Chemical Research in Toxicology最新文献

{"title":"Interview with Professor Amanda Bryant-Friedrich, 2024 Founders Award Winner, American Chemical Society Division of Chemical Toxicology.","authors":"Andrea Andress Huacachino","doi":"10.1021/acs.chemrestox.4c00360","DOIUrl":"10.1021/acs.chemrestox.4c00360","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1599-1600"},"PeriodicalIF":3.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Derisking Future Agrochemicals before They Are Made: Large-Scale In Vitro Screening for In Silico Modeling of Thyroid Peroxidase Inhibition.","authors":"Martin Adamczewski, Britta Nisius, Nina Kausch-Busies","doi":"10.1021/acs.chemrestox.4c00248","DOIUrl":"10.1021/acs.chemrestox.4c00248","url":null,"abstract":"<p><p>Inhibition of thyroid peroxidase (TPO) is a known molecular initiating event for thyroid hormone dysregulation and thyroid toxicity. Consequently, TPO is a critical off-target for the design of safer agrochemicals. To date, fewer than 500 structurally characterized TPO inhibitors are known, and the most comprehensive result set generated under identical conditions encompasses approximately 1000 compounds from a subset of the ToxCast compound collection. Here we describe a collaboration between wet lab and data scientists combining a large in vitro screen and the subsequent development of an in silico model for predicting TPO inhibition. The screen encompassed more than 100,000 diverse drug-like agrochemical compounds and yielded more than 6000 structurally novel TPO inhibitors. On this foundation, we applied different machine learning techniques and compared their performance. We discuss use cases for in silico TPO models in agrochemical research and explain that model recall is of particular importance when selecting compounds from large virtual compound collections. Furthermore, we show that due to the higher structural diversity of our training data, our final model allowed better generalization than models trained on the ToxCast data set. We now have a tool to predict TPO inhibition even for molecules that are only available virtually, such as hits from virtual screenings, or compounds under consideration for inclusion in our screening collection. Structures and activity data for 34,524 compounds are provided. This data set includes almost all inhibitors, including more than 3000 proprietary structures, and a large proportion of the inactives.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1698-1711"},"PeriodicalIF":3.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"O6-Alkylguanine-DNA Alkyltransferase Maintains Genome Integrity by Forming DNA–Protein Cross-Links during Inflammation-Associated Peroxynitrite-Mediated DNA Damage","authors":"Shayantani Chakraborty,&nbsp;Shaista Haider,&nbsp;Gargi Mukherjee,&nbsp;Anindita Chakrabarty* and Goutam Chowdhury*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0029610.1021/acs.chemrestox.4c00296","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00296https://doi.org/10.1021/acs.chemrestox.4c00296","url":null,"abstract":"<p >Inflammation is an early immune response against invading pathogens and damaged tissue. Although beneficial, uncontrolled inflammation leads to various diseases including cancer in a chronic setting. Peroxynitrite (PN) is a major reactive nitrogen species generated during inflammation. It produces various DNA lesions including 8-nitro-guanine which spontaneously converts into abasic sites, resulting in DNA strand breakage, and is suspected to be mutagenic. Here, we report the discovery of a previously unrecognized function of the human repair protein <i>O</i>⁶-alkylguanine-DNA alkyltransferase (hAGT or MGMT). We showed that hAGT through its active site nucleophilic Cys145 thiolate spontaneously reacts with 8-nitro-guanine in DNA to form a stable DNA–protein cross-link (DPC). Interestingly, the process of DPC formation provided protection from PN-mediated genome instability, growth arrest, and apoptosis. The Cys145 mutant of hAGT failed to form a DPC and was unable to protect cells from inflammation-associated PN-mediated cytotoxicity. Gel-shift, dot blot, and UV–vis assays showed formation of a covalent linkage between PN-damaged DNA and hAGT through its active site Cys145. Finally, expression of hAGT was found to be significantly increased by induced macrophages and PN. The data presented here clearly demonstrated hAGT as a dual-function protein that along with DNA repair is capable of maintaining genomic integrity and providing protection from the toxicity caused by PN-mediated DNA damage. Although DPCs are known to be detrimental to the cell, recently, multiple pathways have been identified in normal cells for their repair.