Chemical Research in Toxicology最新文献

{"title":"Identification of Butyrylcholinesterase-Derived Small Molecule Peptides Indicative of Novichok Nerve Agent Exposures","authors":"Susan O. Kim,&nbsp;Tonya T. Lansing,&nbsp;Jonas W. Perez,&nbsp;Brooke G. Pantazides*,&nbsp;Brian S. Crow* and Thomas A. Blake,&nbsp;","doi":"10.1021/acs.chemrestox.4c0039710.1021/acs.chemrestox.4c00397","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00397https://doi.org/10.1021/acs.chemrestox.4c00397","url":null,"abstract":"<p >Novichok nerve agents, such as A-230, A-232, and A-234, were classified as Schedule 1 chemicals under the Chemical Weapons Convention (CWC) by the Organisation for the Prohibition of Chemical Weapons (OPCW) following poisoning incidents in 2018. As a result, the production, storage, and use of these chemicals are strictly prohibited by CWC signatory nations. The identification of biomarkers indicating Novichok exposure in humans is crucial for prompt detection and response to potential incidents involving these banned chemical weapons. In this study, BChE was isolated from human serum samples exposed to Novichok nerve agents <i>in vitro</i> using immunomagnetic capture, followed by enzymatic digestion with Pronase or proteinase K to generate new peptide biomarkers indicative of exposure. We identified nine previously unpublished Novichok-adducted peptides generated through enzymatic digestion with proteinase K and Pronase using liquid chromatography–high-resolution mass spectrometry. Two peptides, [Agent]-serine-alanine for proteinase K digestion and [Agent]-serine-alanine-glycine for Pronase digestion, were selected for optimization due to their abundance. The analysis was subsequently transferred to an LC-triple quadrupole system to enhance throughput and detect these new biomarkers at the limits of detection corresponding to BChE inhibition levels of 3.90% or less. These additional biomarkers can improve laboratory preparedness for OPCW-designated biomedical testing laboratories as well as other clinical and investigative laboratories tasked with responding to emergencies involving these highly toxic chemicals.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 2","pages":"252–259 252–259"},"PeriodicalIF":3.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418778","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":"PFOS-Induced Perturbations in Trophoblast Functions through the Oip5os1/miR-155/Rnd3 Axis in PE","authors":"Xiaomin Ye,&nbsp;Peiqu Zhong,&nbsp;Qiongfang Chen,&nbsp;Dongmei Zhou,&nbsp;Jieyu Luo,&nbsp;Youcai Liang,&nbsp;Jiayuan Zhang and Lijian Zhao*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0018410.1021/acs.chemrestox.4c00184","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00184https://doi.org/10.1021/acs.chemrestox.4c00184","url":null,"abstract":"<p >The widespread use of perfluorooctanesulfonic acid (PFOS) has raised concerns regarding its potential on pregnant women, particularly in relation to the development of pre-eclampsia (PE). This study investigates the impact of PFOS exposure on the LncRNA/Rnd3 axis in pregnant mice and its association with trophoblast cell functions in PE. Bioinformatics analysis revealed PFOS-related gene alterations in PE, with pathways enriched in apoptotic signaling and cytokine interactions. Experimental findings showed the downregulation of Oip5os1 and Rnd3, along with the upregulation of miR-155, affecting trophoblast behavior. Animal experiments confirmed that PFOS-induced gene expression changes are linked to PE progression. PFOS exposure impairs trophoblast proliferation and migration via the Oip5os1/miR-155/Rnd3 axis, contributing to PE development.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 2","pages":"236–251 236–251"},"PeriodicalIF":3.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418776","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":"Revealing Toxicological Mechanisms of Small Molecules Using Chemical Biology","authors":"Anal Jana*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0051410.1021/acs.chemrestox.4c00514","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00514https://doi.org/10.1021/acs.chemrestox.4c00514","url":null,"abstract":"<p >Defining the underlying toxicological mechanisms of various small molecules is of utmost importance in understanding the pathogenesis of chemical exposure-related human diseases and developing safe and effective therapeutics. Herein, we discuss the toxicological mechanisms of different small molecules utilizing the different tools of chemical biology.