Chemical Research in Toxicology最新文献

{"title":"","authors":"Emily M. Kaye, Jitka Becanova, Simon Vojta, Rainer Lohmann, Fabian Christoph Fischer* and Angela Slitt*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.4c00508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665212","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/txv038i007_1961693","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665214","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":"","authors":"Luke A. Thompson, Josiah G. Evans and Slade T. Matthews*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.4c00466","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665217","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":"Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 2 in the Metabolic Activation of 1,8-Dinitropyrene and Its Metabolite 1-Amino-8-nitropyrene via Nitroreduction in Human Lung Cells.","authors":"Anthony L Su, Cátia F Marques, Jacek Krzeminski, Karam El-Bayoumy, Trevor M Penning","doi":"10.1021/acs.chemrestox.5c00101","DOIUrl":"10.1021/acs.chemrestox.5c00101","url":null,"abstract":"<p><p>1,8-Dinitropyrene (1,8-DNP) is a diesel exhaust constituent classified as a possible human carcinogen (Group 2B) by the International Agency for Research on Cancer. Its mutagenic properties can be attributed in part through the formation of covalent DNA adducts that result from mononitroreduction (e.g., <i>N</i>-(deoxyguanosin-8-yl)-1-amino-8-nitropyrene). Recombinant aldo-keto reductases (AKRs) 1C1-1C3 catalyze the nitroreduction of 1,8-DNP, 1-nitropyrene, and 3-nitrobenzanthrone. Although <i>AKR1C1-1C3</i> are induced by nuclear factor erythroid 2-related factor 2 (NRF2), the contribution of NRF2 toward the nitroreduction of 1,8-DNP in human lung cells is currently unknown. We used highly sensitive and specific in-cell fluorescence assays to examine the ability of human lung A549 and HBEC3-KT cells to metabolize 1,8-DNP to yield 1-amino-8-nitropyrene (1,8-ANP) and 1,8-DNP to yield 1,8-diaminopyrene (1,8-DAP) via mono- and bis-nitroreduction, respectively. A549 cells generated both 1,8-ANP and 1,8-DAP from 1,8-DNP. By contrast, HBEC3-KT cells formed 1,8-ANP, but essentially no 1,8-DAP, from 1,8-DNP. We used genetic and pharmacological approaches to investigate the dependence of 1,8-DNP nitroreduction on AKR1C1-1C3 and NRF2. A549 cells with homozygous <i>NFE2L2</i>/NRF2 knockout did not exhibit decreased 1,8-ANP formation but showed decreased 1,8-DAP formation, indicating that the second but not the first nitroreduction step was NRF2-dependent. Treatment of HBEC3-KT cells with NRF2 activators (<i>R</i>-sulforaphane (SFN) or 1-(2-cyano-3,12,28-trioxooleana-1,9(11)-dien-28-yl)-1<i>H</i>-imidazole (CDDO-Im) did not increase the mononitroreduction of 1,8-DNP to 1,8-ANP but increased the conversion of 1,8-ANP to 1,8-DAP consistent with the second step requiring inducible NRF2. AKR1C isoform specific inhibitors showed that these enzymes accounted for the majority of 1,8-ANP and 1,8-DAP formation in both cell lines. The ability of A549 <i>NFE2L2/</i>NRF2 knockout cells to still form 1,8-ANP coupled with their lack of AKR1C isoform expression indicated that a new nitroreductase was expressed as an adaptive response to NRF2 loss. We find that this nitroreductase is not NQO1, thioredoxin reductase, xanthine oxidase, or NADPH-P450 oxidoreductase.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1227-1238"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598906","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":"","authors":"Chao Wu,&nbsp;Jingwen Chen*,&nbsp;Yuxuan Zhang,&nbsp;Zhongyu Wang,&nbsp;Zijun Xiao,&nbsp;Wenjia Liu and Haobo Wang,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.4c00523","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665219","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":"","authors":"Min Nian,&nbsp;Xing Chen and Mingliang Fang*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.4c00555","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665224","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":"Halogen Atoms in Bisphenol A Derivatives Enhance the Inhibitory Potency against Human and Rat Placental 3β-Hydroxysteroid Dehydrogenases.","authors":"Shaowei Wang, Xianghong Fu, Xiya Ren, Peng Yi, Zhigang Wu, Ren-Shan Ge, Bo Peng","doi":"10.1021/acs.chemrestox.5c00156","DOIUrl":"10.1021/acs.chemrestox.5c00156","url":null,"abstract":"<p><p>Halogenated