Chemical Research in Toxicology最新文献

{"title":"Environmentally Persistent Pesticides: In Vitro Effects on Human Aromatase Activity and ERα Signaling","authors":"Francesca Armellino,&nbsp;Sabrina Costa,&nbsp;Francesco Giaretto,&nbsp;Michela Rossi,&nbsp;Gianluca Catucci,&nbsp;Gianfranco Gilardi,&nbsp;Tiziana Schilirò,&nbsp;Giovanna Di Nardo","doi":"10.1021/acs.chemrestox.6c00151","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00151","url":null,"abstract":"<p>The presence andpersistence of pesticides representa concernfor public health due to their potential activity as endocrine disruptingchemicals (EDCs) by interfering with hormone synthesis and signaling,leading to severe effects on human well-being. This work investigatesthe activity of a series of pesticides detected in Italian surfaceand groundwater on two key molecular targets of the endocrine system:human aromatase (CYP19A1), responsible for the conversion of androgensinto estrogens, and estrogen receptor α (ERα), essentialfor the estrogen-induced signaling pathway. Out of the eight pesticidestested, imazamox, metolachlor, and nicosulfuron were found to partiallyinhibit aromatase activity (up to ∼20% inhibition was observedwhen 10 or 50 μM was applied). UV/vis spectroscopy and isothermaltitration calorimetry were used to calculate dissociation constantsfor imazamox and metolachlor that resulted of 18.8 ± 0.8 and1.8 ± 0.7 μM, respectively. For imazamox, it was possiblealso to obtain a dose–response curve and to calculate an IC50of 5.2 ± 0.8 μM. As for the estrogen receptor α,MELN (MCF-7 ERE-β-globin Luciferase Neo) gene reporter assayrevealed that quinclorac and terbuthylazine-desethyl induced nuclearERα-mediated transcriptional activation with a mean EC50 of9.02 × 10^–4 and 1.83 × 10^–5 M, respectively. The data provide new insights into pesticide interferencewith key molecular target enzymes and receptors of the estrogen axisto better understand the impact they could have on human health whenpresent as persistent environmental contaminants that can bioaccumulate.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1723–1734"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003735","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":"Emerging Therapeutic Targets in Oxaliplatin-Induced Acute Peripheral Neuropathy: Biochemical Protection by Organoselenium via Redox and Ionic Regulation","authors":"Vanessa M. E. da Rocha,&nbsp;Ketlyn P. da Motta,&nbsp;Ana Paula B. Wille,&nbsp;Ariana S. Lima,&nbsp;Diéssica Padilha Dalenogare,&nbsp;Vinicius Costa Prado,&nbsp;Diego Alves,&nbsp;Angélica S. Reis,&nbsp;Ethel A. Wilhelm","doi":"10.1021/acs.chemrestox.6c00302","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00302","url":null,"abstract":"<p>Oxaliplatin (OXA), a platinum-based chemotherapeuticagent, frequentlyinduces acute peripheral neuropathy characterized by mechanical andcold allodynia, for which effective therapeutic options remain limited.Here, we investigated the acute antinociceptive and biochemical effectsof 4-amino-3-(phenylselanyl)benzenesulfonamide (4-APSB), a compoundwith antioxidant and antinociceptive properties, in female Wistarrats with OXA-induced acute neuropathy. Animals received OXA (4 mg/kg,i.p.) on two consecutive days and were subsequently treated with 4-APSB(1 mg/kg, i.g.) or duloxetine (30 mg/kg, i.g.) as a reference drug.Nociceptive behaviors were assessed using mechanical and cold sensitivityassays, followed by biochemical analyses in nervous tissues. OXA administrationinduced mechanical and cold hypersensitivity, elevated oxidative stressmarkers, and disrupted membrane enzyme function, reducing Na⁺/K⁺-ATPase activity and increasing acetylcholinesterase(AChE) activity. Treatment with 4-APSB significantly attenuated hypersensitivity,increased Na⁺/K⁺-ATPase and catalase activities,reduced reactive species generation, and attenuated the OXA-inducedincrease in AChE activity in the cerebral cortex, without affectinglocomotor behavior. Collectively, these findings show that 4-APSBproduces acute antinociceptive effects accompanied by the modulationof redox homeostasis, Na⁺/K⁺-ATPase activity,and AChE activity following OXA exposure. The coordinated improvementin behavioral and biochemical parameters supports the potential relevanceof redox balance and membrane-associated enzyme function to the pharmacologicaleffects of 4-APSB. These results identify 4-APSB as a promising compoundfor further investigation as a therapeutic strategy for OXA-inducedperipheral neuropathy.