Chem. Res. Toxicol. [JOURNAL]
Sun
200 papers
Structure-Activity Relationship of Protein-Mediated Molecular Initiating Events of Organ-Specific Toxicities.
Isbaita NHK, Gardoni S, Roncaglioni A … +2 more , Benfenati E, Gadaleta D
Chem Res Toxicol · 2026 Jan · PMID 41439608 · Full text
Toxicological research is facing a major transition from animal models into and models to improve the cost-effectiveness of the testing process, shorten the timeline for primary screening of chemicals, and better align...
Toxicological research is facing a major transition from animal models into and models to improve the cost-effectiveness of the testing process, shorten the timeline for primary screening of chemicals, and better align with the 3Rs principles to reduce animal suffering. In this work, structure-activity relationships were developed based on structural alerts (SAs) that flag the ability of chemicals to trigger specific molecular initiating events (MIEs) upstream of five adversities (cholestasis, steatosis, kidney tubular necrosis, cognitive functional defects, and neural tube closure defects). Twenty-nine protein targets linked to MIEs were identified from published adverse outcome pathway networks, while bioactivity data for chemicals against such targets were collected from ChEMBL 35 database. SARpy 2.0 included in the novel ΔQSAR (DeltaQSAR) software was used to extract rulesets, i.e., collections of structural alerts codifying for protein bioactivity. The rulesets were evaluated using an external test set to assess their real-life predictivity. Good external validation performance was achieved for 22 out of 29 rulesets that returned balanced accuracy ≥ 70% and coverage ≥ 70%, confirming that these rulesets can be used for high-throughput as well as preliminary testing of chemicals. Moreover, combining structure-activity relationship with the adverse outcome pathway concept provides a mechanistic basis to the prediction suggested by the rulesets.
From Toxicity Assessment to In Vivo Validation: Exploring the Molecular Mechanisms of Triclosan-Induced Liver Injury.
Wu S, Zhao J, Fang X … +2 more , Liao P, Liu G
Chem Res Toxicol · 2026 Jan · PMID 41424291 · Publisher ↗
Triclosan (TCS), a synthetic compound initially marketed as a broad-spectrum antibacterial agent, poses significant threats to the environment, animal, and human health due to its inherent toxicity and improper discharge...
Triclosan (TCS), a synthetic compound initially marketed as a broad-spectrum antibacterial agent, poses significant threats to the environment, animal, and human health due to its inherent toxicity and improper discharge. This study first comprehensively assessed the environmental and biological toxicity of TCS. Subsequently, an integrated approach combining network toxicology, molecular docking, and in vivo experiments was employed to analyze and experimentally validate. For the first time, the mechanisms underlying TCS-induced liver injury in weaned piglets. Results identified 31 major targets associated with TCS-induced liver injury. Molecular docking confirmed strong binding affinity between TCS and the top 10 MCC-ranked core targets. Factor-gene and miRNA-gene regulatory networks were constructed for these core targets. Further GO and KEGG analyses revealed significant enrichment of TCS hepatotoxicity targets in biological processes, including redox regulation, and multiple signaling pathways. Validation via in vivo experiments in weaned piglets demonstrated that TCS exposure significantly induced liver damage and histopathological alterations. It disrupted hepatic redox homeostasis, evidenced by significantly decreased T-AOC, SOD, CAT, and GSH levels, alongside increased MDA levels. Furthermore, TCS significantly upregulated the expression of the Rap1-PI3K/AKT, HIF-1/VEGF, and Ras-MAPK signaling pathways. This study provides the first evidence that TCS exerts hepatotoxicity by inducing hepatic oxidative stress and aberrant activation of multiple signaling pathways. The findings offer novel data for the comprehensive toxicological assessment of TCS, contribute to safeguarding animal and human health, and propose a framework for the integrated risk assessment of similar environmental contaminants.
Sterile Inflammation in Mouse Lung Driven by Lipid Mediator Pathways Following MWCNT Exposure.
Ma Q, LeBouf RF, Rimayi CC … +4 more , Lim CS, Fekedulegn D, Park JH, Porter DW
Chem Res Toxicol · 2026 Jan · PMID 41397871 · Publisher ↗
Exposure to respirable particles such as multiwalled carbon nanotubes (MWCNTs) can provoke acute lung inflammation and tissue injury, potentially progressing to chronic disease. Lipid mediators (LMs), including proinflam...