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 1","pages":"4–6 4–6"},"PeriodicalIF":3.7,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143087566","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":"Dried Matrix Spots: An Underutilized and Unexplored Technology in India","authors":"Divya Pulivarthi,&nbsp;Jasmin Chovatiya,&nbsp;Ravikumar Jagani and Syam S. Andra*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0040810.1021/acs.chemrestox.4c00408","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00408https://doi.org/10.1021/acs.chemrestox.4c00408","url":null,"abstract":"<p >Dried Matrix Spot (DMS) is a cost-effective and stable sampling technique used in population-based studies, clinical research, and noninvasive chemical and biomarker screening. DMS is especially useful in developing countries like India, where collaborative initiatives are required for its improved applications.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 1","pages":"1–3 1–3"},"PeriodicalIF":3.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143090967","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":"Activation of V-Domain Immunoglobulin Suppressor of T-Cell Activation by Baloxavir Marboxil Ameliorates Systemic Lupus Erythematosus through Inhibiting Lysophosphatidylcholine/CD40 Ligand","authors":"Zhijie Luo,&nbsp;Tingting Zhang,&nbsp;Penglu Wang,&nbsp;Dingyi Yuan,&nbsp;Shasha Jin,&nbsp;Jianwen Di,&nbsp;Ruixue Ma,&nbsp;Lu Yang,&nbsp;Xinzhi Wang* and Jun Liu*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0044910.1021/acs.chemrestox.4c00449","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00449https://doi.org/10.1021/acs.chemrestox.4c00449","url":null,"abstract":"<p >Deficiency of the V-domain immunoglobulin suppressor of T-cell activation (VISTA) accelerates disease progression in lupus-prone mice, and activation of VISTA shows therapeutic effects in mouse models of a lupus-like disease. Metabolic reprogramming of T cells in systemic lupus erythematosus (SLE) patients is important in regulating T-cell function and disease progression. However, the mechanism by which VISTA affects the immunometabolism in SLE remains unclear. Here, we demonstrated that the deficiency of VISTA promoted the synthesis of the metabolite lysophosphatidylcholine (LPC) using untargeted metabolomics and increased the protein expression of the CD40 ligand (CD40L). Furthermore, baloxavir marboxil (BXM), a small molecule agonist of VISTA, significantly ameliorated autoantibody production, renal damage, and imbalance of immune cell subpopulations in the models of a lupus-like disease in mice (chronic graft-versus-host disease and MRL/MpJ-Faslpr/J mice) possibly by inhibiting LPC synthesis to downregulate CD40L protein expression and inhibiting aberrant activation of noncanonical nuclear factor-κB pathway. Our results indicated that BXM targeting VISTA ameliorated lupus-like symptoms by altering lipid metabolism and CD40L expression, which offers novel mechanisms and a promising therapy for SLE.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 1","pages":"193–205 193–205"},"PeriodicalIF":3.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143091541","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":"Polyamine Adducts with AP Sites: Interaction with DNA Polymerases and AP Endonucleases","authors":"Anna V. Yudkina*,&nbsp;Margarita M. Amanova and Dmitry O. Zharkov*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0031210.1021/acs.chemrestox.4c00312","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00312https://doi.org/10.1021/acs.chemrestox.4c00312","url":null,"abstract":"<p >Biological polyamines, such as spermine, spermidine, and putrescine, are abundant intracellular compounds mostly bound to nucleic acids. Due to their nucleophilic nature, polyamines easily react with apurinic/apyrimidinic (AP) sites, DNA lesions that are constantly formed in DNA by spontaneous base loss and as intermediates of base excision repair. A covalent intermediate is formed, promoting DNA strand cleavage at the AP site, and is later hydrolyzed regenerating the polyamine. Here we have investigated formation of AP site adducts with spermine and spermidine using sodium borohydride trapping technique and shown that they could persist in DNA for long enough to possibly interfere with cell’s replication and transcription machinery. We demonstrate that both adducts placed internally into DNA are strongly blocking for DNA polymerases (Klenow fragment, phage RB69 polymerase, human polymerases β and κ) and direct dAMP incorporation in the rare bypass events. The internal AP site adducts with polyamines can be repaired, albeit rather slowly, by <i>Escherichia coli</i> endonuclease IV and yeast Apn1 but not by human AP endonuclease APE1 or <i>E. coli</i> exonuclease III, whereas the 3′-terminal adducts are substrates for the phosphodiesterase activities of all these AP endonucleases.