Chemical Research in Toxicology最新文献_第3页

Quantification of Flavors, Volatile Organic Compounds, Tobacco Markers, and Tobacco-Specific Nitrosamines in Heated Tobacco Products and Their Mainstream Aerosol. 加热烟草制品及其主流气溶胶中香料、挥发性有机化合物、烟草标记和烟草特异性亚硝胺的定量。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-05-19 Epub Date: 2025-03-20 DOI: 10.1021/acs.chemrestox.5c00005

Saria Hoshino, Kazushi Noro, Takashi Amagai

{"title":"Quantification of Flavors, Volatile Organic Compounds, Tobacco Markers, and Tobacco-Specific Nitrosamines in Heated Tobacco Products and Their Mainstream Aerosol.","authors":"Saria Hoshino, Kazushi Noro, Takashi Amagai","doi":"10.1021/acs.chemrestox.5c00005","DOIUrl":"10.1021/acs.chemrestox.5c00005","url":null,"abstract":"As an alternative to cigarettes, the sales of heated tobacco products (HTPs) have increased in the Japanese market. This may contribute to improving a smoker's health because the levels of most toxic compounds─such as tobacco-specific nitrosamines (TSNAs) and volatile organic compounds (VOCs)─in the mainstream of HTPs are lower than those in cigarettes. However, the risks associated with the flavors that provide attractive tastes to HTPs remain unknown. We demonstrated that compared with cigarettes, HTPs reduce the health risks associated with VOCs and TSNAs while achieving comparable nicotine and flavor levels. The VOC and TSNA concentrations in the mainstream aerosol of HTPs were 0.0039 (benzene)-0.53 (acetaldehyde) times lower than those in cigarettes. Using HTPs may still pose adverse noncarcinogenic and carcinogenic effects on human health, as indicated by hazard quotients >1 for acrolein and acetaldehyde, margins of exposure <100 for (R)-(+)-limonene, and cancer risks >1.0 × 10-6 for acetaldehyde. Additionally, the exhalation of mainstream aerosol may increase the indoor acrolein concentration to 0.069 μg m-3, exceeding the reference concentration for acrolein (0.02 μg m-3). Therefore, reducing acrolein concentrations is an effective measure for improving the safety of HTP use.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"915-922"},"PeriodicalIF":3.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668581","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}

引用次数: 0

HDAC6-Mediated NLRP3 Inflammasome Activation Is Involved in Nickel Nanoparticle-Induced Pulmonary Inflammation and Fibrosis. hdac6介导的NLRP3炎性体活化参与纳米镍颗粒诱导的肺部炎症和纤维化

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-05-19 Epub Date: 2025-04-29 DOI: 10.1021/acs.chemrestox.4c00551

Yiqun Mo, Jisheng Nie, Yue Zhang, Yuanbao Zhang, Jiali Yuan, Qunwei Zhang

{"title":"HDAC6-Mediated NLRP3 Inflammasome Activation Is Involved in Nickel Nanoparticle-Induced Pulmonary Inflammation and Fibrosis.","authors":"Yiqun Mo, Jisheng Nie, Yue Zhang, Yuanbao Zhang, Jiali Yuan, Qunwei Zhang","doi":"10.1021/acs.chemrestox.4c00551","DOIUrl":"10.1021/acs.chemrestox.4c00551","url":null,"abstract":"Nickel nanoparticles (Nano-Ni) are increasingly utilized in industrial and biomedical applications, drawing growing attention to their potential adverse health effects. Our previous studies have demonstrated that Nano-Ni exposure induces severe, widespread, and persistent pulmonary inflammation and fibrosis. However, the underlying mechanisms are still unclear. The NLRP3 inflammasome is a vital component of the innate immune system and inflammatory signaling. In this study, we investigated whether Nano-Ni exposure activated the NLRP3 inflammasome and also examined its role in Nano-Ni-induced pulmonary inflammation and fibrosis. Our findings demonstrated that intratracheal instillation of wild-type mice (C57BL/6J) with 50 μg Nano-Ni per mouse resulted in NLRP3 inflammasome activation, IL-1β production, and extensive pulmonary inflammation and fibrosis. In contrast, Nano-Ni exposure induced only mild pulmonary inflammation and fibrosis in Nlrp3-/- mice (lacking functional NLRP3 inflammasome) or Il-1r1-/- mice (unresponsive to IL-1), highlighting the critical role of NLRP3 inflammasome activation in Nano-Ni-induced pulmonary damage. Further investigations using mouse alveolar macrophages (MH-S) revealed that Nano-Ni acts as a secondary activation signal for the NLRP3 inflammasome, triggering its activation in LPS-primed but not unprimed cells. Moreover, siRNA-mediated knockdown experiments demonstrated that this activation depended on Nano-Ni-induced upregulation of HDAC6. These findings suggest that Nano-Ni activates the NLRP3 inflammasome via HDAC6 as a second activation signal, leading to IL-1β production and subsequent pulmonary inflammation and fibrosis.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"877-891"},"PeriodicalIF":3.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955888","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}

