Chemical Research in Toxicology最新文献

DICTrank Is a Reliable Dataset for Cardiotoxicity Prediction Using Machine Learning Methods.

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-03-27 DOI: 10.1021/acs.chemrestox.4c00428

Yanyan Qu, Ting Li, Zhichao Liu, Weida Tong, Dongying Li

{"title":"DICTrank Is a Reliable Dataset for Cardiotoxicity Prediction Using Machine Learning Methods.","authors":"Yanyan Qu, Ting Li, Zhichao Liu, Weida Tong, Dongying Li","doi":"10.1021/acs.chemrestox.4c00428","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00428","url":null,"abstract":"Drug-induced cardiotoxicity (DICT) is a significant challenge in drug development and public health. DICT can arise from various mechanisms; New Approach Methods (NAMs), including quantitative structure-activity relationships (QSARs), have been extensively developed to predict DICT based solely on individual mechanisms (e.g., hERG-related cardiotoxicity) due to the availability of datasets limited to specific mechanisms. While these efforts have significantly contributed to our understanding of cardiotoxicity, DICT assessment remains challenging, suggesting that approaches focusing on isolated mechanisms may not provide a comprehensive evaluation. To address this, we previously developed DICTrank, the largest dataset for assessing overall cardiotoxicity liability in humans based on FDA drug labels. In this study, we evaluated the utility of DICTrank for QSAR modeling using five machine learning methods─Logistic Regression (LR), K-Nearest Neighbors, Support Vector Machines, Random Forest (RF), and extreme gradient boosting (XGBoost)─which vary in algorithmic complexity and explainability. To reflect real-world scenarios, models were trained on drugs approved before and within 2005 to predict the DICT risk of those approved thereafter. While we observed no clear association between prediction performance and model complexity, LR and XGBoost achieved the best results with DICTrank. Additionally, our significant-feature analyses with RF and XGBoost models provided novel insights into DICT mechanisms, revealing that drug properties associated with descriptors such as \"structural and topological\", \"polarizability\", and \"electronegativity\" contributed significantly to DICT. Moreover, we found that model performance varied by therapeutic category, suggesting the need to tailor models accordingly. In conclusion, our study demonstrated the robustness and reliability of DICTrank for cardiotoxicity prediction in humans using machine learning methods.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727025","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

Diallyl Disulfide Reduces Ethyl Carbamate-Induced Cytotoxicity and Apoptosis in Intestinal and Hepatic Cells.

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-03-27 DOI: 10.1021/acs.chemrestox.4c00439

Caroline Andolfato Sanchez, Estefani Maria Treviso, Cecília Cristina de Souza Rocha, Lusânia Maria Greggi Antunes

{"title":"Diallyl Disulfide Reduces Ethyl Carbamate-Induced Cytotoxicity and Apoptosis in Intestinal and Hepatic Cells.","authors":"Caroline Andolfato Sanchez, Estefani Maria Treviso, Cecília Cristina de Souza Rocha, Lusânia Maria Greggi Antunes","doi":"10.1021/acs.chemrestox.4c00439","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00439","url":null,"abstract":"Epidemiological studies indicate that lifestyle and dietary habits are associated with an increasing cancer incidence. Consuming fermented foods and alcoholic beverages and smoking can expose humans to ethyl carbamate (EC), a probable human carcinogen classified as group 2A by the International Agency for Research on Cancer (IARC). Increasing the intake of bioactive compounds can reduce EC-induced toxicity. Diallyl disulfide (DADS), found in garlic, may protect against damage induced by chemical agents and natural compounds. Here, the potential protective effect of DADS against EC was investigated by evaluating EC-induced cytotoxicity, DNA damage, apoptosis, and reactive oxygen species production in colorectal adenocarcinoma (Caco-2) and hepatocarcinoma (HepG2) cells. To this end, resazurin, comet, and annexin V-FITC staining assays and CM-H2DCFDA markers were used to evaluate the effect on Caco-2 and HepG2 cells of protocols combining DADS (10-120 μM) and EC (80 mM). The protocols were as follows: (i) cells pretreated with DADS for 2 h and exposed to EC for 24 h; (ii) cells pretreated with DADS for 24 h and exposed to EC for 24 h; (iii) cells simultaneously exposed to DADS and EC for 24 h; (iv) cells exposed to EC for 24 h and treated with DADS for 2 h. EC induced cytotoxicity and apoptosis in Caco-2 and HepG2 cells and oxidative damage in Caco-2 cells. Combined exposure to DADS and EC for 24 h decreased EC-mediated cytotoxicity and apoptosis in both Caco-2 and HepG2 cells. These findings encourage further studies on the mechanisms of action of the combined DADS and EC.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717600","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

RNA Methylation and Transcriptome Analysis Reveal Key Regulatory Pathways Related to Cadmium-Induced Liver Damage.

