Chemical Research in Toxicology最新文献

{"title":"","authors":"Max J. Carlsson, Natalie Herzog, Christina Felske, Gabriel Ackermann, Alexander Regier, Simon Wittmann, Raúl Fernández Cereijo, Shana J. Sturla, Jan-Heiner Küpper and Jörg Fahrer*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00133","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422747","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":"Alexey A. Tinkov, Anatoly V. Skalny, Xiong Guo, Tatiana V. Korobeinikova, Yujie Ning, Joao B. T. Rocha, Feng Zhang and Michael Aschner*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00095","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422307","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":"Anne Zwartsen*, Marco Zeilmaker, Waldo J. de Boer, Emiel Rorije and Hilko van der Voet, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.4c00287","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422306","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":"Xiang-Rong Jiang,  and , Bao Ting Zhu*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00058","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422742","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":"Short-Term and Long-Term Effects of Electronic Cigarettes on Mouse Lungs Following Nose-Only Exposures.","authors":"Indu Sinha, Zachary Bitzer, Stephanie Barnett, Lisa Reinhart, Todd M Umstead, Zissis C Chroneos, Matthew Lanza, Dongxiao Sun, Junjia Zhu, John P Richie, Raghu Sinha","doi":"10.1021/acs.chemrestox.4c00525","DOIUrl":"10.1021/acs.chemrestox.4c00525","url":null,"abstract":"<p><p>Health effects of electronic cigarettes (ECs) remain unknown, despite their popularity. We have determined that ECs produce highly reactive free radicals that could potentially cause damage in exposed tissues, mainly lungs. Goal for this study was to investigate the short- and long-term effects of ECs in mouse lungs. We focused on evaluating lung functions, oxidative stress related markers, and lung injury following nose-only exposures in male and female mice after 4- and 12-week periods. The EC exposure was modeled <i>in vivo</i> using nose-only exposures to C57BL/6 mice. For all studies, E-liquid (60:40; PG:VG) aerosols were compared to sham (compressed air) and to very low non-nicotine cigarette smoke (CS) controls in both sexes. Oxidative stress biomarkers (GSH, 8-Isoprostane, REDD1, and pGSK3β) and their selected downstream (RPS6) as well as upstream (AKT) target proteins in addition to pH2AX were measured by Western blot analysis. Lung function in mice was assessed by flexiVent and the injury scores were calculated following lung histology. Changes in cytology were also observed in cytospins from bronchoalveolar lavage (BALF). The lung injury (LI) score following 12-week exposures was significantly higher with EC and CS in female mice. Higher cell counts in BALF were mainly observed in CS exposed males and females at 4 and 12 weeks. 8-Isoprostane levels were significantly higher in EC and CS exposed males at 12 weeks. pGSK3β/GSK3β was low in males and higher in female mice at 4 weeks, and this difference was more pronounced at 12 weeks in CS exposed mice. Some mice exposed to EC and CS also showed DNA damage, as measured by pH2AX/H2AX expression. Based on the LI score, ECs were placed in between compressed air and CS. Our results showed the differentially expressed inflammation and oxidative stress/damage-related pathways from <i>in vivo</i> exposures to EC aerosols vs CS that could be an effective strategy for identifying EC relevant biomarkers of exposure and potential harm.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1019-1036"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12175837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118379","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":"Thalita Cirino*,&nbsp;Luis Pinto,&nbsp;Mateusz Iwan,&nbsp;Alexis Dougha,&nbsp;Bono Lučić,&nbsp;Antonija Kraljević,&nbsp;Zaven Navoyan,&nbsp;Ani Tevosyan,&nbsp;Hrach Yeghiazaryan,&nbsp;Lusine Khondkaryan,&nbsp;Narek Abelyan,&nbsp;Vahe Atoyan,&nbsp;Nelly Babayan,&nbsp;Yuma Iwashita,&nbsp;Kyosuke Kimura,&nbsp;Tomoya Komasaka,&nbsp;Koki Shishido,&nbsp;Taichi Nakamura,&nbsp;Mizuho Asada,&nbsp;Sankalp Jain,&nbsp;Alexey V. Zakharov,&nbsp;Haobo Wang,&nbsp;Wenjia Liu,&nbsp;Vladimir Chupakhin and Yoshihiro Uesawa,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422304","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":"The DNA Repair Protein MGMT Protects against the Genotoxicity of <i>N</i>-Nitrosodimethylamine, but Not <i>N</i>-Nitrosodiethanolamine and <i>N</i>-Nitrosomethylaniline, in Human HepG2 Liver Cells with CYP2E1 Expression.","authors":"Max J Carlsson, Natalie Herzog, Christina Felske, Gabriel Ackermann, Alexander Regier, Simon Wittmann, Raúl Fernández Cereijo, Shana J Sturla, Jan-Heiner Küpper, Jörg Fahrer","doi":"10.1021/acs.chemrestox.5c00133","DOIUrl":"10.1021/acs.chemrestox.5c00133","url":null,"abstract":"<p><p><i>N</i>-nitrosamines are genotoxic contaminants that occur in the diet, consumer products, and the environment. More recently, <i>N</i>-nitrosamines were also detected as drug impurities. After uptake, <i>N</i>-nitrosamines undergo metabolic activation by cytochrome P450 monooxygenases (CYPs), resulting in DNA damage and tumor formation. In this study, the genotoxicity and cytotoxicity of three <i>N</i>-nitrosamines with structurally distinct substituents, <i>N</i>-nitrosodimethylamine (NDMA), <i>N</i>-nitrosodiethanolamine (NDELA) and <i>N</i>-nitrosomethylaniline (NMA), were analyzed in human HepG2 liver cell models proficient or deficient in CYP2E1 biotransformation. Furthermore, the impact of the DNA repair protein <i>O</i>⁶-methylguanine-DNA methyltransferase (MGMT) was investigated. The novel genetically engineered HepG2-CYP2E1 cell line strongly expressed CYP2E1, which was not detectable in wildtype (WT) HepG2 cells. We then confirmed that the CYP2E1 substrate NDMA caused <i>O</i>⁶-methyldesoxyguanosine adducts and DNA strand breaks in a CYP2E1-dependent manner, leading to cytotoxicity. By the same approach, we demonstrated that NDELA induced DNA strand breaks in HepG2-CYP2E1 cells, whereas no effect was observed for NMA. However, NMA was revealed to cause DNA cross-links. Furthermore, both NDELA and NMA were cytotoxic in HepG2-CYP2E1 cells, but not in WT cells. Subsequently, the pharmacological MGMT inhibitor <i>O</i>⁶-benzylguanine was used to deplete MGMT in both HepG2 cell models. MGMT inhibition clearly increased DNA strand break levels due to NDMA exposure, whereas DNA strand break formation by NDELA and NMA were not affected by inhibiting MGMT. In line with these findings, the clastogenic effects of NDMA were potentiated in the absence of MGMT. In contrast to that, NDELA- and NMA-induced clastogenicity was not influenced by MGMT inhibition. Taken together, our study revealed that all three structurally diverse <i>N</i>-nitrosamines are cytotoxic and clastogenic in a CYP2E1-dependent manner, while only NDMA and NDELA caused DNA strand breaks. Furthermore, we demonstrated for the first time that DNA repair by MGMT does not confer protection against NDELA and NMA-triggered DNA strand break induction and clastogenicity.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1134-1146"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100968","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":"DNA-Protein Cross-Links Derived from Abasic DNA Lesions: Recent Progress and Future Directions.","authors":"Cameron Bryan, Joel Cepeda, Bingru Li, Kun Yang","doi":"10.1021/acs.chemrestox.5c00125","DOIUrl":"10.1021/acs.chemrestox.5c00125","url":null,"abstract":"<p><p>Covalent DNA-protein cross-links (DPCs), if not resolved, can block DNA replication and transcription, resulting in genome instability. Compared to other types of DNA damage, how DPCs are formed and repaired is less understood. This review focuses on recent findings concerning DPCs derived from two types of abasic DNA lesions, apurinic/apyrimidinic sites and 3'-phospho-α,β-unsaturated aldehydes. It summarizes the newly reported DPCs and their identification by liquid chromatography tandem mass spectrometry. It also reviews the approaches for synthesizing stable and site-specific DPCs, and their applications for discovering the corresponding repair mechanisms. Finally, it discusses the future directions to better understand the mechanistic formation and repair of those DPCs.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"997-1005"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092079","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":"Uncertainties in the Extrapolation of In Vitro Data in Human Risk Assessment: A Case Study of qIVIVE for Imazalil Using the Monte Carlo Risk Assessment Platform.","authors":"Anne Zwartsen, Marco Zeilmaker, Waldo J de Boer, Emiel Rorije, Hilko van der Voet","doi":"10.1021/acs.chemrestox.4c00287","DOIUrl":"10.1021/acs.chemrestox.4c00287","url":null,"abstract":"<p><p>New approach methodologies (NAMs) are promising for refining, reducing, and replacing animal experiments for hazard characterization. Quantitative in vitro-in vivo extrapolation (qIVIVE) is essential to extrapolate an in vitro-based point of departure to an in vitro-based human equivalent dose and subsequently to an in vitro-based health-based guidance or threshold value. The use of NAMs for hazard characterization leads to the need for various new extrapolations and linked uncertainties that preferably are quantified. Currently, qIVIVE is often performed without addressing these uncertainties. A clear description and, if possible, quantification of extrapolations and uncertainties when using NAMs for risk assessment will aid the regulatory implementation of NAMs for risk assessment. A case study of a qIVIVE-based assessment on the risk of liver steatosis from dietary exposure to imazalil is reported, using a human cell line in vitro test method as an example of a NAM to replace animal experiments. We consider the uncertainties related to the extrapolations from in vitro to in vivo effects, from in vitro nominal concentrations to in vitro intracellular concentrations, from in vitro concentrations to external doses (reverse dosimetry), from in vitro exposure durations to in vivo exposure situations, and from the average human to a sensitive individual. The case study addresses these uncertainties in a mainly quantitative approach, using available data and the Monte Carlo Risk Assessment platform.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1006-1018"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12175163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074919","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":"Serge Maeder*,&nbsp; and ,&nbsp;Cyril Jeannet,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.4c00544","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422312","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}