Exposure to respirable particles such as multiwalled carbon nanotubes (MWCNTs) can provoke acute lung inflammation and tissue injury, potentially progressing to chronic disease. Lipid mediators (LMs), including proinflammatory and pro-resolving species, play a critical role in regulating this process. This study investigated LM biosynthesis in acute lung inflammation induced by fibrogenic MWCNTs. Adult C57BL/6J mice were exposed to MWCNTs (Mitsui-7; 1860.4 μg/kg) via oropharyngeal aspiration. Lung tissues collected 24 h postexposure exhibited neutrophil infiltration, elevated inflammatory cytokines, and tissue damage. Enzymes involved in prostanoid synthesis─phospholipase A2, cyclooxygenase-2, and prostaglandin E synthase─were significantly upregulated. Lipidomic profiling was performed by using C18 spin column enrichment and UPLC-MS/MS. MWCNT exposure significantly increased the levels of prostanoids (PGE2, PGD2, PGF2α, thromboxane B2) and hydroxyeicosatetraenoic acids (5-, 12-, 15-HETE). Elevated levels of protectin DX, 14()-, and 17-HDHA derived from docosahexaenoic acid, and 12-, 15-, and 18-HEPE derived from eicosapentaenoic acid were also observed. In vitro, MWCNTs induced intracellular lipid accumulation in macrophages. These findings reveal rapid activation of LM biosynthetic pathways, particularly those producing proinflammatory prostanoids, in mouse lungs following nanoparticle exposure. The study underscored the utility of lipidomic profiling for mechanistic insights into nanoparticle-induced sterile inflammation and toxicity in limited tissue samples.
Molecular Aspects of Methylcadmium Toxicity: Effects on the HO Reduction by Cysteine and Selenocysteine Disclosed In Silico.
Rubbi A, Lambertini F, Nogara PA … +3 more , Bortoli M, Rocha JBT, Orian L
Chem Res Toxicol · 2026 Jan · PMID 41379003 · Full text
Cadmium (Cd), like the other group 12 elements (Zn and Hg), has a high affinity for sulfur (S) and selenium (Se), a property that strongly influences its adverse biological effects. Although the symptoms of Cd toxicity a...
Cadmium (Cd), like the other group 12 elements (Zn and Hg), has a high affinity for sulfur (S) and selenium (Se), a property that strongly influences its adverse biological effects. Although the symptoms of Cd toxicity are diverse, a common denominator is found in oxidative stress, resulting in the disruption of redox balance in cells and the proliferation of reactive oxygen species (ROS) and harmful radicals. Methylcadmium (CHCd) is a convenient model to study Cd pro-oxidant activity in silico. In this work, the effect of CHCd on the peroxy-reducing potential of cysteine (Cys) and selenocysteine (Sec) is investigated at the ZORA-BLYP-D3(BJ)/TZ2P level and compared to our current knowledge on the analogous molecular aspects of methylmercury's toxicity (CHHg). Molecular docking simulations indicate that CHCd binds favorably to the catalytic sites of the GPx1 and TrxR1 enzymes. The short distances between the metal and Sec suggest that a nucleophilic attack by Se to Cd leading to the inhibition of the enzyme is indeed possible. Methylcadmium pro-oxidant activity is─if not equal─only slightly inferior to that of methylmercury.
Impact of Dietary Practices on DNA Adduct Formation by Aristolochic Acid I in Mice: Drinking Alkaline Water as a Risk Mitigation Strategy.
Kwok HC, Zhang J, Pavlović NM … +1 more , Chan W
Chem Res Toxicol · 2026 Jan · PMID 41359359 · Full text
Balkan endemic nephropathy (BEN) is a chronic kidney disease associated with the consumption of aristolochic acids (AAs) through contaminated food sources. AAs are known to form DNA adducts that are implicated in tumorig...
Balkan endemic nephropathy (BEN) is a chronic kidney disease associated with the consumption of aristolochic acids (AAs) through contaminated food sources. AAs are known to form DNA adducts that are implicated in tumorigenesis and kidney fibrosis. Given the sensitivity of DNA adduct formation to dietary factors, this study aimed to investigate the impact of various dietary practices on AA-DNA adduct formation, thereby assessing the risk of developing BEN. We quantified AA-DNA adducts in DNA extracted from the kidneys and livers of mice subjected to high-fat, high-protein, high-sucrose, and high-salt diets, utilizing a highly sensitive liquid chromatography-tandem mass spectrometry method combined with stable isotope dilution. Our results demonstrated that unbalanced diets significantly elevated the formation of DNA adducts from AAs. Notably, mice fed high-fat diets exhibited increases in adduct levels of 71 and 114% for diets containing 17 and 25% fat, respectively. Mice on a 20% sucrose diet showed an 80% increase in adduct levels compared to those on a standard diet. Further investigations using gut sacs from the small intestines of these mice revealed that the increased level of DNA adduct formation was primarily attributed to enhanced intestinal absorption. Additionally, we observed that drinking alkaline water reduced adduct levels by 30% compared to tap water, likely by decreasing AA absorption. In contrast, commonly used dietary supplements, such as vitamin C and cysteine, significantly increased AA-DNA adduct levels by enhancing the activity of enzymes involved in the metabolic activation of AAs. These findings highlight the critical role of a balanced diet in mitigating the risk of BEN and suggest that alkaline water consumption may serve as a protective strategy for individuals living in AA-contaminated regions.
Metabolism Profiles of Trimethoprim in Idiosyncratic Adverse Drug Reaction-Affected Tissues.