引用次数: 0

Nuclear SUMOylation and Proteotoxic Stress Responses to Metals with Different Ligand Preferences. 核SUMOylation和对不同配体偏好金属的蛋白质毒性胁迫反应。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-05-19 Epub Date: 2025-04-17 DOI: 10.1021/acs.chemrestox.5c00040

Giorgiana Madalina Ursu, Casey Krawic, Anatoly Zhitkovich

{"title":"Nuclear SUMOylation and Proteotoxic Stress Responses to Metals with Different Ligand Preferences.","authors":"Giorgiana Madalina Ursu, Casey Krawic, Anatoly Zhitkovich","doi":"10.1021/acs.chemrestox.5c00040","DOIUrl":"10.1021/acs.chemrestox.5c00040","url":null,"abstract":"Proteins are vulnerable to damage by a broad range of electrophiles, and cells contain several proteotoxic stress-monitoring systems. Main transcriptional responses to protein damage are driven by cytosolic HSF1 and NRF2 using soft nucleophile Cys-SH as sensors of electrophiles. It is unclear what stress responses are activated by poorly SH-reactive hard electrophiles. We examined protein damage responses in normal human lung cells with equitoxic doses of three carcinogenic metals with different electrophilic softness: soft, cadmium(II), intermediate, cobalt(II), and hard, chromium(III) delivered into cells using chromium(VI)/chromate. Cd(II) strongly activated cytosolic NRF2 and HSF1, produced soluble and insoluble polyubiquitinated proteins in the cytosol, and moderately elevated ER and mitochondrial unfolded protein responses and nuclear polySUMOylation. Cr(III) primarily induced nuclear protein damage and polySUMOylation and was negative for the activation of all cytoplasmic stress responses. Co(II) triggered HSF1, NRF2, and other responses seen with both Cr(III) and Cd(II) except for cytosolic polyubiquitin aggregates. Physiological levels of the antioxidant ascorbate inhibited but did not eliminate NRF2 activation by Co(II) and enhanced polySUMOylation by Cr(VI/III). For all three metals, SUMOylated proteins accumulated in nuclear PML bodies, and their formation was suppressed by PML knockdown. Inhibition of SUMOylation decreased transcription and, even more severely, protein expression of NRF2 and HSF1 targets by Cd(II) and Co(II), revealing the importance of this nuclear response in the functionality of cytosolic stress-activated pathways. Our findings demonstrate that soft and hard metal electrophiles elicit distinct proteotoxic stress responses, with the notable inability of the hard electrophile Cr(III) to trigger cytosolic damage-monitoring systems.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"942-953"},"PeriodicalIF":3.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951557","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}

引用次数: 0

Formation of Carboxymethyl-Phosphotriester Adducts in DNA. DNA中羧基甲基-磷酸三酯加合物的形成。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-05-19 Epub Date: 2025-04-16 DOI: 10.1021/acs.chemrestox.4c00547

Garrit Clabaugh, Yinsheng Wang

引用次数: 0

Sex-Specific Formation of 1,2:3,4-Diepoxybutane-Derived Hemoglobin Adducts in 1,3-Butadiene-Exposed Workers. 1,3-丁二烯暴露工人中1,2:3,4-二氧基丁烷衍生的血红蛋白加合物的性别特异性形成。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-05-19 Epub Date: 2025-04-22 DOI: 10.1021/acs.chemrestox.4c00530

Nadia I Georgieva, Eric R Siegel, Radim J Šrám, Pamela M Vacek, Vernon E Walker, Richard J Albertini, James A Swenberg, Gunnar Boysen