bisphenol A (BPA) derivatives are extensively utilized in industrial production and have been detected in the environment, as well as in human samples. The 3β-HSDs are important for the catalytic transformation of pregnenolone into progesterone. But inhibition by BPA derivatives on 3β-HSD activity is still unclear. The inhibition of 3β-HSD by 8 halogen BPA derivatives was assessed by means of an in vitro test. Tetrachloro BPA was found to be the strongest 3β-HSDs in both human and rat models with IC₅₀ values of 1.48 and 3.81 μM. Other derivatives, including 3-chloro BPA, bisphenol C, 3,3',5-trichloro BPA, tetrabromo BPA, and 4,4'-thiodiphenol, also exhibited inhibitory effects on human and rat placental 3β-HSD activity, albeit with lower potency. 3-Chloro BPA and bisphenol C exerted mixed inhibition against human 3β-HSD1, while the others functioned as competitive inhibitors. These compounds significantly suppressed progesterone secretion in human JAr cells. The inhibitory effects were inversely correlated with the Log P (lipophilicity) and halogen atoms. Docking analysis showed hydrophobic and hydrogen bond interactions that played key roles in the inhibition mechanism. In this paper, a new pharmacological model, which includes both hydrophobic and aromatics, has been proposed for the prediction of inhibition of BPA derivatives. In summary, some halogen-containing derivatives are strong suppressors of 3β-HSDs in placenta, and the inhibition effect of these compounds is mainly dependent on the lipophilicity.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1266-1280"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281682","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":"Untargeted DNA Adductomics Identifies Aristolochic Acid III as a Potent DNA-Damaging Agent among 11 Substituted Aromatic Genotoxicants in the Rat Urinary System.","authors":"Medjda Bellamri, Scott J Walmsley, Lihua Yao, Thomas A Rosenquist, Christopher J Weight, Peter W Villalta, Robert J Turesky","doi":"10.1021/acs.chemrestox.5c00126","DOIUrl":"10.1021/acs.chemrestox.5c00126","url":null,"abstract":"<p><p>An untargeted, data-independent acquisition high-resolution accurate tandem mass spectrometry method using an Orbitrap mass spectrometer was employed to screen for DNA adducts formed from 11 environmental and dietary aromatic or substituted aromatic carcinogens in the kidney, urinary bladder, prostate, pancreas, liver, and the lung of male rats 24 h after treatment. Among the carcinogens investigated, DNA adducts of the structurally related nitrophenanthrenes 3-nitrobenzanthrone (3-NBA), an atmospheric pollutant, and 8-methoxy-6-nitrophenanthro[3,4-<i>d</i>]-1,3-dioxole-5-carboxylic acid (AA-I), a naturally occurring genotoxicant from Aristolochiaceae plants, were the most abundant across most organs, forming both 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) adducts. In contrast, significantly lower DNA adduct levels were formed with the aromatic amine 4-aminobiphenyl and 2-nitrofluorene, an oxidized derivative of 2-aminofluorene; the heterocyclic aromatic amines 2-amino-3,8-dimethylimidazo[4,5-<i>f</i>]quinoxaline, 2-amino-1-methyl-6-phenylimidazo[4,5-<i>b</i>]pyridine, 2-amino-α-carboline, and 2-amino-3-methyl-α-carboline; and the polycyclic aromatic hydrocarbon benzo[<i>a</i>]pyrene. DNA adducts of <i>o</i>-toluidine and 2-naphthylamine were not detected. Most notably, 10-methoxy-6-nitrophenanthro[3,4-<i>d</i>]-1,3-dioxole-5-carboxylic acid (AA-III), an isomer of AA-I, which was later identified as a minor contaminant (5.3%) in the purified herbal extract assayed, exhibited strong organotropism for DNA damage within the urinary system. Dose-adjusted levels of dA and dG adducts of AA-III were 30 to 80 times higher than those of AA-I in the kidney and urinary bladder. This strikingly high organ-specific DNA adduct formation in the urinary system was unique to AA-III and was not observed for the structurally related 3-NBA and AA-I, or the other carcinogens tested. Given that AA-III frequently occurs with AA-I in <i>Aristolochia</i> herbs, these findings underscore the need for further research into the carcinogenic potential of AA-III and its role in renal and urinary bladder cancer associated with traditional herbal medicines.