Chem. Res. Toxicol. [JOURNAL]
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200 papers
Advancements in Nanomedicine for Allergic Diseases: Diagnosis, Toxicity, and Therapeutic Strategies.
Ramezani Farani M, Mirzaee D, Hassanpour M … +6 more , Nayebizadeh B, Mohades F, Azarian M, Chamani S, Simchi A, Huh YS
Chem Res Toxicol · 2025 Nov · PMID 41143631 · Publisher ↗
Allergic diseases affect over one billion people worldwide as a common chronic condition. Conventional treatments often relieve symptoms but lack long-term efficacy or safety. Over the past decade, nanomedicine, i.e., na...
Allergic diseases affect over one billion people worldwide as a common chronic condition. Conventional treatments often relieve symptoms but lack long-term efficacy or safety. Over the past decade, nanomedicine, i.e., nanoscale drugs and delivery systems, has emerged as a promising alternative that leverages the tunable physicochemical properties of nanoparticles (NPs) and enhances both diagnosis and treatment of hypersensitivity disorders. In diagnostics, nanoparticle-based biosensors have achieved detection limits as low as 42 fg/mL with specificity exceeding 90% for food and aeroallergen proteins. Therapeutic applications comprise various NPs, including gold, silver, iron oxide, carbon-based, lipid-mediated, polymeric, dendrimeric, and virus-like, as delivery vehicles and as immunomodulators. Preclinical models detect >50% reductions in pro-inflammatory cytokines (IL-4, IL-5) and two- to 3-fold reductions in eosinophil infiltration following NP-augmented allergen immunotherapy, with antigen-specific IgE titers reduced by up to 70%. Although such advancement has occurred, nanotoxicology studies highlight dose-dependent organ concentration and prolonged pulmonary half-lives that necessitate rigorous biosafety evaluation. Regulatory and manufacturability concerns remain significant hurdles for clinical translation. This article reviews up-to-date quantitative performance metrics for nanoparticle therapeutics and diagnostics in allergy control, critically examines the toxicity profiles and translational issues, and brings out directions toward individualized, safe nanotheranostic platforms.
l-Cysteine-Glutathione Mixed Disulfide, a Novel Bioavailable Sulfhydryl-Modified Glutathione Precursor, Protects against Early Liver Injury Induced by Short-Term Hypercholesterolemia.
Martínez-Gili L, Fucho R, Caballero F … +8 more , Núñez S, Jaara HS, Alarcón-Vila C, Rico N, Nagasawa HT, García-Ruiz C, Fernández-Checa JC, Torres S
Chem Res Toxicol · 2025 Nov · PMID 41127960 · Full text
Oxidative stress contributes to the damage of biological molecules and is linked to the development of multiple diseases, including liver disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD...
Oxidative stress contributes to the damage of biological molecules and is linked to the development of multiple diseases, including liver disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD). In mammals, reduced glutathione (GSH) is a pivotal antioxidant that regulates cellular responses to redox imbalances caused by reactive oxygen and nitrogen species. The presence of reduced GSH within mitochondria is especially crucial for preserving the organelle's routine performance by eliminating hydrogen peroxide generated under both physiological and pathological conditions. Cumulative evidence indicates that MASLD is associated with a diminished mitochondrial GSH (mGSH) pool, attributed to alterations in mitochondrial membrane fluidity due to cholesterol accumulation. Therefore, strategies aimed at boosting mGSH may offer therapeutic benefits against MASLD-associated liver injury. This study aims to investigate whether l-cysteine-glutathione disulfide (l-CySSG), a proposed GSH donor and precursor, can effectively restore total and mGSH in vitro and in vivo in mice fed cholesterol-enriched (HC) or methionine-choline-deficient (MCD) diets. Additionally, -adenosylmethionine (SAM), a compound that serves as both a GSH precursor and a membrane fluidizer, along with -acetylcysteine (NAC), a GSH precursor by providing cysteine, was used as the control molecules in the study. Our findings show that l-CySSG has great potential as a liver protector, especially due to its good oral bioavailability. Although it does not restore GSH levels in the mitochondria as efficiently as SAM does, l-CySSG can still offer protection against liver damage, possibly through mechanisms that are not yet fully understood. Overall, l-CySSG emerges as a promising alternative for treating conditions related to oxidative stress and mitochondrial dysfunction, paving the way for future research and therapeutic development.