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-03-26 DOI: 10.1021/acs.chemrestox.4c00539

Hao Huang, Guoliang Li, Sihui Guo, Kaile Li, Wei Li, Qinwen Zhou, Zhini He, Xingfen Yang, Lili Liu, Qinzhi Wei

{"title":"RNA Methylation and Transcriptome Analysis Reveal Key Regulatory Pathways Related to Cadmium-Induced Liver Damage.","authors":"Hao Huang, Guoliang Li, Sihui Guo, Kaile Li, Wei Li, Qinwen Zhou, Zhini He, Xingfen Yang, Lili Liu, Qinzhi Wei","doi":"10.1021/acs.chemrestox.4c00539","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00539","url":null,"abstract":"Cadmium (Cd) is a prevalent environmental and industrial contaminant that causes significant damage to liver function. However, the role of m6A methylation─a critical epigenetic modification─in Cd-induced liver injury remains poorly understood. This study aimed to investigate the effects of m6A methylation in Cd-induced liver damage. A mouse model of Cd-induced liver injury was established, and exposure to CdCl2 (20 mg/kg) for 90 days resulted in reduced m6A methylation levels. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-Seq), we characterized the m6A methylation profiles in both control and Cd-exposed groups. A total of 8355 unique m6A peaks and 1,101 unique m6A-modified genes were identified. Among these, 673 genes exhibited differential m6A methylated modifications, including 463 hyper-methylated and 210 hypo-methylated genes. Conjoint analysis of MeRIP-seq and RNA-Seq data unveiled genes that showed both differential methylation and expression. These genes were significantly enriched in the AGE-RAGE and PI3K-Akt signaling pathway. Through bioinformatics screening, five key genes (Il-1β, Ccl2, Tlr2, Itgax, and Ccr2) were identified, and expression validation indicated that Itgax and Ccr2 may play pivotal roles in Cd-induced liver injury. Notably, elevated expression of methyltransferase-like 14 (METTL14) was observed in both in vivo and in vitro models. Inhibition of Mettl14 can regulate Cd-induced liver inflammation through m6A-dependent regulation of Ccr2 expression. Collectively, our findings highlight the crucial role of Mettl14 and Ccr2 in Cd-induced liver injury, providing novel insights into the epigenetic mechanisms underlying liver diseases and potential biomarkers for diagnosis and therapy.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707734","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

Deconjugation of Polychlorinated Biphenyl Sulfates to Hydroxylated PCBs by Anaerobically Cultured Mouse and Human Gut Microbiota.

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-03-25 DOI: 10.1021/acs.chemrestox.5c00016

Xueshu Li, Joe J Lim, Cayen Rong, Hans-Joachim Lehmler, Julia Yue Cui

引用次数: 0

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 : 2025-03-20 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":"https://doi.org/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":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-20","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

Nanoparticle-Mediated Embryotoxicity: Mechanisms of Chemical Toxicity and Implications for Biological Development.

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-03-19 DOI: 10.1021/acs.chemrestox.4c00472

Biswajeet Acharya, Amulyaratna Behera, Srikanta Moharana, Bhupendra G Prajapati, Suchismeeta Behera

{"title":"Nanoparticle-Mediated Embryotoxicity: Mechanisms of Chemical Toxicity and Implications for Biological Development.","authors":"Biswajeet Acharya, Amulyaratna Behera, Srikanta Moharana, Bhupendra G Prajapati, Suchismeeta Behera","doi":"10.1021/acs.chemrestox.4c00472","DOIUrl":"10.1021/acs.chemrestox.4c00472","url":null,"abstract":"Nanoparticles, defined by their nanoscale dimensions and unique physicochemical properties, are widely utilized in healthcare, electronics, environmental sciences, and consumer products. However, increasing evidence of their potential embryotoxic effects during pregnancy underscores the need for a molecular-level understanding of their interactions during embryonic development. Nanoparticles such as titanium dioxide, silver, cerium oxide, copper oxide, and quantum dots can cross the placental barrier and interfere with crucial developmental processes. At the molecular level, they disrupt signaling pathways like Wnt and Hedgehog, induce oxidative stress and inflammation, and cause genotoxic effects, all critical during sensitive phases, such as organogenesis. Furthermore, these nanoparticles interact directly with cellular components, including DNA, proteins, and lipids, impairing cellular function and viability. Innovative strategies to mitigate nanoparticle toxicity, such as surface modifications and incorporation of biocompatible coatings, are discussed as potential solutions to reduce adverse molecular interactions. Various laboratory animal models used to investigate nanoparticle-induced embryotoxicity are evaluated for their efficacy and limitations, providing insights into their applicability for understanding these effects. This Account examines the molecular mechanisms by which nanoparticles compromise embryonic development and emphasizes the importance of designing safer nanoparticles to minimize maternal-fetal exposure risks, particularly in biomedical applications.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655467","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

Systematic Investigation of CYP3A4 Using Side-by-Side Comparisons of Apo, Active Site, and Allosteric-Bound States.