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1239-1256"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300690","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":"ROS-Dependent Endoplasmic Reticulum Stress Is Involved in Silica-Induced Pulmonary Fibrosis through the GRP78/CHOP/TXNIP/NLRP3 Signaling Pathway in Rats.","authors":"Gui-Zhi Han, Shuang Li, Yuan-Yuan Cui, Bo Shao, Ye Song, Shun-Li Jiang, Zhao-Qiang Zhang","doi":"10.1021/acs.chemrestox.5c00135","DOIUrl":"10.1021/acs.chemrestox.5c00135","url":null,"abstract":"<p><p>Several studies have suggested that silica-induced reactive oxygen species (ROS) stimulate the endoplasmic reticulum to undergo endoplasmic reticulum stress (ERS), which eventually leads to pulmonary fibrosis. However, the mechanisms by which ROS-dependent ERS leads to silicosis and fibrosis remain unclear. In this study, male rats were intratracheally instilled with a single dose of crystalline silica (SiO2) suspension (100 mg/mL, 1 mL) to establish silicosis and then were injected intravenously with 1 mL of N-Acetylcysteine (NAC) (at the dose of 20, 40, or 80 mg/kg, respectively) daily to inhibit ROS-dependent ERS. Rats given a single intratracheal dose of SiO₂ suspension and subsequently receiving daily intravenous injections of phosphate buffer solution (PBS) served as models, while those given a single intratracheal dose of PBS and subsequently receiving daily intravenous injections of PBS served as controls. After 40 days, lung samples were taken for pathological observation, and the levels of glucose-regulated protein 78(GRP78), CCAAT-enhancer-binding protein homologous protein (CHOP), thioredoxin-interacting protein (TXNIP), and nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 inflammasome (NLRP3 inflammasome) were assessed. The results showed that compared with the control group, the lung tissues of the model rats exhibited obvious fibrosis and ERS, accompanied by the elevated levels of GRP78, CHOP, TXNIP, and NLRP3 inflammasome. After ROS were inhibited with NAC, the degree of lung fibrosis and ERS was significantly alleviated, and the levels of the aforementioned cytokines were also reduced. Moreover, the higher the dose of NAC intervention, the more pronounced the effects. The results demonstrated that ROS-dependent ERS is deeply involved in silica-induced pulmonary fibrosis through the GRP78/CHOP/TXNIP/NLRP3 signaling pathway in rats.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1257-1265"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598907","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 Models Based on Enlarged Chemical Spaces for Screening Carcinogenic Chemicals.","authors":"Chao Wu, Jingwen Chen, Yuxuan Zhang, Zhongyu Wang, Zijun Xiao, Wenjia Liu, Haobo Wang","doi":"10.1021/acs.chemrestox.4c00523","DOIUrl":"10.1021/acs.chemrestox.4c00523","url":null,"abstract":"<p><p>Machine learning (ML) models for screening carcinogenic chemicals are critical for the sound management of chemicals. Previous models were built on small-scale datasets and lacked applicability domain (AD) characterization that is necessary for regulatory applications of the models. In the current study, an enlarged dataset containing 1697 compounds (940 carcinogens and 757 non-carcinogens) was curated and employed to construct screening models based on 12 types of molecular fingerprints, four ML algorithms, and two graph neural networks. The AD of the optimal model was defined by a state-of-the-art characterization methodology (AD_SAL) based on the analysis of structure-activity landscapes (SALs). Results showed that an optimal model based on the random forest algorithm with the PubChem fingerprints outperformed previous ones, with an area under the receiver operating characteristic curve of 86.2% on the validation set imposed with the AD_SAL. The optimal model, coupled with the AD_SAL, was employed to screen carcinogenic chemicals in the Inventory of Existing Chemical Substances of China (IECSC) and plastic additives datasets, identifying 1282 chemicals from the IECSC and 841 plastic additives as carcinogenic chemicals. The screening model coupled with AD_SAL may serve as a promising tool for prioritizing chemicals of carcinogenic concern, facilitating the sound management of chemicals.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1192-1202"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511274","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}