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1854–1866"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003750","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":"FTO Mediates the Tobacco Carcinogen NNK-Induced Beas-2B Cells Malignant Transformation via the DIXDC1/PI3K/AKT Signaling Axis","authors":"Yibo Wu,&nbsp;Ru Liu,&nbsp;Jian Zhang,&nbsp;Xuan Sun,&nbsp;Minmin Huang,&nbsp;Shengsheng Li,&nbsp;Nuoyan Wang,&nbsp;Zhuolin Liu,&nbsp;Qiuxian Wan,&nbsp;Jianjun Wu","doi":"10.1021/acs.chemrestox.6c00211","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00211","url":null,"abstract":"<p>Cigarette smoking is a primary etiologicalfactor in lung cancer,and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a prototypicaltobacco-specific nitrosamine carcinogen. Although FTO has been implicatedin the progression of various cancers, its specific role in smoking-associatedlung carcinogenesis remains incompletely understood. In this study,we built a model of NNK-induced malignant transformation of humanbronchial epithelial Beas-2B cells (designated Beas-2B-NNK cells)to explore the function and regulatory mechanism of FTO during NNK-inducedlung carcinogenesis. Through quantitative real-time PCR (RT-qPCR)assays, FTO levels were found to be notably higher in Beas-2B-NNKcells when compared with their parental Beas-2B cell line. Then, knockingdown FTO expression using short hairpin RNA (shRNA) led to markedrepression of proliferation, migration, and cell-cycle progressionin Beas-2B-NNK cells. Bioinformatics analysis revealed a positivecorrelation between FTO and DIXDC1, and when FTO was knocked out,the sharpest drop in DIXDC1 expression was seen in Beas-2B-NNK cells.Combined bioinformatic and Western blot analysis observed that DIXDC1regulates the malignant transformation of Beas-2B-NNK cells via thePI3K/AKT signaling pathway. In summary, these findings suggest thatFTO participates in NNK-induced malignant transformation of Beas-2Bcells via the DIXDC1/PI3K/AKT signaling axis.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1835–1846"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003674","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":"Toxic Metal Content and Exposure-Relevant Release from Synthetic Hair under Realistic Conditions: Comparative Assessment of Adult, Children’s, and Toy-Doll Products","authors":"Olubukola S. Alimi,&nbsp;Leah Chibwe","doi":"10.1021/acs.chemrestox.6c00135","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00135","url":null,"abstract":"<p>Releaseof metals from synthetic hair during use and disposal isunknown. We quantified 25 metals in adult (<em>n</em> = 18),children (<em>n</em> = 4), and doll hair (<em>n</em> = 5), evaluated leaching in water and artificial sweat, and assessedexposure using estimated daily intake (EDI) and maximum allowabledose levels (MADLs). Sixteen priority metals were detected in allproducts. Children’s hair contained up to 2-fold higher metalconcentrations than adult hair. Several adult samples exceeded Canadianimpurity limits for lead and antimony. Artificial sweat leachatesyielded higher metal concentrations and enhanced metal release byup to 3 orders of magnitude relative to water. Oral exposure (maxEDI 1.9 × 10^–3 mg/kg/day) exceeded dermal exposureby over 2 orders of magnitude, and lead surpassed MADLs in selectsamples, highlighting a previously underrecognized exposure source.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1716–1722"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003690","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":"Characterization of 4-Bromo-2,5-dimethoxyphenethyl Tosylate, a Synthetic Intermediate of 2C–B, Identified in a Seized Pink Heart-Shaped Tablet","authors":"Sara Casati,&nbsp;Roberta F. Bergamaschi,&nbsp;Michele Dei Cas,&nbsp;Alessandro Ravelli,&nbsp;Lea Sicuro,&nbsp;Gabriella Roda,&nbsp;Chiara Ciccarelli,&nbsp;Luca Mollica,&nbsp;Claudio Guidotti,&nbsp;Alessio Battistini,&nbsp;Paola Rota","doi":"10.1021/acs.chemrestox.6c00170","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00170","url":null,"abstract":"<p>A pink heart-shaped tablet, seized by law enforcementauthorities,was found to contain a compound structurally related to 4-bromo-2,5-dimethoxyphenethylamine(2C–B), a new psychoactive substance (NPS). An extensive analyticalinvestigation based on one- and two-dimensional nuclear magnetic resonance(NMR) experiments, combined with liquid chromatography coupled tohigh-resolution mass spectrometry (LC–HRMS) and gas chromatographycoupled to mass spectrometry (GC–MS) analyses, enabled theunambiguous identification of a new compound as 4-bromo-2,5-dimethoxyphenethyltosylate, a putative synthetic intermediate in the synthesis of 2C–B.Finally, the targeted synthesis of the proposed structure providedindependent confirmation of the correct structural assignment.