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-03-19 DOI: 10.1021/acs.chemrestox.4c00387

Pranchal Shrivastava, Somnath Mondal, Shivani Thakur, Anu Manhas, Rukmankesh Mehra

{"title":"Systematic Investigation of CYP3A4 Using Side-by-Side Comparisons of Apo, Active Site, and Allosteric-Bound States.","authors":"Pranchal Shrivastava, Somnath Mondal, Shivani Thakur, Anu Manhas, Rukmankesh Mehra","doi":"10.1021/acs.chemrestox.4c00387","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00387","url":null,"abstract":"Cytochrome P450 (CYP) 3A4 (CYP3A4) is a complex enzyme that metabolizes diverse substrates. It contains a large binding site accommodating diverse ligands, binding to active or allosteric sites. CYP3A4 does not always follow Michaelis-Menten kinetics. While Km reflects substrate affinity, it does not necessarily determine the enzyme's activity, though it is often considered indicative of substrate binding characteristics. The mechanism may be highly sophisticated and driven by multiple factors. This suggests that the ligand binding affinity alone may not explain the differential behavior of the enzyme conformational stability. Here, we analyzed sequence conserveness of 57 CYPs, followed by a detailed molecular dynamics simulation study (9 μs) on CYP3A4. We studied three CYP3A4 enzyme states (apo-state, active-site, and allosteric-site ligand-bound states) collected from the same experimental setup to reduce the systematic error. We found that the enzyme conformational stability followed a consistent trend of allosteric > active > apo states, which was inconsistent with the enzyme-ligand (active/allosteric) binding affinity and the ligand conformational stability. However, the heme group showed a significant protein affinity and stability pattern directly related to the enzyme stability, suggesting that the active/allosteric binding may work by influencing the heme-CYP3A4 binding affinity, and the allosteric ligand appeared to form the most stable enzyme state of the three studied states.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655468","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

Dr. Nathaniel Snyder, 2024 Young Investigator Award Recipient, American Chemical Society Division of Chemical Toxicology.

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-03-17 Epub Date: 2025-02-12 DOI: 10.1021/acs.chemrestox.4c00474

Don Pivithuru Liyanarachchi

引用次数: 0

Correction to "Oxymatrine Inhibits Liver Cancer Progression by Regulating SIRT1/YY1/GPX4 Axis-Mediated Ferroptosis".

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-03-17 Epub Date: 2025-03-05 DOI: 10.1021/acs.chemrestox.5c00086

Jing Hu, Fuyi Zhang, Xiaoshan Qin, Xinlei Nong, Xiaoyan Shi, Xihan Zhou, Yueqiu Qin

引用次数: 0

Electronic Cigarette-Derived Metals: Exposure and Health Risks in Vapers.

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-03-17 DOI: 10.1021/acs.chemrestox.4c00520

Ahmad Besaratinia

{"title":"Electronic Cigarette-Derived Metals: Exposure and Health Risks in Vapers.","authors":"Ahmad Besaratinia","doi":"10.1021/acs.chemrestox.4c00520","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00520","url":null,"abstract":"Despite the popularity of electronic cigarettes (e-cigs) among adolescent and youth never-smokers and adult smokers seeking a less harmful substitute for tobacco cigarettes, the long-term health impact of vaping is largely unknown. Biochemical, molecular, and toxicological analyses of biospecimens from e-cig users as well as assays in relevant in vitro models and in silico studies can identify chemical constituents of e-cig emissions that may contribute to the disease-causing potential of vaping. E-cig aerosol contains a wide range of toxic and carcinogenic compounds, of which metals are of particular concern. This is due to the known or suspected role of various metals in the pathogenesis of numerous diseases. Many metals and metalloids (herein referred to as \"metals\") have been detected in e-cig liquid (e-liquid) and aerosol and/or in cells, tissues, biofluids, or other specimens from e-cig users. Metals can contaminate the ingredients of e-liquid or corrode from the internal components of the e-cig device. Metals may also be directly aerosolized from the surface of the heating element or other parts of the device. Inhalation of e-cig metal emissions in habitual vapers and nonusers through secondary exposure may increase the body burden of toxic and carcinogenic chemicals. This review summarizes the state of research on e-cig-derived metals and their contributions to the estimated health risks of vaping. Highlighting the chemical composition of e-cig liquid and aerosol, it focuses on the metal contents of the inhaled aerosol and the health risks associated with this exposure. Emphasis is placed on adolescents and youth who are vulnerable populations and bear a disproportionate burden of risk and harm from tobacco products. The gaps in knowledge, methodological challenges, and opportunities ahead are discussed. The importance of translating research findings into actionable information that can be used for the regulation of the manufacturing of tobacco products is underscored.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646498","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