Predictive Modeling of DNA Damage Outcomes: Classification of Mutational Determinants Using Augmented Machine Learning Techniques.
Balasubramanian S, Dayanidhi D, Velmurugan H … +4 more , Rajkumar K, Bhoopalan R, Vasagam SN, Vaidyanathan Ganesan V
Chem Res Toxicol · 2025 Nov · PMID 41086395 · Publisher ↗
The mutational outcome of DNA damage as a direct result of constant chemical assault is governed by major factors, including the structure and nature of damage, replication, and repair machinery . The role of the size of...
The mutational outcome of DNA damage as a direct result of constant chemical assault is governed by major factors, including the structure and nature of damage, replication, and repair machinery . The role of the size of the adduct, adduct-flanking bases, and the type of polymerase involved in the replication pathway is prominently seen through existing and studies. In this work, machine learning methods have been developed to predict the critical parameters for the mutational outcome of the adducts when they encounter polymerase in a particular sequence context. We carried out the analysis with three different classification models: Logistic Regression (LR), Decision Tree (DT), and Support Vector Machine (SVM). Using the literature data, mutational results of covalent DNA adducts and abasic sites were used to train the classification models. Following this, we used a generative network method with the available information on the structure of the DNA damage, polymerase, and sequence context to generate synthetic data that accurately mirrors the real data. Further, we employed an Extreme Gradient Boosting Classifier to identify the parameter that most influences the DNA mutational outcome. Metrics such as Accuracy, Sensitivity, Precision, F1 score, and AUC value have been used to evaluate the performance of classifier methods. The proposed Bootstrapped-Variational Autoencoder (BT-VAE) model enhanced the overall prediction accuracy of classifiers by 40%. The SVM model delivered the best performance across all classification metrics in predicting mutational outcomes among the three classification models evaluated. By providing the size of the carcinogen/covalent DNA adduct, polymerase, and flanking base as input, the proposed BT-VAE framework can predict the mutational outcome (match or mismatch for covalent DNA adducts and adenine or nonadenine for abasic site), an additional tool for and studies in the field of toxicology.
Industry Perspective on Nonclinical Approaches for Hepatotoxicity Risk Assessment: Insights from Two Longitudinal Surveys Conducted in 2023 and 2017.
Sakatis MZ, Norona LM, Karmel JE … +14 more , Proctor WR, Sarr FH, Rana P, Zane D, Caverly Rae J, Faber SC, Kodihalli RC, Regev A, Luffer-Atlas D, Irrechukwu O, Alpers DH, Jackson JP, Irizarry Rovira AR, Williams DP
Chem Res Toxicol · 2025 Nov · PMID 41081640 · Publisher ↗
The Nonclinical Translation Working Group of the IQ Drug-Induced Liver Injury (DILI) Consortium conducted two surveys in 2023 and 2017 to canvas member companies on approaches and experiences in the preceding 5-year peri...
