Chemical Research in Toxicology最新文献

{"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":"Halogen Atoms in Bisphenol A Derivatives Enhance the Inhibitory Potency against Human and Rat Placental 3β-Hydroxysteroid Dehydrogenases","authors":"Shaowei Wang,&nbsp;Xianghong Fu,&nbsp;Xiya Ren,&nbsp;Peng Yi,&nbsp;Zhigang Wu*,&nbsp;Ren-shan Ge* and Bo Peng*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00156","DOIUrl":"10.1021/acs.chemrestox.5c00156","url":null,"abstract":"<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":"38 7","pages":"1266–1280"},"PeriodicalIF":3.8,"publicationDate":"2025-06-13","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":"Toxicokinetics and Perfluorooctanesulfonic Acid-Induced Liver Protein Expression Are Markedly Altered in Mice Lacking Albumin","authors":"Emily M. Kaye,&nbsp;Jitka Becanova,&nbsp;Simon Vojta,&nbsp;Rainer Lohmann,&nbsp;Fabian Christoph Fischer* and Angela Slitt*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00508","DOIUrl":"10.1021/acs.chemrestox.4c00508","url":null,"abstract":"<p >Perfluorooctanesulfonic acid (PFOS) is a ubiquitous perfluoroalkyl substance (PFAS) linked to liver disease and obesity in humans. Binding studies suggest that albumin is a crucial blood protein influencing PFOS toxicokinetics and hepatotoxicity; however, its role has not been mechanistically tested in vivo. This study used an albumin-deficient mouse model to investigate the relevance of albumin in PFOS tissue distribution and liver disease end points. Adult male C57BL/6J wild-type (Alb^+/+) and albumin-deficient (Alb^–/–) mice were orally gavaged daily for 7 days with either vehicle or PFOS at 0.5 or 10 mg/kg body weight. The measured PFOS concentrations in plasma were significantly lower in Alb^–/– mice compared to those in Alb^+/+ mice, while liver concentrations were significantly higher in Alb^–/– mice. Binding experiments confirmed these findings, indicating that PFOS toxicokinetics are driven by plasma and tissue binding. Significant changes in liver protein expression did not translate into differences in liver disease end points between genotypes, suggesting the need for chronic exposure studies. Our data imply that disease-related albumin deficiency in humans can influence PFAS toxicokinetics and susceptibility to hepatotoxicity. Our framework using knockout mice can be adapted in future studies to assess the relevance of protein binding and membrane transporters in PFAS distribution and elimination.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"1183–1191"},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256637","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":"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}

{"title":"Evaluation of the Effectiveness of l-Ergothioneine in Conjunction with Reactive Intermediates Derived from Model Pharmaceuticals","authors":"Jianyao Wang*,&nbsp;Lu Chen and Kaushik Mitra,&nbsp;","doi":"10.1021/acs.chemrestox.5c0011210.1021/acs.chemrestox.5c00112","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00112https://doi.org/10.1021/acs.chemrestox.5c00112","url":null,"abstract":"<p >During our investigation into a compound’s disposition within our discovery portfolio, we identified an <span>l</span>-ergothioneine to generate reactive intermediates. These drugs included acetaminophen, diclofenac, carbamazepine, clozapine, nefazodone, raloxifene, tamoxifen, ticlopidine, troglitazone, and ethacrynic acid. The drugs were incubated with human liver microsomes supplemented with NADPH and ET, followed by analysis with liquid chromatography–mass spectrometry (LC-MS). This process led to the detection of ET conjugates in six of the ten compounds, which exhibited structural differences: for instance, acetaminophen, raloxifene, and troglitazone presented with +ET-2H, while diclofenac, nefazodone, troglitazone, and tamoxifen showed +O + ET-2H. Additionally, nefazodone yielded +ET + O-HCl. The paper discusses structure–activity relationships (SAR) and underlying mechanisms. The proposed structures indicate that ET effectively incorporates reactive intermediates featuring highly conjugated moieties, such as quinones and quinone-imines, yet is less effective with epoxides, α-β-unsaturated ketones, and nitrenium ions. To further investigate ET’s detoxification capabilities, we analyzed metabolic products from acetaminophen, diclofenac, nefazodone, and raloxifene using rat, monkey, and human hepatocytes without GSH and ET supplementation. Interestingly, we detected conjugates of ET and GSH corresponding to +ET/GSH-2H and +O + ET/GSH-2H. Notably, our findings suggest that, in addition to scavenging reactive oxygen species, ET can also shield cells from reactive xenobiotic intermediates, similar to GSH. This research presents the first evidence of ET’s role as a trapping agent for reactive drug intermediates.