{"title":"Sex-Specific Formation of 1,2:3,4-Diepoxybutane-Derived Hemoglobin Adducts in 1,3-Butadiene-Exposed Workers.","authors":"Nadia I Georgieva, Eric R Siegel, Radim J Šrám, Pamela M Vacek, Vernon E Walker, Richard J Albertini, James A Swenberg, Gunnar Boysen","doi":"10.1021/acs.chemrestox.4c00530","DOIUrl":"10.1021/acs.chemrestox.4c00530","url":null,"abstract":"1,3-Butadiene (BD) is an important industrial chemical that is classified as a human carcinogen. BD carcinogenicity has been attributed to several reactive epoxide metabolites, and the formation of highly mutagenic 1,2:3,4-diepoxybutane (DEB) has been suggested to drive mutagenesis and carcinogenesis at exposures experienced in humans. We report herein the formation of DEB-specific N,N-(2,3-dihydroxy-1,4-butadiyl)-valine (pyr-Val) in occupationally BD-exposed workers as an indirect biomarker of DEB-induced mutagenicity. pyr-Val was determined in BD-monomer and -polymer plant workers that had been previously analyzed for several other biomarkers of exposure and effect. In this second study, pyr-Val was detected in 92 out of 94 (98%) individuals, ranging from 0.001 to 0.697 pmol/g of globin. Surprisingly, pyr-Val was observed in 43 of 44 administrative control subjects not known to be exposed to BD, suggesting environmental sources of BD. The mean ± SD amounts of pyr-Val were 0.049 ± 0.044, 0.029 ± 0.032, 0.030 ± 0.035, and 0.074 ± 0.093 pmol/g globin in female control, female exposed, male control, and male exposed, respectively, clearly demonstrating the formation of DEB in environmentally and occupationally exposed BD workers. The amounts of pyr-Val found in this study suggest that humans are much less efficient in the formation of DEB than mice or rats at similar BD exposures. The formation of pyr-Val was lower than that associated with increased mutagenesis in rodents.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"858-864"},"PeriodicalIF":3.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955635","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}

引用次数: 0

DNA-Protein Cross-Links Derived from Abasic DNA Lesions: Recent Progress and Future Directions. 从基本DNA损伤中衍生的DNA-蛋白质交联：最新进展和未来方向。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-05-19 DOI: 10.1021/acs.chemrestox.5c00125

Cameron Bryan, Joel Cepeda, Bingru Li, Kun Yang

引用次数: 0

BoostDILI: Extreme Gradient Boost-Powered Drug-Induced Liver Injury Prediction and Structural Alerts Generation. BoostDILI：极端梯度boost驱动的药物性肝损伤预测和结构警报生成。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-05-19 Epub Date: 2025-04-16 DOI: 10.1021/acs.chemrestox.4c00532

Hillul Chutia, Gori Sankar Borah, Hridoy Jyoti Mahanta, Selvaraman Nagamani

{"title":"BoostDILI: Extreme Gradient Boost-Powered Drug-Induced Liver Injury Prediction and Structural Alerts Generation.","authors":"Hillul Chutia, Gori Sankar Borah, Hridoy Jyoti Mahanta, Selvaraman Nagamani","doi":"10.1021/acs.chemrestox.4c00532","DOIUrl":"10.1021/acs.chemrestox.4c00532","url":null,"abstract":"Over the past 60 years, drug-induced liver injury (DILI) has played a key role in the withdrawal of marketed drugs due to safety concerns. Early prediction of DILI is crucial for developing safer pharmaceuticals, yet current in vitro and in vivo testing methods are complex and cumbersome. In this study, we developed an extreme gradient boosting (XGB)-powered machine learning (ML) model for DILI prediction. Comparing various DILI prediction models is challenging because they rely on different public data sets. We comprehensively evaluated the proposed BoostDILI model to address two crucial questions: 1. Can insights derived from public data sets help in DILI prediction for Food and Drug Administration (FDA) approved drugs? 2. Can we generate structural alerts to improve the model's explainability? To address the first question, we developed a DILI prediction model using four publicly available data sets. This effort led to the creation of the BoostDILI model, which achieved a 5-fold CV accuracy of 0.70. A sequential feature selection method was employed to identify relevant descriptors. This model integrates feature-level representations derived from RDKit (12 features) and Mordred (23 features) features. Bayesian statistics was applied to identify high-performance substructures iteratively, and a structural alerts model was developed to address the second question. The developed model was further validated with two FDA-approved drug data sets, DILIst and DILIRank. The BoostDILI model offers a trustable solution for evaluating the DILI risk in preclinical research. The structural alerts help in identifying the substructures that may be responsible for DILI. The data set and the source code are available at https://github.com/Naga270588/BoostDILI.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"865-876"},"PeriodicalIF":3.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951237","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}