Tessman RT, Nolte W, Flores-Ascencio P … +1 more , Goldman J
Chem Res Toxicol · 2025 Dec · PMID 41264640 · Full text
Trimethoprim (TMP) is an essential antibiotic used in combination with sulfamethoxazole to treat and prevent bacterial infections. Idiosyncratic adverse drug reactions (IADRs) to TMP occur in a small but significant perc...
Trimethoprim (TMP) is an essential antibiotic used in combination with sulfamethoxazole to treat and prevent bacterial infections. Idiosyncratic adverse drug reactions (IADRs) to TMP occur in a small but significant percentage of the treatment population. TMP IADRs manifest as mild to life-threatening skin rashes, pulmonary failure, or hepatotoxicity. Currently, our incomplete knowledge of TMP metabolism is a barrier to understanding the TMP-IADR etiology. In this study, we investigated TMP phase I and II metabolism in tissues involved with IADRs including liver, lung, and skin using human s9 subcellular fractions. Triple-quadrupole and quadrupole-time-of-flight mass spectrometry were used to compare trimethoprim phase I and phase II metabolism in these organ systems and to detect identified metabolites in the urine of subjects taking and tolerating TMP. In this study, we found that phase I TMP metabolites are formed predominantly in the liver, and phase II TMP metabolites are formed differentially in extrahepatic tissues. This characterization of TMP metabolism in affected tissues is an important step toward a better understanding of the mechanisms involved in the TMP IADRs.
Human APE2 and TREX2 Repair 3'-DNA-Peptide Cross-links Derived from Abasic Sites.
Wei X, Cepeda J, Chung JM … +2 more , Lee SE, Yang K
Chem Res Toxicol · 2025 Dec · PMID 41257340 · Full text
Histones react with one of the most abundant endogenous DNA lesions, the apurinic/apyrimidinic (abasic, AP) site, to form reversible but long-lived Schiff base DNA-protein cross-links at 3'-DNA termini (3'-histone-DPCs)....
Histones react with one of the most abundant endogenous DNA lesions, the apurinic/apyrimidinic (abasic, AP) site, to form reversible but long-lived Schiff base DNA-protein cross-links at 3'-DNA termini (3'-histone-DPCs). These DPCs need to be repaired, because 3'-hydroxyl groups are required for DNA repair synthesis and strand ligation. We previously identified three human enzymes, including tyrosyl-DNA phosphodiesterase 1, AP endonuclease 1 (APE1), and three-prime repair exonuclease 1 (TREX1), that can repair chemically synthesized adducts that closely resemble the proteolyzed Schiff base 3'-histone-DPCs. Here, we report another two human enzymes, APE2 and TREX2, that have a similar function.
Per- and Polyfluoroalkyl Substances Induce Cardiotoxicity and Alter Protein Profiles of Extracellular Matrix, Metabolism, and Mitochondrial Function in Human Cardiomyocytes.
Zhang W, Wang Z, Reid O … +13 more , Harris F, Man K, Wang M, Li S, Armand LC, Lane A, Patel G, Faundez V, Du Y, Wu R, Brown LA, Caudle WM, Xu C
Chem Res Toxicol · 2026 Jan · PMID 41240326 · Full text
Per- and polyfluoroalkyl substances (PFAS), common environmental contaminants, can cause cardiotoxic effects particularly during fetal development. However, the effect of combined PFAS exposure, which more closely reflec...
Per- and polyfluoroalkyl substances (PFAS), common environmental contaminants, can cause cardiotoxic effects particularly during fetal development. However, the effect of combined PFAS exposure, which more closely reflects real-world environmental conditions, remains poorly understood. In this study, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were exposed to three common PFAS compounds─perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), and perfluorodecanoic acid (PFDA)─individually or in combination (20-200 μM; consistent with serum levels reported in occupationally exposed populations). Compared with single compounds, combined PFAS exposure induced synergistic cytotoxicity, significantly reducing hiPSC-CM viability after 5 or 10 days. Sublethal combined exposure for 10 days altered mitochondrial membrane potential and mitochondrial content in a dose-dependent manner and shifted cysteine metabolism, potentially reflecting adaptation to oxidative challenge. After 14 days, combined PFAS increased vimentin, a fibroblast marker, and reduced NKX2.5, α-actinin, and cardiac troponin T, key markers of cardiomyocytes, as detected by immunocytochemistry. Proteomics further showed enrichment of pathways in extracellular matrix organization, cholesterol metabolism, and antioxidant defense, as well as downregulation of mitochondrial proteins. Consistent with changes in protein profiles related to oxidative stress and bioenergetic impairment, exposure of hiPSC-CMs to combined PFAS also increased the level of mitochondrial superoxide, reduced ATP content, and decreased cellular respiration. Together, these data demonstrate that PFAS mixtures drive mitochondrial dysfunction, oxidative stress, metabolic changes, and extracellular matrix remodeling in hiPSC-CMs, underscoring the importance of evaluating PFAS mixtures to better understand cardiac risks from environmental exposure.