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1780–1786"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003784","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":"Exposure to Toxicologically Relevant Inorganic Elements and Nicotine Content Variability in Electronic Nicotine Delivery System (ENDS) E-Liquids","authors":"Lara M. Catarino,&nbsp;Giovanna M. Iozzi,&nbsp;Cristiane B. Silva,&nbsp;Santos A.V. Neto,&nbsp;Graziele A. Reis,&nbsp;Silvana C. Jacob,&nbsp;Lisia M. G. dos Santos","doi":"10.1021/acs.chemrestox.6c00266","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00266","url":null,"abstract":"<p>In recent years,electronic nicotine delivery systems (ENDS) havegained prominence as alternatives to conventional cigarettes, raisingconcerns due to the increasing number of lung injury cases associatedwith their use. These devices rely on e-liquids composed primarilyof propylene glycol, glycerin, flavorings, and nicotine, which areheated to produce inhalable aerosols. In this context, the presentstudy aimed to quantify nicotine concentrations and assess the presenceof toxicologically relevant inorganic elements in e-liquids to evaluatepotential inhalation-related risks. Nicotine was quantified usinghigh-performance liquid chromatography with diode-array detection(HPLC–DAD), whereas inorganic contaminants were determinedusing inductively coupled plasma–mass spectrometry (ICP–MS).Nicotine concentrations ranged from nondetectable to 33.4 mg·mL^–1, and significant discrepancies were identified inthe labeling information. Arsenic (As), lead (Pb), nickel (Ni), chromium(Cr), and mercury (Hg) were detected at variable concentrations; notably,the estimated daily exposures for Cr and Hg exceeded the permitteddaily exposure (PDE) limits established by the International Councilfor Harmonization (ICH). Overall, these findings indicate that ENDSmay be a significant source of toxic metal exposure, posing potentialrisks to human health.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 9","pages":"1847–1853"},"PeriodicalIF":4.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149010659","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":"Screening the Tox21 Compound Library for Chemicals That Stimulate the Adrenergic β1 Receptor","authors":"Precious A. Adesina,&nbsp;Li Zhang,&nbsp;Chainarong Sukhawanit,&nbsp;Savannah Wood,&nbsp;Jinghua Zhao,&nbsp;Zoe Li,&nbsp;Srilatha Sakamuru,&nbsp;Stephen S. Ferguson,&nbsp;Jui-Hua Hsieh,&nbsp;David M. Reif,&nbsp;Ruili Huang,&nbsp;Menghang Xia","doi":"10.1021/acs.chemrestox.5c00501","DOIUrl":"10.1021/acs.chemrestox.5c00501","url":null,"abstract":"<p>Beta-1 adrenergic receptors (ADRβ1) are criticalregulatorsof cardiac function; however, the potential modulation of ADRβ1by environmental chemicals remains largely underexplored, raisingconcerns about unintended impacts on cardiovascular health. We applieda quantitative high-throughput screening (qHTS) approach to identifyADRβ1 agonists within the Tox21 10K compound library, whichincludes environmental chemicals, pharmaceuticals, industrial agents,and consumer products, using an HTRF-based cAMP assay in ADRβ1-overexpressingHEK293 cells. Primary screening of 8,947 unique compounds identified118 potential ADRβ1 agonists. Among these, 94 were confirmedand further evaluated for β-adrenergic receptor subtype selectivity(ADRβ2 and ADRβ3) and hERG channel inhibition to assesspotential cardiotoxicity liability. Known ADRβ1 agonists, isoproterenol(EC₅₀, 0.91 nM) and dobutamine (EC₅₀, 10 nM),were identified, supporting the validity of the assay. In addition,several compounds with limited prior ADRβ1-specific characterization,such as GR 103691 and <em>N</em>,<em>N</em>′-dibenzylethane-1,2-diamine,demonstrated subtype-selective or mixed agonist profiles, with someexhibiting minimal hERG inhibition. These findings expand the catalogof ADRβ1 modulators and demonstrate the utility of qHTS foridentifying chemicals that may affect cardiovascular signaling pathways.