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 1","pages":"102–114 102–114"},"PeriodicalIF":3.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143090773","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":"Challenges of Biological Complexity in the Study of Nanotoxicology","authors":"Andrew B. Northwick,&nbsp; and ,&nbsp;Erin E. Carlson*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0022010.1021/acs.chemrestox.4c00220","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00220https://doi.org/10.1021/acs.chemrestox.4c00220","url":null,"abstract":"<p >The scale of nanoparticle use in consumer goods has grown exponentially over several decades owing to the unique properties of materials in this size range. At the same time, well-defined end of life cycle disposal strategies have not been developed for most materials, meaning that we are approaching the potential for a new ecological disaster with the release of millions of metric tons of nanoparticles into the waste stream. The field of nanotoxicology has grown to meet the challenge of investigating the potential hazards of these materials and has already identified toxicity mechanisms that affect multiple tropes of life. However, there are stipulations on how applicable many of these results are to real world applications. These limitations largely arise from the complex network of variables that must be considered during these investigations. Herein, we focus on the challenges posed by the transformations that nanoparticles undergo when they are introduced into a biological environment. For example, biomolecules, such as proteins, rapidly coat nanoparticles with a shell, called a corona, that can modulate the toxicity of the core materials and/or aid its internalization into cells. As such, unlike in the evaluation of small molecule toxicity, one cannot assume that they know the composition of the nanoparticle-biomolecule species at any given time. This additional layer of complication, as well as the noncovalent nature of the corona, have made it difficult to identify consistent toxicity trends. In this Perspective, we highlight current analysis strategies and the difficulties in studying nanotoxicity, recent advances to aid in these studies, and efforts to reduce nanotoxicity and outline remaining challenges.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 1","pages":"7–14 7–14"},"PeriodicalIF":3.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143091358","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":"Phototoxic Effects on Skin Biomolecules Induced by a Domestic Nail Polish Dryer Device","authors":"Carlos A. Ardila Padilla,&nbsp;Mariana Vignoni,&nbsp;Mariana P. Serrano* and M. Laura Dántola*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0040110.1021/acs.chemrestox.4c00401","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00401https://doi.org/10.1021/acs.chemrestox.4c00401","url":null,"abstract":"<p >UVA radiation and visible light can lead to indirect damage to DNA, proteins, and lipids through photosensitized reactions, where a molecule undergoes a photochemical alteration by the initial absorption of radiation by another molecular entity called photosensitizer (Sens). The chemical changes undergone by biomolecules in photosensitized reactions can trigger important adverse processes such as photoallergy, phototoxicity, and skin cancer, among others. Despite the knowledge about photosensitized reactions and the fact that many endogenous compounds present in the skin can act as Sens, UVA, and visible light are widely used in several devices for domestic and general use without a thorough evaluation of their possible harmful effects; one prominent example is UV-nail polish dryers. The information in the literature about the possible damage that can be caused by using this type of radiation source is controversial. In this work, we demonstrate that the radiation dose emitted by the nail polish dryer device during a typical gel nail manicure session effectively degrades molecules present in the skin under physiological and pathological conditions. Additionally, it may induce damage to biomolecules such as proteins and lipids due to the photosensitization process, leading to the loss of their biological functions.