Comparative Study of Molecular Descriptors and AI-Based Embeddings for Toxicity Prediction.
Gray M, Wu L
Chem Res Toxicol · 2025 Dec · PMID 41235418 · Full text
Accurate toxicity prediction is a critical component of pharmaceutical development and regulatory safety evaluation, traditionally relying on molecular descriptor-based models. This study compares the performance of desc...
Accurate toxicity prediction is a critical component of pharmaceutical development and regulatory safety evaluation, traditionally relying on molecular descriptor-based models. This study compares the performance of descriptor-based features (Mordred, RDKit) with embeddings from ten AI language models applied to SMILES strings, chemical names, and simple descriptions, using logistic regression classifiers across the Tox21, ClinTox, and DILIst datasets. For the Tox21 dataset, Mordred achieved the highest average ROC-AUC of 0.855, outperforming language models. However, on specific endpoints, language models showed competitive performance, with MolBERT reaching an average ROC-AUC of 0.801 for SMILES-based embeddings. In contrast, language models outperformed descriptor models on the ClinTox dataset. While RDKit achieved an ROC-AUC of 0.721, GPT-3 reached 0.996 by using simple descriptions. Similarly, for the DILIst dataset, language models surpassed descriptor models, with GPT-3 achieving an ROC-AUC of 0.806 using chemical names, compared to RDKit's 0.620. These results demonstrate the promise of AI language models in predictive toxicology, particularly for specific toxicity endpoints and datasets. While molecular descriptors remain robust for multiendpoint predictions like Tox21, language models show superior performance on focused toxicity classifications such as ClinTox and DILIst. This study supports the future integration of molecular descriptors with textual embeddings to enhance overall performance and adaptability across diverse toxicity prediction tasks.
Cannabinoid Vaping Products: Regulation, Composition, Toxicological Effects, and Emerging Research.
Love CA, Porter NA, Kim HH … +1 more , Jaspers I
Chem Res Toxicol · 2025 Dec · PMID 41218137 · Full text
The 2018 U.S. Farm Bill inadvertently paved the way for a market of unregulated, hemp-derived cannabinoid vaping products, including cannabidiol (CBD) and Δ8-tetrahydrocannabinol (Δ8-THC). These products contain extremel...
The 2018 U.S. Farm Bill inadvertently paved the way for a market of unregulated, hemp-derived cannabinoid vaping products, including cannabidiol (CBD) and Δ8-tetrahydrocannabinol (Δ8-THC). These products contain extremely high cannabinoid concentrations, contaminants, and potentially harmful byproducts from heating, raising concerns about respiratory toxicity. This review examines the regulatory landscape, manufacturing practices, composition, and toxicological mechanisms associated with hemp-derived cannabinoid vaping products. While vaping-related lung injuries, such as E-cigarette or Vaping, Product use-Associated Lung Injury (EVALI), have been linked to vitamin E acetate (VEA), a definitive mechanism of injury has not been established, and cases continue to be reported. Studies reveal multiple mechanisms of lung toxicity associated with cannabinoid vaping, including inflammatory responses, oxidative stress, and damage from contaminants like heavy metals and flavoring agents. Emerging evidence also highlights the formation of reactive cannabinoid quinones (e.g., CBDQ) during vaping, which form covalent adducts with protein cysteine residues, potentially altering their function, and also have the potential to drive oxidative damage through redox cycling. These electrophilic quinones may act as pleiotropic modifiers of cellular function and represent an important, yet understudied, contributor to cannabinoid vaping toxicity. This review identifies key research gaps, including the need for studies on chronic exposure models, mechanisms of lung injury, and the interplay between VEA, cannabinoid quinones, and other harmful byproducts. Additionally, given the potential for both therapeutic benefits and toxic effects, research should investigate optimal temperatures and formulations that balance efficacy and safety over potential toxicity caused by thermal oxidation. Overall, a comprehensive understanding of the toxicological mechanisms of cannabinoid vaping products is essential to guide public health decisions, inform regulatory frameworks, and support the development of safer products.
Differential Reactivity of Airborne Quinones on Human Red Blood Cells: Insights into Their Biochemical and Morphological Alterations.
Yadav N, P M J, Mondal SK … +1 more , Mandal AK
Chem Res Toxicol · 2025 Nov · PMID 41199497 · Publisher ↗
Airborne fine particulate matter (PM) exposure has been epidemiologically linked to increased risk of cardiovascular complications, thrombosis, and hypoxia-related disorders. Quinones, prevalent constituents of PM, are s...