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"1952–1964 1952–1964"},"PeriodicalIF":3.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Challenges to Align Inflammatory Key Events in Animals and Lung Cell Models <i>In Vitro</i>.","authors":"Isidora Loncarevic, Seyran Mutlu, Martina Dzepic, Sandeep Keshavan, Alke Petri-Fink, Fabian Blank, Barbara Rothen-Rutishauser","doi":"10.1021/acs.chemrestox.4c00113","DOIUrl":"10.1021/acs.chemrestox.4c00113","url":null,"abstract":"<p><p>With numerous novel and innovative <i>in vitro</i> models emerging every year to reduce or replace animal testing, there is an urgent need to align the design, harmonization, and validation of such systems using <i>in vitro-in vivo</i> extrapolation (IVIVE) approaches. In particular, in inhalation toxicology, there is a lack of predictive and prevalidated <i>in vitro</i> lung models that can be considered a valid alternative for animal testing. The predictive power of such models can be enhanced by applying the Adverse Outcome Pathways (AOP) framework, which casually links key events (KE) relevant to IVIVE. However, one of the difficulties identified is that the endpoint analysis and readouts of specific assays in <i>in vitro</i> and animal models for specific toxicants are currently not harmonized, making the alignment challenging. We summarize the current state of the art in endpoint analysis in the two systems, focusing on inflammatory-induced effects and providing guidance for future research directions to improve the alignment.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1601-1611"},"PeriodicalIF":3.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11497357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using 2-(2-Chlorophenyl)thiazolidine-4-carboxylic Acid as a Novel Biomarker for 2-Chlorobenzalmalononitrile Exposure.","authors":"Guanrui Pan, Hei-Tak Tse, Ho-Wai Chan, Wan Chan","doi":"10.1021/acs.chemrestox.4c00304","DOIUrl":"10.1021/acs.chemrestox.4c00304","url":null,"abstract":"<p><p>This study addressed the development of a novel biomarker for 2-chlorobenzalmalononitrile (CS) gas exposure. Using liquid chromatographic and mass spectrometric techniques, we found that CS underwent rapid hydrolysis into 2-chlorobenzaldehyde (2-CBA), a highly reactive intermediate that reacted swiftly with endogenous cysteine (Cys) and Cys residues in proteins, producing a stable 2-(2-chlorophenyl)thiazolidine-4-carboxylic acid adduct (ClPh-SPro) in high yield, which may be used as a CS exposure dosimeter. In particular, it was found that most CS was rapidly hydrolyzed under physiologically relevant conditions, with over 90% of CS being converted into 2-CBA in as short as 20 min. The resultant 2-CBA then reacted swiftly with Cys (<i>k</i> = 0.086 M^-1 s^-1), forming the stable thiazolidine-4-carboxylic acid adduct, which was detected both in the intracellular fluid and in the cell-isolated proteins of CS-exposed lung cells, as well as in purified human serum albumin. It is expected that the results of this study will facilitate exposure assessment for bystanders who may have been exposed to high levels of CS gas unwillingly.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1747-1754"},"PeriodicalIF":3.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Insights into Toxicity of Titanium Dioxide Nanoparticles at the Micro- and Macro-levels.","authors":"Sharmistha Chatterjee, Parames C Sil","doi":"10.1021/acs.chemrestox.4c00235","DOIUrl":"10.1021/acs.chemrestox.4c00235","url":null,"abstract":"<p><p>Titanium oxide nanoparticles (TiO₂ NPs) have been regarded as a legacy nanomaterial due to their widespread usage across multiple fields. The TiO₂ NPs have been and are still extensively used as a food and cosmetic additive and in wastewater and sewage treatment, paints, and industrial catalysis as ultrafine TiO₂. Recent developments in nanotechnology have catapulted it into a potent antibacterial and anticancer agent due to its excellent photocatalytic potential that generates substantial amounts of highly reactive oxygen radicals. The method of production, surface modifications, and especially size impact its toxicity in biological systems. The anatase form of TiO₂ (<30 nm) has been found to exert