The Nonclinical Translation Working Group of the IQ Drug-Induced Liver Injury (DILI) Consortium conducted two surveys in 2023 and 2017 to canvas member companies on approaches and experiences in the preceding 5-year periods that inform how DILI risk assessment has evolved in the past decade. Surveys comprised 53 detailed questions to understand the current status, temporal changes, and future direction and to gain insights. Focusing on the 2023 survey for the most contemporary data, responses indicated that DILI still remains a problem during drug development, with 41% of companies in the 2023 survey (50% in 2017) filing at least one clinical expedited safety report in the last 5 years. Most companies have common nonclinical screening approaches, with the majority of companies incorporating target safety assessments, considering physicochemical properties and dose, and using multiple in vitro approaches including cytotoxicity, mitotoxicity, BSEP inhibition, and various reactive metabolite assays, with the utilization of many of these being increased in the 2023 survey compared to the 2017 survey. The impact of in vivo toxicology studies on clinical study design and compound progression is also reviewed in both the 2023 and 2017 surveys. A large majority of companies now report having new modality drugs in their portfolios, including antibody-based and oligonucleotide-based modalities, cell therapies, protein degraders, and peptide-based medicines; yet only 1 or 2 companies report having modality-specific approaches to assess DILI risk despite these modalities having very different mechanisms of causing DILI compared to small molecules. This is a key area for growth in the nonclinical assessment of hepatotoxicity to support these emerging modalities and the tremendous potential that they offer for unmet clinical needs. Collaborative partnerships will be key to driving new capabilities forward in this area, contributing to the development of safer novel therapeutics for patients.
Olaparib Metabolism: Quantum Chemistry, Docking, and Dynamics-Based Insights into Mechanisms and Reactivity.
Nuthi A, Murty US, Dixit VA
Chem Res Toxicol · 2025 Nov · PMID 41077879 · Publisher ↗
Olaparib, an anticancer drug, has been recently associated with major side effects (hepatotoxicity and hematotoxicity). Human CYP450 3A4/5 metabolizes olaparib and forms dehydrogenated () and hydroxylated (, metabolites...
Olaparib, an anticancer drug, has been recently associated with major side effects (hepatotoxicity and hematotoxicity). Human CYP450 3A4/5 metabolizes olaparib and forms dehydrogenated () and hydroxylated (, metabolites. The major (dehydrogenated: ) metabolite is unreactive due to the stability of its amide bonds. Thus, the recently reported toxicities (hepato- and hemato) remain mysterious. Here, we investigate olaparib's metabolic pathways using model systems to gain insights into metabolic preferences, reactive metabolite formation, and associated toxicities. Potential energy surface (PES) analysis using activation (Δ), reaction (Δ°) free energies, and molecular docking, dynamics-based accessibility (distance of site of metabolism: SOM from heme-Fe) is utilized to explain metabolic preferences. Quantum chemical calculations showed that the formation of dehydrogenated ( and hydroxylated ( is favored relative to aromatic hydroxylated ( metabolites (reaction free energies: T = 18.5 kcal/mol as cutoff). The detailed analysis of the metabolic pathway for the major metabolite ( formation showed that hydroxylation follows the E1 mechanism, leading to dehydration and the formation of a tetrahydropyrazine derivative. The olaparib piperazine ring C approaches the heme-Fe within activating distance (6 ± 2 Å) in most docked poses and during 200 ns MD simulations. The C10 leading to hydroxylated metabolite ( remains at >10 Å, making the reactive formation less likely. Furthermore, the MM-GBSA-based per-residue calculations showed that 13 active-site residues, including Arg105, contribute significantly to the binding energy (avg: -1.24 kcal/mol). DFT-based global and local reactivity (electrophilicity: ω) analysis showed that the 4-acetylphthalazin-1(2H)-one group in the metabolite (formed from ) is highly electrophilic and might explain the idiosyncratic toxicities. These findings may offer valuable insights into the mechanisms of toxicity and for the design of novel and less toxic olaparib analogs.
Metabolic Profile of Male Cannabis Users and Estimation of Candidate Biomarkers.
Oz E, Kasikci M, Celik İ … +1 more , Gurler M
Chem Res Toxicol · 2025 Oct · PMID 41070685 · Full text
Tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, is the most widely abused substance worldwide, with an annual prevalence of 4.3% of adults and 5.3% of the 15-16 year-old population estimated as...
Tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, is the most widely abused substance worldwide, with an annual prevalence of 4.3% of adults and 5.3% of the 15-16 year-old population estimated as of 2022. THC has both acute and chronic effects through the dopaminergic and endocannabinoid systems. This study was conducted to better understand the metabolites and metabolic pathways in biological systems affected by cannabis, which may help find practical diagnostic and treatment approaches for people with cannabis dependence in the future. Metabolomic analysis of urine samples was performed using gas chromatography-mass spectrometry (GC-MS). MetaboAnalyst software was used to determine sample metabolite profiles, which were then subjected to multivariate statistical analysis. From data of over 200 metabolites in each sample of cannabis users, 92 metabolites with a -value of less than 0.05 were selected for further analyses, of which 38 showed a decrease and 54 showed an increase compared to the nonuser group. Based on 43 metabolites (VIP > 1), subjected to MetaboAnalyst and CPDB, amino acid metabolism (especially arginine, methionine, and cysteine), vitamin metabolism (particularly biotin), and the urea cycle were the primarily affected metabolic pathways. The AUC values of the four metabolites (salsoline, 6-thiourate, procollagen 5-hydroxy--lysine, and biotin) with the highest VIP scores were between 0.93 and 0.98, with no significant difference. Metabolites with high VIP scores hold promise as biomarker candidates for identifying cannabis users, and the prominent pathways provide new insights into the understanding of the metabolic effects of cannabis.
Carbon Nanoarchitectures: Toxicity Barrier and Therapeutic Advancement.
Ganguly S, Sarkar P, Sarkar D … +2 more , Debnath B, Sil SK
Chem Res Toxicol · 2025 Oct · PMID 41066698 · Publisher ↗
Advancement of therapeutic modalities using carbon-based nanomaterials (CBNMs) has mounted in the last few decades. The concept of therapeutic advancement consists of a possible application by understanding the toxicity...
Advancement of therapeutic modalities using carbon-based nanomaterials (CBNMs) has mounted in the last few decades. The concept of therapeutic advancement consists of a possible application by understanding the toxicity issues and their fate in the living biological system. Carbon based nanomaterials are recently exploited for their unique properties, and their utilization toward biomedical application such as drug delivery system (DDS), tissue regeneration, nonviral immunotherapy, biosensing, bioimaging, etc. is well reported. Despite such a report, it is very much required to understand their toxicity assessment with fate within the human body. The present review assesses the toxic behavior of various carbonaceous materials and the therapeutic advancement in spite of their toxicity issues. Carbon nanostructures (carbon quantum dot, carbon nanotube, fullerene, graphene, carbon nanohorn, carbon nanodiamond, etc.) impart various cellular toxicities, which are based on their geometric structure as well as chemical composition and physicochemical parameters (size, morphology, surface passivation). Moreover, this review also includes an additional section describing various sources of carbon with their preparation and their properties. Regardless of the toxicity barrier, carbon based materials are still ameliorating the therapeutic advancement with respect to various biomedical applications, which are also highlighted in this review along with their use by suppressing their toxic behavior.
Integrated , , and Framework for Early Derisking of Mast Cell Degranulation in Peptide Drug Candidates.
Shah F, Wang R, Vega BA … +11 more , Chen F, Bhatt B, Boyer NC, Hanisak J, Tucker TJ, Dong S, Josien H, Biswas K, Hu A, Li N, Gonzalez RJ
Chem Res Toxicol · 2025 Oct · PMID 41061142 · Publisher ↗
Recent studies have shown that certain peptides and small molecules can induce pseudoanaphylaxis reactions by triggering mast cell degranulation (MCD), resulting in the release of vasoactive and proinflammatory mediators...