Airborne fine particulate matter (PM) exposure has been epidemiologically linked to increased risk of cardiovascular complications, thrombosis, and hypoxia-related disorders. Quinones, prevalent constituents of PM, are suspected mediators of these health effects. Yet, the molecular mechanisms underpinning these associations remain poorly understood. Red blood cells (RBCs) have a central role in oxygen transport and vascular physiology. Thus, we investigated the effects of four environmentally relevant quinones (70 μg/mL), such as methyl-p-benzoquinone (MBQ), 1,4-naphthoquinone (NQ), 9,10-phenanthrenequinone (9,10-PQ), and 9,10-anthraquinone (9,10-AQ), on human RBCs. MBQ, NQ, and PQ significantly depleted intracellular glutathione, subsequently elevated reactive oxygen species, and triggered lipid peroxidation. Morphological analysis revealed membrane blebbing and surface protrusions of RBCs, indicative of impaired deformability and altered rheology. MBQ and NQ exposure further disrupted membrane proteins, impairing membrane fluidity and compromising membrane integrity. Tandem mass spectrometry confirmed covalent binding of MBQ and NQ to the βCys93 residue of hemoglobin via Michael addition. Native mass spectrometry revealed reduced stability of the αβ tetramer of hemoglobin. These findings were further corroborated by altered hemoglobin structure, methemoglobin formation, and hemoglobin aggregation. Mechanistically, MBQ and NQ induce RBC damage via both one-electron redox reaction and Michael addition to thiol groups, while PQ acts primarily through redox cycling without direct thiol binding. In contrast, AQ exhibited negligible effects, likely due to its low electrophilicity and steric hindrance. Our findings reveal distinct mechanistic pathways by which environmental quinones compromise RBC structure and function. This study offers a novel molecular link between airborne quinone exposure and pollution-driven health pathologies.
A Chemically Stable Interstrand Cross-Link Generated via a Reductive Amination Process Involving an Apurinic/Apyrimidinic Site and an Adenine Residue in Duplex DNA.
Islam T, Price NE, Amin SBM … +5 more , Yang Z, Johnson KM, Lei Z, Wang Y, Gates KS
Chem Res Toxicol · 2025 Nov · PMID 41195563 · Publisher ↗
Apurinic/apyrimidinic (AP) sites are unavoidably generated in the DNA of living organisms by the spontaneous or catalyzed loss of coding nucleobases from the deoxyribose backbone. AP sites can lead to the generation of i...
Apurinic/apyrimidinic (AP) sites are unavoidably generated in the DNA of living organisms by the spontaneous or catalyzed loss of coding nucleobases from the deoxyribose backbone. AP sites can lead to the generation of interstrand DNA cross-links via reactions between the ring-opened AP-aldehyde residue and exocyclic NH groups of nucleobases on the opposing strand of the double helix. Earlier works showed that dG-AP cross-links, which are generated in 2-5% equilibrium yields, can be converted via a reductive amination process to higher yields (15-50%) of a chemically stable alkylamine cross-link when NaBHCN is present in the reaction mixture. A dA-AP cross-link can be generated in equilibrium yields of 15-80%, but until now, it has been uncertain whether this cross-link could be reduced to the corresponding alkylamine cross-link by NaBHCN. The results presented here show that the dA-AP cross-link can indeed be reduced by NaBHCN to generate a chemically stable alkylamine cross-link. However, yields of the reduced dA-AP cross-link are limited by a faster, competing reduction of the AP-aldehyde to the corresponding AP-alcohol by NaBHCN. Similarly, faster reduction of the dG-AP cross-link in a 5'CXT/AAG sequence (X = AP), where both guanine and adenine residues compete for reaction with a single AP site, leads to a shift in the major site of the AP-derived cross-link attachment from adenine in the absence of NaBHCN to guanine in the presence of NaBHCN. The results show that two different nucleobase cross-links can coexist in equilibrium at a single AP site in duplex DNA. Overall, the reductive amination process may prove useful for detecting the dA-AP cross-link in cellular DNA using LC-MS/MS methods similar to those described here. In addition, these methods may be useful for the chemical synthesis of DNA duplexes containing chemically stable, site-specific cross-links.
RNA Oxidative Damage by the Iron-Fenton Reaction is Influenced by Bicarbonate Concentration and Ligand Strength.
Dingman JC, Fleming AM, Burrows CJ
Chem Res Toxicol · 2025 Nov · PMID 41186277 · Full text
Oxidative damage to RNA is associated with neurodegeneration, cardiovascular diseases, and cancer development. Studies that monitor RNA damage by HO often omit the physiological buffer bicarbonate in the reaction, which...
