE ALKYLATION INDEX GUINEA PIG SENSITIZATION URUSHIOLS ORTHOQUINONES OVERLOAD EFFECT

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quantitative structure-activity relationships: sulfonate esters in the local lymph node assay

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CONTACT DERMATITIS 2000年第3期42卷 154-161页

作者： Roberts, DW Basketter, DA Unilever Res Port Sunlight Lab Wirral CH63 3JW Merseyside England Unilever Res SEAC Toxicol Sharnbrook MK44 1LQ Beds England

The biological activity of skin-sensitizing chemicals is related to their ability to react, either directly or after metabolic activation, with appropriate skin proteins. For direct acting electrophilic compounds, this ability can be modelled, using the RAI (relative alkylation index) approach by a combination of electrophilicity and hydrophobicity parameters. The development of predictive quantitative structure-activity relationships (QSAR) models of skin sensitization, using mechanism-based physicochemical parameters, has been greatly facilitated by the introduction of the murine local lymph node assay (LLNA), which is able to describe the extent of the biological response in objective and quantitative terms. In the present work, sensitization response data in the LLNA is generated For a series of 6 sulfonate esters. An RAI-based hybrid QSAR/dose-response relationship is derived using a negative hydrophobicity coefficient in the RAI expression, to model the effect of retention of the hydrophobic test chemicals in the stratum corneum. Dose-response analyses are used to estimate EC3 and EC20 values as quantitative indices of skin sensitization potential for each compound, and regression analysis is applied to develop QSARs correlating these EC3 and EC20 values with an RAI-based parameter. The high statistical quality of these QSARs demonstrates both the consistency of the LLNA method for generating high quality skin sensitization data, and the value of the RAI approach in development of mathematical models for skin sensitization.

关键词： contact sensitization potential quantitative structure-activity relationships murine local lymph node assay mouse sensitization sulfonate esters relative alkylation index dose-response relationships

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quantitative structure-activity relationships for phosphoramidothioate toxicity in housefly

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COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY 1999年第3期123卷 241-255页

作者： Singh, AK Univ Minnesota Coll Vet Med Dept Vet Diagnost Med St Paul MN 55108 USA Univ Minnesota Coll Vet Med Minnesota Vet Diagnost Lab St Paul MN 55108 USA

quantitative structure-activity relationships were formulated for a series of phosphoramidothioate (Ace) analogs. Ace II- and Ace IV-induced inhibition of fly-head AChE was influenced by the spatial configuration of the inhibitor. The 3D structure of a potent phosphoramidothioate such as methamidophos was such that its P-O- group interacted with the enzyme's 'oxy-anion hole', NH2+ group formed an H-bond with the enzyme's H-bonding site, and leaving group (-S) oriented toward the AChE 'gorge' opening. An alteration in its 3D structure also altered its toxicity. The iii for Ace II-induced inhibition of fly-AChE correlated with sterimol indices L-1 (the substituent's length), B-1 (minimum axis perpendicular to this length), and B-3 (-90 degrees to B-1) and E-bend. The k(i) for Ace IV-induced inhibition of fly-AChE correlated with dispersion, H-bond donor, and E-dihedral. Thus, the 3D characteristics of a substituent and molecular charge play a key role in the inhibition of fly-head AChE by phosphoramidothioate. LD50 for housefly exposed to Ace I, II, III, and IV analogs was governed by their electronic, topological, steric, and sterimol (steric effects of substituents) properties. Hydrophobic interaction either played a minor role or adversely affected their toxicity in housefly. (C) 1999 Elsevier Science Inc. All rights reserved.

关键词： housefly phosphoramidothioate quantitative structure-activity relationships

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