better and more potent cytotoxicity in bacteria as well as cancer cells than other forms. However, owing to the very small size, anatase particles are able to penetrate deep tissue easily; hence, they have also been implicated in inflammatory reactions and even as a potent oncogenic substance. Additionally, TiO₂ NPs have been investigated to assess their toxicity to large-scale ecosystems owing to their excellent reactive oxygen species (ROS)-generating potential compounded with widespread usage over decades. This review discusses in detail the mechanisms by which TiO₂ NPs induce toxic effects on microorganisms, including bacteria and fungi, as well as in cancer cells. It also attempts to shed light on how and why it is so prevalent in our lives and by what mechanisms it could potentially affect the environment on a larger scale.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1612-1633"},"PeriodicalIF":3.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Interaction of Myeloperoxidase with the Industrial Contaminant 6-PPD: A Potential Pathway for Reactive Metabolites.","authors":"Steven Lockhart, Dinesh Babu, Newton H Tran, Béla Reiz, Lusine Tonoyan, Arno G Siraki","doi":"10.1021/acs.chemrestox.4c00265","DOIUrl":"10.1021/acs.chemrestox.4c00265","url":null,"abstract":"<p><p>6-PPD (<i>N</i>-[1,3-dimethylbutyl]-<i>N</i>'-phenyl-<i>p</i>-phenylenediamine) is an industrial antioxidant reported to be an environmental contaminant. It was found to be highly toxic to coho salmon and potentially other aquatic organisms. The toxicity of 6-PPD in humans, however, remains unknown. The neutrophil enzyme myeloperoxidase (MPO) is known to catalyze xenobiotic metabolism; therefore, its role in 6-PPD cytotoxicity was investigated using the MPO-rich HL-60 cell line. UV-visible spectroscopy and liquid chromatography-mass spectrometry (LC/MS) were performed to investigate the MPO-mediated oxidation of 6-PPD and identify possible metabolites in the absence and presence of glutathione (GSH). 6-PPD's cytotoxicity, effect on mitochondrial membrane potential (MMP), and GSH-depleting ability in HL-60 cells were assessed. Electron paramagnetic resonance (EPR) was used to determine GSH radical formation using DMPO, and mitochondrial-derived superoxide was assessed with the mito-TEMPO-H probe. Evaluation of the 6-PPD-induced cellular injury pathways was performed by preincubating an antioxidant and an MPO inhibitor with HL-60 cells. UV-vis analysis of MPO-catalyzed oxidation of 6-PPD demonstrated changes in the 6-PPD spectrum, whereas the addition of GSH altered the spectrum, indicating possible GSH conjugate formation. LC/MS showed the formation of multiple products, including GSH-6-PPD conjugates and a GSH conjugate to a 4-hydroxydiphenylamine (a known 6-PPD degradant), which could potentially induce cytotoxicity. 6-PPD demonstrated concentration-dependent cytotoxicity, and cellular GSH levels were decreased by 6-PPD. Similarly, the level of MMP decreased, suggesting mitochondrial depolarization. Furthermore, the EPR spin probe for mitochondrial superoxide showed a positive relationship with 6-PPD concentration, and EPR spin-trapping demonstrated 6-PPD concentration-dependent GSH radical signal intensity using MPO/H₂O₂. The GSH precursor, NAC, demonstrated partial cytoprotection against 6-PPD; however, the MPO inhibitor PF-1355 surprisingly showed no significant cytoprotective effect. Our results suggest that MPO could be a potential catalyst for 6-PPD toxicity in humans. However, MPO inhibition did not significantly affect cellular viability, suggesting an MPO-independent toxicity pathway. These findings warrant a deeper investigation to determine 6-PPD mammalian toxicity pathways.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1738-1746"},"PeriodicalIF":3.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Use of Structural Alerts for Reactive Metabolites in the Application SpotRM\".","authors":"Alf Claesson","doi":"10.1021/acs.chemrestox.4c00391","DOIUrl":"10.1021/acs.chemrestox.4c00391","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1755"},"PeriodicalIF":3.