Oxidative damage to RNA is associated with neurodegeneration, cardiovascular diseases, and cancer development. Studies that monitor RNA damage by HO often omit the physiological buffer bicarbonate in the reaction, which fails to account for the influence of the buffer on the iron-Fenton reaction. Herein, we monitored two in vitro systems to understand how bicarbonate redirects the iron-Fenton reaction from a hydroxyl radical (HO) generator in the absence of bicarbonate to one that predominantly yields carbonate radical anion (CO) in the presence of this buffer. Using the HO-selective fluorophore terephthalic acid, we found that the Fe(II)-ligand identity impacted the bicarbonate concentration required to transition the Fenton reaction to predominantly yield CO. These findings were then corroborated by following the oxidation of guanosine (rG), which reports on oxidation by both radicals, and uridine (rU) oxidation, which responds to only HO as the oxidizing species. The studies found that as the Fe(II)-ligand complex stability increased, the bicarbonate concentration inflection point to favor CO production and rG oxidation also increased. Regardless of the ligand strength, the crossover values obtained were below physiologically relevant bicarbonate concentrations (<20 mM). Next, or HEK293T cells were pre-equilibrated with bicarbonate from 0 to 20 mM before a bolus addition of HO. The bicarbonate-dependent inflection points for favoring CO over HO (or ferryl) for (7.3 mM) and HEK293T (11.3 mM) cells differed, but were below physiologically relevant concentrations, supporting the hypothesis that the cellular iron-Fenton reaction normally yields CO. The redox-cycling compound menadione was used for continuous in-cell generation of HO to find bicarbonate dependencies in oxidation reactions of RNA. The studies herein point toward the redirection of the iron-Fenton reaction in cells to predominantly yield CO that selectively damages rG sites in the transcriptome.
Maternal-Fetal Transfer and Toxicokinetics of 2,2',5,5'-Tetrachlorobiphenyl, [C]-PCB52, Following Intratracheal Administration.
Adamu Y, Adamcakova-Dodd A, Jing X … +2 more , May D, Thorne PS
Chem Res Toxicol · 2025 Nov · PMID 41182394 · Full text
Despite increased recognition of the adverse impacts of PCB exposure on human health, comprehensive risk assessments, particularly regarding inhalation exposure and effects on the developing fetus, are lacking. Out of al...
Despite increased recognition of the adverse impacts of PCB exposure on human health, comprehensive risk assessments, particularly regarding inhalation exposure and effects on the developing fetus, are lacking. Out of all PCB congeners, lower-chlorinated PCBs have been more prevalent in indoor and outdoor atmospheres. Thus, we investigated toxicokinetics and placental transfer of radiolabeled [C]-PCB52 (0.157 mg/kg administered intratracheally) in Sprague-Dawley rats at gestational day 11 ± 1. Following dosing, 99.4 ± 0.5% of the administered dose was distributed to the systemic circulation. Radioactivity disappeared biexponentially following lung exposure, with 41.1% of the dose retained after 96 h. PCB52 was rapidly distributed to the maternal serum, lung, heart, and liver, with subsequent accumulation in the ovaries, brain, white and brown adipose, muscle, and mammary glands. The time to reach a maximum concentration in the maternal serum was 0.21 h, with an apparent terminal elimination half-life of 40.7 h. The peak concentration of [C]-PCB52 and its metabolites in the placenta, fetus, and amniotic fluid was achieved 1.7 h after exposure, with a fetal half-life of 34.8 h. The maternal serum level was significantly correlated with levels in amniotic fluid, placenta, fetus, and the maternal brain. However, PCB52 exposure in the placenta, fetus, and amniotic fluid was limited with their respective maternal serum exposure ratio values of 0.5, 0.27, and 0.05. These results demonstrate for the first time a comprehensive whole-body disposition of PCB52 in dams and fetuses after lung exposure during gestation. PCB52 and its metabolites accumulate predominantly in the ovaries, brain, and mammary glands. The apparent half-life of PCB52 in developing fetuses and placenta is comparable to that of maternal serum. This study provides novel quantitative foundations for the development and evaluation of physiologically based toxicokinetic modeling to inform the exposure and risk assessment for public health decisions.
Effects of Atmospheric Aging on the Respiratory Toxicity of Polystyrene Nanoplastic Particles.
Dodero AJ, Lampe OCG, Gagan S … +3 more , Niu S, Johnson NM, Zhang Y
Chem Res Toxicol · 2025 Nov · PMID 41182232 · Full text
Inhalation exposure to nanoplastic particles (NPPs) can lead to significant pulmonary toxicity; however, the effects of environmental processing on their toxicity remain poorly understood. This study examines the toxicit...
Inhalation exposure to nanoplastic particles (NPPs) can lead to significant pulmonary toxicity; however, the effects of environmental processing on their toxicity remain poorly understood. This study examines the toxicity of polystyrene (PS) NPPs on lung cells following controlled atmospheric aging. Human bronchial epithelial cells (16HBE) were cultured in vitro at the air-liquid interface and acutely exposed to oxidized PS NPPs through electrostatic precipitation. Expression of proinflammatory genes interleukin-8 (-8) and tumor necrosis factor alpha (-α) was significantly elevated at 6 and 48 h postexposure to aged NPPs, with corresponding increases in interleukin-6 (IL-6) protein levels supporting an inflammatory response. The oxidative stress marker heme oxygenase-1 (HO-1) also showed significantly increased expression at 6 h postexposure, supported by protein analysis. Atomic force microscopy (AFM) and aerosol mass spectrometry (AMS) revealed increased surface roughness and oxygen to carbon ratios in the atmospherically aged NPPs. Together, these results demonstrate that atmospheric aging alters the chemical composition and surface morphology of PS NPPs, enhancing proinflammatory and oxidative stress responses in bronchial epithelial cells, highlighting the critical role of environmental processing in determining the toxicity of nanoplastics.
