Chemical Research in Toxicology最新文献

{"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":"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":"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":"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":"","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}

{"title":"The Role of Endoplasmic Reticulum Stress in Fine Particulate Matter-Induced Phenotype Switching of Vascular Smooth Muscle Cells.","authors":"Linyuan Huang, Ruiyang Ding, Kanglin Yan, Junchao Duan, Zhiwei Sun","doi":"10.1021/acs.chemrestox.5c00056","DOIUrl":"10.1021/acs.chemrestox.5c00056","url":null,"abstract":"<p><p>As a major component of air pollution, fine particulate matter (PM_2.5) was the second global leading cause of death in 2021. Evidence from humans suggested that PM_2.5 was associated with an enhanced coronary calcium score (CAC), and animal studies indicated that PM_2.5 induced vascular calcification, while mechanisms remained largely unknown. In this study, PM_2.5 enhanced the proliferative potential and migration capacity of human aortic vascular smooth muscle cells (VSMCs), as well as disturbing intracellular Ca²⁺ homeostasis. Subsequent transcriptomic analysis implicated that PM_2.5 could influence genes involved in the IRE1α-mediated unfolded protein responses and reduce the expression of DNAJB9, a co-chaperone that formed a complex with BiP/IRE1α to inhibit the activation of endoplasmic reticulum (ER) stress. Further mechanistic investigations indicated that PM_2.5 activated the IRE1α/XBP1 signaling pathway and enhanced the expression of osteogenic phenotype-related hallmarks. In contrast, pretreatment with an ER stress antagonist (4-PBA) could suppress PM_2.5-associated calcium dysregulation and osteogenic transformation via alleviation of ER stress. Taken together, this study revealed the role of ER stress in the phenotype switching of VSMCs induced by PM_2.5, highlighted the regulation of DNAJB9, provided insights into the mechanisms of air pollution-related vascular calcification, and pointed out molecules for future investigations.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1072-1081"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074918","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":"Cameron Bryan,&nbsp;Joel Cepeda,&nbsp;Bingru Li and Kun Yang*,&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.5c00125","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422310","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 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/txv038i006_1947264","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422744","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":"Facile Biological Oxidation of Dopamine to 6-Hydroxydopamine p-Quinone in a Sequential Two-Step Process: Implications for Parkinson’s Disease","authors":"Xiang-Rong Jiang,&nbsp; and ,&nbsp;Bao Ting Zhu*,&nbsp;","doi":"10.1021/acs.chemrestox.5c0005810.1021/acs.chemrestox.5c00058","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00058https://doi.org/10.1021/acs.chemrestox.5c00058","url":null,"abstract":"<p >6-Hydroxydopamine (6-OHDA), a hydroxyl-derivative of the endogenous neurotransmitter dopamine, can selectively induce Parkinsonian symptoms in animal models. At present, most researchers consider 6-OHDA a man-made neurotoxicant, due to the lack of strong evidence for its presence and/or formation in biological systems. The present study aims to determine whether 6-OHDA can be formed under physiologically relevant conditions. Here, we report in the Fenton reaction system (containing 15 μM Fe²⁺, 142 μM ascorbic acid and 80 μM EDTA in 50 mM phosphate buffer, pH 7.4), dopamine can undergo facile oxidation to 6-OHDA <i>p</i>-quinone (a stable, oxidized form of 6-OHDA) in a sequential two-step process: the first step involves dopamine oxidation to its <i>o</i>-quinone (DAQ), and this process is facilitated by oxidants like transition metal ions Fe^2+/3+ and Mn^2+/3+; and the second step involves the further oxidization of DAQ to 6-OHDA <i>p</i>-quinone by hydroxyl radical or hydrogen peroxide. The chemical mechanism by which H₂O₂ oxidizes DAQ to 6-OHDA <i>p</i>-quinone likely results from the attack of H₂O₂-derived ⁻OOH at the C–6 position of DAQ. We also demonstrate that while catalase abolishes 6-OHDA <i>p</i>-quinone formation by removing hydrogen peroxide or hydroxyl radical, glutathione and cysteine provide effective protection by forming conjugates with DAQ and 6-OHDA <i>p</i>-quinone. The results of this study demonstrate that 6-OHDA can be readily formed from dopamine under physiologically relevant conditions, and thus provide important tangible support for the long-held speculation that 6-OHDA is an intrinsic etiological factor in Parkinson’s disease.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1082–1090 1082–1090"},"PeriodicalIF":3.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290416","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":"A Review of the Most Frequent Compounds, Metals, and Compound and Metal Mixtures Found at U.S. Superfund Sites and Their Carcinogenic Potential","authors":"June K. Dunnick*,&nbsp;Charles P. Schmitt and Darlene Dixon*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0050610.1021/acs.chemrestox.4c00506","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00506https://doi.org/10.1021/acs.chemrestox.4c00506","url":null,"abstract":"<p >The United States Environmental Protection Agency’s (U.S. EPA) National Priorities List (NPL) is a list of sites in the U.S. and its territories of national priority that are sources of known hazardous contaminants, pollutants, or substances that pose a significant risk to human health and the environment. These sites are commonly termed U.S. Superfund sites and contain many harmful compounds and metals. This paper reviews the carcinogenic potential of the most frequent compounds, metals, and mixtures at U.S. Superfund sites. Of the most frequent compounds and metals identified at U.S. Superfund sites, some are classified as human carcinogens and some as probable/possible human carcinogens. The most frequent mixtures of three individual carcinogenic compound or metals at U.S. Superfund sites include: nickel, arsenic, and cadmium (496 sites); benzene, arsenic, trichloroethene (451 sites); benzene, vinyl chloride, trichloroethene (420 sites); and arsenic, vinyl chloride, trichloroethene (386 sites). Many compounds or metals that are frequently found at U.S. Superfund Sites have not been evaluated for carcinogenic activity because of limited data including copper, xylene, mercury, barium, and iron. Factors in human cancer development include both environmental factors and genetic disease susceptibility backgrounds. Thus, future mixture toxicology studies should be conducted with a design that looks at mixture toxicology in a variety of models with varied genetic backgrounds.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"963–974 963–974"},"PeriodicalIF":3.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00506","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290402","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}