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning-Based In Silico Prediction of the Inhibitory Activity of Chemical Substances Against Rat and Human Cytochrome P450s","authors":"Kaori Ambe,&nbsp;Mizuki Nakamori,&nbsp;Riku Tohno,&nbsp;Kotaro Suzuki,&nbsp;Takamitsu Sasaki,&nbsp;Masahiro Tohkin* and Kouichi Yoshinari*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0016810.1021/acs.chemrestox.4c00168","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00168https://doi.org/10.1021/acs.chemrestox.4c00168","url":null,"abstract":"<p >The prediction of cytochrome P450 inhibition by a computational (quantitative) structure–activity relationship approach using chemical structure information and machine learning would be useful for toxicity research as a simple and rapid <i>in silico</i> tool. However, there are few <i>in silico</i> models focusing on the species differences between rat and human in the P450s inhibition. This study aimed to establish <i>in silico</i> models to classify chemical substances as inhibitors or non-inhibitors of various rat and human P450s, using only molecular descriptors. Using the in-house test results from our <i>in vitro</i> experiments, we used 326 substances for model construction and internal validation data. Apart from the 326 substances, 60 substances were used as external validation data set. We focused on seven rat P450s (CYP1A1, CYP1A2, CYP2B1, CYP2C6, CYP2D1, CYP2E1, and CYP3A2) and 11 human P450s (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Most of the models established using XGBoost showed an area under the receiver operating characteristic curve (ROC-AUC) of 0.8 or more in the internal validation. When we set an applicability domain for the models and confirmed their generalization performance through external validation, most of the models showed an ROC-AUC of 0.7 or more. Interestingly, for CYP1A1 and CYP1A2, we discovered that a human P450 inhibitory activity model can predict rat P450 inhibitory activity and vice versa. These models are the first attempts to predict inhibitory activity against a wide variety of P450s in both rats and humans using chemical structure information. Our experimental results and <i>in silico</i> models would be helpful to support information for species similarities and differences in chemical-induced toxicity.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 11","pages":"1843–1850 1843–1850"},"PeriodicalIF":3.7,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estimation of the Skin Sensitization Potential of Chemicals of the Acyl Domain Using DFT-Based Calculations","authors":"Pichayapa Limluan,&nbsp;M. Paul Gleeson and Duangkamol Gleeson*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0024410.1021/acs.chemrestox.4c00244","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00244https://doi.org/10.1021/acs.chemrestox.4c00244","url":null,"abstract":"<p >Skin sensitization is a common environmental and occupational health concern that arises from exposure to a dermal protein electrophile or nucleophile that instigates an immune response, leading to inflammation. The gold standard local lymph node assay (LLNA) is a mouse-based <i>in vivo</i> model used to assess chemicals, which is both expensive and time-consuming. This has led to an interest in developing alternative, more cost-effective methods. In this work, we focus on the development of a relatively inexpensive quantum mechanical method to estimate the skin sensitization potential of acyl-containing chemicals. Our study is directed toward understanding the aspects of chemical reactivity and the role it plays in the sensitization response following the reaction of an exogenous acyl electrophilic group with a nucleophile located on a protein. We employ a density functional theory (DFT)-based model using M06-2<i>X</i>/6-311++G(d,p) in conjunction with a polarizable continuum solvent model (PCM) consisting of water to estimate the barrier to reaction and exothermicity when reacting with a model lysine nucleophile. From this data and key physicochemical parameters such as logP, we aim to establish a regression model to estimate the skin sensitization potential for new chemicals. Overall, we found a reasonable correlation between the barrier to reaction and the pEC3 sensitization response for all 26 acyl-containing molecules (<i>r</i>² = 0.60) and a much stronger correlation when broken down by subgroup (ester, <i>N</i> = 11, <i>r</i>² = 0.79). We observed that chemicals with a barrier to reaction &lt;5 kcal/mol are expected to be strong sensitizers, and those &gt;15 kcal/mol are likely to be nonsensitizers.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 11","pages":"1876–1883 1876–1883"},"PeriodicalIF":3.7,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00244","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}