E-Cigarette and Endothelial Function─A Critical Review of Preclinical Studies.
Bitar M, Pourchez J, Le Hello C … +2 more , Bertoletti L, Forest V
Chem Res Toxicol · 2025 Nov · PMID 41165203 · Publisher ↗
The electronic cigarette has been suggested as a safer alternative to the conventional tobacco cigarette. However, some vaping products have been shown to have cardiovascular effects, although this remains controversial....
The electronic cigarette has been suggested as a safer alternative to the conventional tobacco cigarette. However, some vaping products have been shown to have cardiovascular effects, although this remains controversial. Several clinical studies have identified a possible alteration of endothelial function due to exposure to e-cigarette aerosols. However, the underlying biological mechanisms responsible for this observation in humans are still unclear. Thus, the development of preclinical mechanistic studies seems necessary. The aim of this review is, therefore, to provide a comprehensive overview of preclinical studies addressing the question of how e-cigarettes may cause endothelial dysfunction, a predictive marker of cardiovascular events. 53 papers were included in the analysis. We analyzed these papers qualitatively and quantitatively and discussed their limitations. We found that while 30% of in vitro studies showed no effect of e-cigarette aerosols on endothelial cells 26% showed variable effects, and 44% showed a significant adverse effect on endothelial function. In vivo studies were more consistent, with the vast majority (96%) reporting negative effects of e-cigarettes on endothelial function. We concluded that e-cigarettes should not be considered harmless in terms of cardiovascular effects, as they may impair endothelial function through various mechanisms such as oxidative stress and inflammation. However, more studies with standardized and optimized designs are still needed to distinguish the role of nicotine, which is known to affect the cardiovascular system, from that of other components in e-cigarette aerosol.
Free Radicals in Cannabis Smoke.
Yeh K, Abbatt JPD
Chem Res Toxicol · 2025 Nov · PMID 41162195 · Publisher ↗
Tobacco and cannabis smoke are both complex chemical mixtures generated through combustion of biomass material. The presence of free radicals in tobacco smoke has been established for nearly seven decades. Despite simila...
Tobacco and cannabis smoke are both complex chemical mixtures generated through combustion of biomass material. The presence of free radicals in tobacco smoke has been established for nearly seven decades. Despite similarities between cannabis and tobacco smoke and the known presence of radicals in the latter, analysis of free radicals in cannabis smoke has yet to be conducted. In this work, electron paramagnetic resonance (EPR) spectroscopy was used to detect short-lived radicals and environmentally persistent free radicals (EPFRs) in cannabis smoke. Spin-trapping techniques were employed to aid in identification of the short-lived radicals. Congruent with findings from studies conducted on tobacco smoke, short-lived free radicals were detected in the gas phase, and EPFRs were detected in the particle phase of cannabis smoke. Gas phase results indicate the presence of oxygen-centered radicals in cannabis smoke, though the shape of the resulting EPR spectra differs slightly from that of tobacco smoke. Particle phase results for cannabis match well with those from previous studies conducted on tobacco smoke, regardless of the spin trap used (or lack thereof). Quantitative findings indicate that cannabis smoke contains approximately the same radical concentration as tobacco smoke, on the order of 10 gas-phase spins and 10 particle-phase spins per cannabis preroll or tobacco cigarette. The impacts of burning method (continuous vs puffing) and cannabinoid composition on radical concentrations were also investigated here. While puffing was observed to lower radical concentrations, the cannabinoid composition of the strain of cannabis burned had no observable impact on the amount or identity of free radicals detected.
Comparative Chemical Space Analysis of Pesticides and Substances with Genotoxicity Data.
Foil DH, König J, Herrmann K … +3 more , Jacob RA, Kneuer C, Kirchmair J
Chem Res Toxicol · 2025 Nov · PMID 41160725 · Full text
Experimental genotoxicity data are required for pesticidal and biocidal active substances prior to regulatory approval, while for their metabolites and impurities, in silico predictions are often accepted. Nonetheless, t...