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 1","pages":"182–192 182–192"},"PeriodicalIF":3.7,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143090357","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":"Analytical Quality Evaluation of the Tox21 Compound Library","authors":"Ann M. Richard,&nbsp;Dingyin Tao,&nbsp;Christopher A. LeClair,&nbsp;William Leister,&nbsp;Kirill V. Tretyakov,&nbsp;Edward White V,&nbsp;Ken C. Lewis,&nbsp;Andrea Sefler,&nbsp;Paul Shinn,&nbsp;Bradley J. Collins,&nbsp;Dac-Trung Nguyen,&nbsp;Lin Ye,&nbsp;Tongan Zhao,&nbsp;Tuan Xu,&nbsp;Antony J. Williams,&nbsp;Suramya Waidyanatha,&nbsp;Russell S. Thomas,&nbsp;Raymond Tice,&nbsp;Anton Simeonov and Ruili Huang*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0033010.1021/acs.chemrestox.4c00330","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00330https://doi.org/10.1021/acs.chemrestox.4c00330","url":null,"abstract":"<p >The analytical quality of compounds subjected to high-throughput screening (HTS) impacts accurate interpretation of assay results, with poor quality samples potentially leading to false negatives or positives. The Tox21 “10K” library consists of over 8900 unique compounds, spanning a diverse landscape of environmental and pharmaceutical chemicals, posing opportunities and challenges for analytical quality control (QC) determinations. Tox21 sample plates stored in DMSO at ambient conditions for 0 (T0) and/or 4 months (T4), totaling more than 13K unique sample identifiers (Tox21 IDs), were subjected to various analyses, including liquid and gas chromatography mass spectrometry (LC-MS, GC-MS) and nuclear magnetic resonance (NMR). Results for each sample at T0 or T4 underwent expert review and, where possible, a QC grade conveying purity, identity, and concentration was assigned. Herein, we relate details of the methods applied and report on the original (v0) Tox21 ID level results. Thirteen QC grades were condensed to 5 quality scores to aid global analysis, resulting in reinterpretation and improvement of &gt;700 sample grades. Of the 92% T0 samples successfully graded, 76% exceeded 90% purity. For 76% of samples that were also tested at T4, 89% showed no evidence of sample loss or degradation. Prioritized quality bins were used to summarize thousands of replicate sample-level QC results to a compound-level QC score to support structure-based analyses. ToxPrint chemotype analysis identified structural features enriched in unstable compounds, as well as in high and low quality T0 subsets. Predicted vapor pressure was weakly correlated with low-concentration QC indicators, reflecting likely entanglement with method amenability and quality issues. Finally, an ongoing EPA effort to re-evaluate the original QC spectra is generating insights that will further modify QC grades. Tox21 QC spectra and results will be made available in a new public QC browser, facilitating further evaluation to support HTS interpretation and modeling applications.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 1","pages":"15–41 15–41"},"PeriodicalIF":3.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00330","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143087137","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":"Comparative Studies on Bulky DNA Damage Binding by Nucleotide Excision Repair Proteins Using Surface Plasmon Resonance, Differential Scanning Fluorometry, and DNase I Footprinting","authors":"Ang Cai,&nbsp;Katelyn L. LaVigne,&nbsp;Alicia M. Crisalli,&nbsp;Sarah Delaney,&nbsp;Jung-Hyun Min and Bongsup P. Cho*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0045610.1021/acs.chemrestox.4c00456","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00456https://doi.org/10.1021/acs.chemrestox.4c00456","url":null,"abstract":"<p >Nucleotide excision repair is a crucial cellular mechanism that ensures genomic stability, thereby preventing mutations that can lead to cancer. The human XPC and its yeast ortholog Rad4 protein complexes are central to this process and were the focus of the study. We used surface plasmon resonance and differential scanning fluorimetry to study the binding characteristics of XPC and Rad4 when bound to the bulky cluster di-FAAF-containing 55-mer duplex DNA. Our findings revealed that XPC binds 10 times more significant affinity to control and di-FAAF-modified DNA than Rad4 with greater protein–DNA interactions. Differential scanning fluorimetry indicates that Rad4 causes comparatively more significant conformational changes upon complexation with the damaged DNA. We conducted DNase I footprinting of the Rad4/DNA complex for the first time by determining the regions protected from DNase I digestion. The DNA at the lesion is entirely resistant to digestion by DNase I in the absence of Rad4 several nucleotides to the 3′-side of the first FAAF lesion. The lack of DNase I cleavage at the lesions did not change upon adding Rad4. However, in the presence of Rad4, a footprint is observed on the 7-nucleotide region (5′-TGGTGAT-3′) of the complementary strand to the 3′ side of the lesion.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 1","pages":"206–215 206–215"},"PeriodicalIF":3.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143087010","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}