Recent studies have shown that certain peptides and small molecules can induce pseudoanaphylaxis reactions by triggering mast cell degranulation (MCD), resulting in the release of vasoactive and proinflammatory mediators. This mechanism can result in severe adverse drug reactions with potentially life-threatening consequences in humans or loss of tolerability in animal studies, representing a considerable challenge in the development of peptide and small-molecule therapeutics. Therefore, early identification of drug candidates with MCD potential is crucial for an efficient Design-Make-Test-Analyze (DMTA) cycle while promoting the 3Rs principle (replacement, reduction, refinement) in animal research. In the present work, we introduce a proactive risk mitigation strategy aimed at evaluating and minimizing the MCD activity of peptide drug candidates. We developed an rat peritoneal mast cell degranulation (rMCD) assay to screen and prioritize candidates that do not exhibit rMCD activity during the lead optimization phase. Importantly, structure-activity relationships (SAR) were established by leveraging rMCD data sets which included ∼3000 diverse peptides across 28 internal programs targeting multiple therapeutic areas. Critical physicochemical properties were identified as predictive calculated parameters for rMCD outcomes. Additionally, we developed a directed message passing neural network (D-MPNN) model that combines structural features with calculated and predicted physicochemical properties, demonstrating strong predictive performance for rMCD outcomes. This model facilitates the early prioritization of peptide drug candidates for rMCD assays during the candidate selection phase and accelerates hit-to-lead and lead optimization by identifying peptides within a series that exhibit minimal rMCD liabilities. Notably, the D-MPNN model outperformed traditional property-based calculators in our prospective validation study. Furthermore, to address species-specific SAR, we also established a human MCD (hMCD) assay, revealing an 80% concordance in MCD outcomes between species. This hMCD assay identifies the MCD liabilities of compounds that differ from those in rats, indicating potential risks in humans. This comprehensive and approach enables drug discovery teams to advance drug candidates that are free from MCD liability in a resource-efficient manner, thereby increasing the likelihood of success in both nonclinical and clinical studies.
Inhibition of Ferroptotic Toxicity by 4-Hydroxyindole.
Jakaria M, Cannon JR
Chem Res Toxicol · 2025 Nov · PMID 41060843 · Full text
Hydroxyindoles are organic compounds characterized by the presence of a hydroxy group attached to an indole ring (six-membered benzene ring fused to a five-membered pyrrole ring). These compounds are naturally occurring...
Hydroxyindoles are organic compounds characterized by the presence of a hydroxy group attached to an indole ring (six-membered benzene ring fused to a five-membered pyrrole ring). These compounds are naturally occurring and play a role in the synthesis of various medicinal drugs. One notable example is 4-Hydroxyindole (4-HI), which contains a hydroxy group at the fourth position of the indole ring. In a recent study, we tested various hydroxyindole compounds for their antiferroptotic activity, including 3-hydroxyindole, which demonstrated strong resistance to ferroptosis. Ferroptosis is a regulated form of cell death that occurs due to uncontrolled phospholipid peroxidation and is associated with the development of degenerative conditions, such as neurodegenerative diseases. Here, we tested the hypothesis that 4-HI could protect against ferroptosis, similar to other hydroxyindole compounds. To induce ferroptosis, we utilized established modulators, including erastin, RSL3, and FINO2. We assessed cytotoxicity using the calcein AM assay and measured lipid peroxidation caused by ferroptosis inducers with the C11-BODIPY assay. Our results indicated that 4-HI protects various brain-related cell types, including HT-22, N27, and RBE4 cells, from ferroptosis. We also utilized our newly developed cell-free assay, in which combined iron and arachidonic acid were used to oxidize C11-BODIPY, allowing us to investigate the radical scavenging activity of 4-HI. We discovered that 4-HI exhibits antioxidant effects in cell-free assays, suggesting that its protective action against ferroptosis is likely due to its radical-scavenging capabilities. Interestingly, we found that 4-hydroxyindole-3-carbaldehyde, a structural analog of 4-HI, did not effectively prevent ferroptosis. This suggests that the carbaldehyde group, which is an electron-withdrawing group, may reduce the antiferroptotic activity of 4-HI. In summary, 4-HI appears to be a promising inhibitor of ferroptosis, warranting further research to explore its potential in protecting against neurotoxicity and neurodegeneration associated with this type of cell death.