Experimental genotoxicity data are required for pesticidal and biocidal active substances prior to regulatory approval, while for their metabolites and impurities, in silico predictions are often accepted. Nonetheless, the extent to which these compounds are represented in publicly available genotoxicity databases remains unclear. Herein, we utilize chemical space methods to define the overlap between pesticide substances (active substances, metabolites, and impurities) and activity data for six genotoxicity test types commonly employed in regulatory toxicology: the Ames test, the in vitro mammalian cell gene mutation test, the in vitro micronucleus test, the in vitro chromosomal aberration test, the in vivo micronucleus test, and the in vivo chromosomal aberration test. After merging and performing structure standardization on 18 public pesticide/biocide databases, we identified 4826 unique substances. Within 19 public genotoxicity databases, 19,897 substances had at least one data point in at least one genotoxicity test. The chemical space overlap between the pesticide substances and each genotoxicity set was evaluated by calculating physicochemical descriptors and molecular fingerprints, which were visualized by using dimensionality reduction methods. The chemical space of pesticide substances is well represented by substances with Ames test data and, to varying degrees, by substances with data from the other genotoxicity tests, with particularly low coverage for in vivo chromosomal aberration. The major scaffolds identified in pesticide substances were present in all of the genotoxicity data sets. Compared to pesticide substances, the genotoxicity data sets were enriched in functional groups characteristic of genotoxic compounds, such as annulated rings, but depleted in pesticide-typical structural motifs like halogens. Chemical space methods can assist regulatory toxicologists in understanding regions of pesticide substance chemical space that are well- or poorly characterized by genotoxicity data. This understanding is important for the accurate and targeted use of databases and data-based nontesting methods in line with regulatory requirements.
Comprehensive Survey of Mycotoxin Occurrence in Indian Food Commodities.
Mishra S, Jha G, Sharma D … +4 more , Tomar B, Kanchan S, Sushma, Rath SK
Chem Res Toxicol · 2025 Nov · PMID 41160058 · Publisher ↗
Mycotoxins are toxic secondary metabolites produced by fungi that contaminate food worldwide and pose serious health risks to humans and livestock. According to the Food and Agriculture Organization, nearly one-fourth of...
Mycotoxins are toxic secondary metabolites produced by fungi that contaminate food worldwide and pose serious health risks to humans and livestock. According to the Food and Agriculture Organization, nearly one-fourth of global food crops are affected. India's climatic conditions, including unseasonal rains and flash floods, create a favorable environment for mold growth and mycotoxin contamination by increasing grain moisture levels. Survey data suggest that fumonisin B1 is the most prevalent mycotoxin in Indian food commodities, followed by aflatoxin B1 and combined aflatoxins. While aflatoxin B1 is frequently detected, more studies have focused on aflatoxins than fumonisin B1, with fewer studies specifically analyzing fumonisin B1 in Indian food samples. Despite this, the highly reported incidence of fumonisin B1 suggests that it may be more widespread than currently recognized. This review is the first to comprehensively compile and analyze all available survey data on mycotoxins in Indian food commodities. It examines their prevalence, toxicological impact, and associated risks for consumers. Food safety regulations concerning mycotoxins in India are less stringent than those enforced by the European Union or the United States Food and Drug Administration. This regulatory gap raises concerns about food security, especially since mycotoxin contamination in India often exceeds permissible limits. As the world's most populous country, accounting for 17.76% of the global population, India faces significant challenges due to mycotoxins in food. Given its role as a leading producer and exporter of agricultural commodities, the issue extends beyond national borders, impacting global food trade and safety. Strengthening food safety regulations, increasing surveillance, and promoting awareness are crucial steps toward mitigating mycotoxin risks. This review serves as a valuable resource for researchers, policymakers, and consumers concerned with food safety and public health.
Production of 3-Cyanopyridine upon Vaping Nicotinamide and Evaluation of the Toxicological Effects of Individual and Combined Exposures via Isobologram-Based Analysis.
Jefferis T, Sengupta M, Bui A … +4 more , Dawkins C, Griffin K, Strongin RM, Sayes CM
Chem Res Toxicol · 2025 Nov · PMID 41150859 · Publisher ↗
Nicotine has been used in e-cigarettes for many years; however, recently, nicotine analogs have risen in popularity. E-cigarettes containing nicotine analogs such as nicotinamide and 6-methylnicotine are currently sold w...
Nicotine has been used in e-cigarettes for many years; however, recently, nicotine analogs have risen in popularity. E-cigarettes containing nicotine analogs such as nicotinamide and 6-methylnicotine are currently sold without regulatory oversight. They are marketed as safer alternatives to nicotine-containing products, although there is little or no scientific evidence to support this claim. This study investigated the nicotine analog, nicotinamide (NA), along with its major degradant, 3-cyanopyridine (3CP), which is produced when NA is vaped. Upon heating and aerosolization, both chemicals are present in the exposure dose. Dose-response curves are created for relative concentrations of NA and 3CP, and an isobologram is formed to investigate their mixture effects. NA is toxic at concentrations greater than 2637 ppm; however, 3CP is harmful in concentrations as low as 0.0001 ppm. The most significant finding is that the isobologram indicates that the mixture effects are synergistic, where a decrease in viability can be seen in minimal doses of 3CP (i.e., 0.000001 ppm) and 1350 ppm of NA. The interaction index was calculated for each point, and all values were less than 1, indicating a statistically synergistic biological response. The study highlights how such small levels of 3CP can play a large role in inducing toxic responses of a presumed safe chemical (i.e., nicotinamide or niacinamide, a form of vitamin B3 (niacin)). These results indicate that chemical and biochemical reactions, as well as interactions between e-cigarette aerosol components, including nicotine analogs, warrant further investigation.
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