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1508–1517"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434362","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":"Advancing Science in India: Chemistry and Toxicology","authors":"Vaidyanathan Vaidyanathan Ganesan,&nbsp;Praveena Bhatt,&nbsp;Shana J. Sturla","doi":"10.1021/acs.chemrestox.6c00346","DOIUrl":"10.1021/acs.chemrestox.6c00346","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1463–1464"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148596661","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":"Evaluation of the Methemoglobin-Haptoglobin Protein Complex for Detoxification of Cyanide, Azide, and Sulfide in In Vitro Binding Models","authors":"Griffin J. Beyer,&nbsp;Mohd Asim Khan,&nbsp;Quintin O’Boyle,&nbsp;Tanmay Salvi,&nbsp;Ana Carolina S Barbeta,&nbsp;Kenechukwu H. Adimorah,&nbsp;Andre F. Palmer","doi":"10.1021/acs.chemrestox.6c00228","DOIUrl":"10.1021/acs.chemrestox.6c00228","url":null,"abstract":"<p>Cyanide, azide, and sulfide are potent anion inhibitorsof mitochondrialenzymes, causing rapid disruption of cellular energy metabolism andpotentially fatal outcomes. Current treatments for these toxic anionsare limited, highlighting the need for broadly effective antidotes.Methemoglobin (methHb), the ferric form of hemoglobin (Hb), can bindthese ligands with high affinity, acting as a mechanistic scavengerthat prevents their interaction with mitochondrial targets. BindingmethHb to haptoglobin (Hp), an endogenous Hb-binding plasma protein,offers a strategy to enhance methHb stability and potentially increasecirculation time while reducing potential oxidative side effects.Hence, in this work, we examine the detoxification potential of bothcell-free methHb and methHb–Hp protein complexes against theseanions using <em>in vitro</em> binding assays. Analyses bysize exclusion high-performance liquid chromatography (SEC-HPLC) anddynamic light scattering (DLS) indicate that methHb-Hp complex formationexhibits a similar increase in molecular size relative to the Hp solution,while circular dichroism spectroscopy confirms maintenance of proteinsecondary structure. Kinetic studies using UV–visible spectroscopyand stopped-flow techniques reveal rapid and efficient sequestrationof cyanide, azide, and sulfide by both methHb and methHb–Hp.These results demonstrate that Hp association stabilizes methHb withoutcompromising its multiligand binding capacity, supporting its promiseas a flexible platform for developing broad-spectrum toxic anion antidotes.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1595–1608"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429375","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":"Engineered PS and PAN Microplastic Fibers Elicit Stronger A549 Epithelial Responses than Spherical Polystyrene Particles","authors":"Sewoon Kim,&nbsp;David M. Cwiertny,&nbsp;Dongkeun Lee,&nbsp;Jong Sung Kim,&nbsp;Jon A. Doering,&nbsp;Qinglin Wu","doi":"10.1021/acs.chemrestox.6c00243","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.6c00243","url":null,"abstract":"<p>Polymeric fibers are a prevalent form of airborne micro-and nanoplastics(MNPs), yet their inhalation hazards remain poorly constrained becausetoxicological studies have largely relied on spherical particles orheterogeneous fiber materials. Here, polystyrene (PS) and polyacrylonitrile(PAN) fiber MNPs were fabricated by electrospinning followed by cryomilling,probe sonication, and filtration, yielding discrete fibers with comparablediameters and lengths. FTIR confirmed preservation of polymer identityand showed no detectable residual solvent signal in the isolated fibers.Using A549 lung epithelial cells as an inhalation-relevant in vitromodel, we found that PS and PAN fiber MNPs induced dose-dependentreductions in viability together with increased membrane damage, oxidativestress, and IL-8 release, whereas spherical PS particles elicitedcomparatively limited responses at the tested mass concentrations.Scanning electron microscopy further showed abnormal cell–fiberinteractions, including membrane deformation and apparent partialmembrane wrapping around fibers, consistent with morphology-dependentcellular injury. Together, these results show that engineered polymericfiber MNPs elicit stronger epithelial stress and inflammatory responsesthan spherical particle controls under the tested conditions, supportingmorphology-aware evaluation of airborne MNP hazards.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 8","pages":"1609–1616"},"PeriodicalIF":4.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729370","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}