引用次数: 0

Conditional Binding of Arsenic Trioxide (ATO) to Cysteine-Rich Zinc Finger Motifs within RBCC Domain of PML Protein. 三氧化二砷（ATO）与PML蛋白RBCC结构域富含半胱氨酸的锌指基元的条件结合。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-05-19 Epub Date: 2025-04-12 DOI: 10.1021/acs.chemrestox.5c00087

Pei Han Yu, Yu-Ki Tanaka, Yang Gao, Gaowa Wureng, Chen Ying Zhu, Yuan Yuan Kang, Chang Yang, Xin Wang, Yasumitsu Ogra, Hua Naranmandura

引用次数: 0

Bioactivation of the β-Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor Atabecestat Leads to Protein Adduct Formation on Glutathione S-Transferase Pi. β-淀粉样前体蛋白切割酶1抑制剂Atabecestat的生物活化导致谷胱甘肽s -转移酶Pi上蛋白质加合物的形成。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-05-19 Epub Date: 2025-05-06 DOI: 10.1021/acs.chemrestox.5c00070

Megan Ford, Paul J Thomson, Adam Lister, Jan Snoeys, Laurent Leclercq, Filip Cuyckens, Dean J Naisbitt, Xiaoli Meng

引用次数: 0

Consensus Modeling Strategies for Predicting Transthyretin Binding Affinity from Tox24 Challenge Data. 基于Tox24挑战数据预测转甲状腺素结合亲和力的共识建模策略。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-05-15 DOI: 10.1021/acs.chemrestox.5c00018

Thalita Cirino, Luis Pinto, Mateusz Iwan, Alexis Dougha, Bono Lučić, Antonija Kraljević, Zaven Navoyan, Ani Tevosyan, Hrach Yeghiazaryan, Lusine Khondkaryan, Narek Abelyan, Vahe Atoyan, Nelly Babayan, Yuma Iwashita, Kyosuke Kimura, Tomoya Komasaka, Koki Shishido, Taichi Nakamura, Mizuho Asada, Sankalp Jain, Alexey V Zakharov, Haobo Wang, Wenjia Liu, Vladimir Chupakhin, Yoshihiro Uesawa

{"title":"Consensus Modeling Strategies for Predicting Transthyretin Binding Affinity from Tox24 Challenge Data.","authors":"Thalita Cirino, Luis Pinto, Mateusz Iwan, Alexis Dougha, Bono Lučić, Antonija Kraljević, Zaven Navoyan, Ani Tevosyan, Hrach Yeghiazaryan, Lusine Khondkaryan, Narek Abelyan, Vahe Atoyan, Nelly Babayan, Yuma Iwashita, Kyosuke Kimura, Tomoya Komasaka, Koki Shishido, Taichi Nakamura, Mizuho Asada, Sankalp Jain, Alexey V Zakharov, Haobo Wang, Wenjia Liu, Vladimir Chupakhin, Yoshihiro Uesawa","doi":"10.1021/acs.chemrestox.5c00018","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00018","url":null,"abstract":"Transthyretin (TTR) is a key transporter of the thyroid hormone thyroxine, and chemicals that bind to TTR, displacing the hormone, can disrupt the endocrine system, even at low concentrations. This study evaluates computational modeling strategies developed during the Tox24 Challenge, using a data set of 1512 compounds tested for TTR binding affinity. Individual models from nine top-performing teams were analyzed for performance and uncertainty using regression metrics and applicability domains (AD). Consensus models were developed by averaging predictions across these models, with and without consideration of their ADs. While applying AD constraints in individual models generally improved external prediction accuracy (at the expense of reduced chemical space coverage), it had limited additional benefit for consensus models. Results showed that consensus models outperformed individual models, achieving a root-mean-square error (RMSE) of 19.8% on the test set, compared to an average RMSE of 20.9% for the nine individual models. Outliers consistently identified in several of these models indicate potential experimental artifacts and/or activity cliffs, requiring further investigation. Substructure importance analysis revealed that models prioritized different chemical features, and consensus averaging harmonized these divergent perspectives. These findings highlight the value of consensus modeling in improving predictive performance and addressing model limitations. Future work should focus on expanding chemical space coverage and refining experimental data sets to support public health protection.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074917","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}

引用次数: 0