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1113–1121 1113–1121"},"PeriodicalIF":3.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290329","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":"Per- and Polyfluoroalkyl Substances Suppress Macrophage Alternative Activation to Disrupt Hepatic Lipid Metabolism","authors":"Lijuan You,&nbsp;Xiaohong Wang,&nbsp;Yuan Zhi,&nbsp;Huiling Wang,&nbsp;Zhisen Zhuang,&nbsp;Jing Yang,&nbsp;Qiannan Zhang,&nbsp;Hailin Shang,&nbsp;Yongning Li,&nbsp;Yi Wan,&nbsp;Xudong Jia and Hui Yang*,&nbsp;","doi":"10.1021/acs.chemrestox.5c0006610.1021/acs.chemrestox.5c00066","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00066https://doi.org/10.1021/acs.chemrestox.5c00066","url":null,"abstract":"<p >Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental pollutants with diverse toxic effects (e.g., hepatotoxicity and metabolism disorder). Macrophages played a key role in metabolic response; however, the effect of macrophage on PFAS-induced toxicity and the underlying mechanisms remain poorly understood. In this study, we constructed a high-content cell model by utilizing the activation and differentiation of human THP-1 monocytes into alternative activation of macrophages, enabling rapid quantitative screening of numerous PFAS. We applied the cell model to screen 10 PFASs and identified that PFOA and PFUnDA significantly suppressed alternative activation of macrophages by disrupting the PPAR signaling pathway. Oral exposure to PFOA and PFUnDA in WT mice also significantly impaired alternative activation of macrophages in the liver and induced hepatocyte hypertrophy, liver dysfunction, and systemic lipid metabolism disorders. Moreover, macrophage-specific knockout of PPARγ exacerbated PFOA and PFUnDA-induced suppression of macrophage alternative activation and subsequent hepatotoxicity. Activation balance between PPARα and PPARγ may be a critical factor by PFOA and PFUnDA to affect the alternative activation of macrophage. These findings highlight the immunometabolism regulatory role of macrophage activation in PFAS-induced hepatotoxicity in humans.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1091–1102 1091–1102"},"PeriodicalIF":3.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290278","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":"Refining the Amino Reactivity-Based Identification of Respiratory Sensitizers","authors":"Martin Simoneit,&nbsp;Helene Langer,&nbsp;Nadin Ulrich and Alexander Böhme*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0054510.1021/acs.chemrestox.4c00545","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00545https://doi.org/10.1021/acs.chemrestox.4c00545","url":null,"abstract":"<p >The sensitization of the respiratory tract may lead to various pulmonary diseases such as asthma. It can be triggered by the chemical reaction of organic electrophiles with nucleophiles of lung proteins with amino groups being of particular interest in this case. For assessing the dermal sensitization potential of chemicals, the direct peptide reactivity assay (DPRA) has become an OECD-accepted nonanimal test system. However, issues with the identification of known respiratory sensitizers such as isocyanates and anhydrides based on their amino reactivity in the DPRA have been reported. Hence, in this study the chemoassay employing glycine-<i>para</i>-nitroanilide (Gly-pNA) as model nucleophile is applied to eight iso(thio)cyanates, seven anhydrides, four dinitrobenzenes, one triazine, five acrylates, glutaraldehyde, and chloramine T to quantify their amino reactivity in terms of the second order rate constant <i>k</i>_Gly and the DPRA-like 24 h percent depletion <i>D</i>_Gly. A comparison of <i>D</i>_Gly with respective DPRA amino reactivity data (<i>D</i>_DPRA) showed that in particular iso(thio)cyanates and anhydrides are substantially more reactive toward Gly-pNA. This can be rationalized by the unintentional and so far not considered reaction of the test compounds with the ammonium acetate buffer used for DPRA testing. A detailed analysis of this reaction includes half-lives and analytically determined adduct patterns and indicates that it can hamper the envisaged depletion of the DPRA amino nucleophile. Finally, the obtained log <i>k</i>_Gly values range from −3.73 to ≥ 4.52 and allow for an improved identification of respiratory sensitizers. Hence, the Gly-pNA chemoassay may serve as a nonanimal screening method as one part of a mechanism-informed integrated testing and assessment strategy for respiratory sensitizers.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1046–1060 1046–1060"},"PeriodicalIF":3.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00545","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290296","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}