Applicability Domain of Peroxidase Peptide Reactivity Assay (PPRA): Chemical Structure Analysis and Grouping of Peptide Depletion Patterns.
Yan G, Kern PS, Ellingson K … +5 more , Zhang M, Gerberick GF, Lee I, Ryan C, Schember I
Chem Res Toxicol · 2025 Oct · PMID 41037328 · Publisher ↗
Skin sensitization is a critical endpoint in human safety risk assessment of chemicals. Risk assessment approaches have evolved, and the field has seen a shift toward adopting new approach methods (NAMs) instead of relyi...
Skin sensitization is a critical endpoint in human safety risk assessment of chemicals. Risk assessment approaches have evolved, and the field has seen a shift toward adopting new approach methods (NAMs) instead of relying solely on animal or human data. While the direct peptide reactivity assay (DPRA) is considered one of the NAMs of key event (KE) 1 within the OECD guideline 497 in combination with other NAMs for predicting skin sensitization hazard or potency, the assay is limited by the lack of activation features for pre-/pro-haptens. To address this, the peroxidase peptide reactivity assay (PPRA) was developed, utilizing horseradish peroxidase (HRP) and HO to facilitate the oxidation and activation of test substances. However, limited information is available on the chemical substrate scope and applicability domain of the PPRA. In this study, we investigated the substrate scope of HRP to gain insights into the mechanism of the PPRA. Based on our analysis, the substrates of HRP include substituted phenols (or aromatic alcohols) and aniline (or aromatic amines) as well as their O- or N-alkyl derivatives. By considering the substrate scope of HRP, depletion patterns and mechanisms in the DPRA/PPRA, and the underlying chemistry of the assays, we categorized chemicals into five distinct chemical groups with unique structural features and depletion patterns in the DPRA/PPRA. This study elucidates the relationship between chemical structures, assay results of the DPRA and PPRA, and their applicability for predicting the skin sensitization potential. These findings contribute to a better understanding of the predictive capabilities of the PPRA and provide valuable insights for incorporating PPRA into next-generation risk assessments (NGRAs).
Uncovering the Dual Effect of Menthol and Nicotine Levels in Electronic Nicotine Delivery Systems on Pulmonary Surfactant Function.
Harb Y, El Khatib K, Rey B … +3 more , Mcheik A, George C, Hayeck N
Chem Res Toxicol · 2025 Oct · PMID 41030075 · Publisher ↗
Electronic nicotine delivery systems (ENDS) are now increasingly used, with commercial electronic cigarettes frequently containing high levels of nicotine and menthol, which is a popular flavoring agent. This has raised...
Electronic nicotine delivery systems (ENDS) are now increasingly used, with commercial electronic cigarettes frequently containing high levels of nicotine and menthol, which is a popular flavoring agent. This has raised multiple concerns about the health risks associated with menthol-flavored ENDS. Although menthol and nicotine are known for their individual effects on respiratory health, their combined impact on pulmonary surfactants remains poorly understood. Therefore, this study aimed at understanding the interactions between the primary components of all ENDS liquids (PG and VG), nicotine and menthol flavoring, and the pulmonary surfactant. This in vitro study used 1,2 dipalmitoyl--glycero-3-phosphocholine (DPPC) and a stoichiometric mixture of DPPC/1-palmitoyl-2-Oleoyl--glycero-3-phosphocholine (POPC)/2-Oleoyl-1-palmitoyl--glycero-3- phospho-rac-(1-glycerol) sodium salt (POPG)/cholesterol at 48/32/10/10 to mimic the pulmonary surfactant. These systems were probed using a Langmuir-Blodgett Trough and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The results indicate a concentration dependence of the impact of different nicotine concentrations combined with menthol on the surfactant mimics. Our findings also reveal the effect of menthol on the surface pressure. The combination of nicotine and menthol appears to alter the conformational state of the surfactant, proximately altering characteristic vibrational groups. Moreover, different behaviors are unveiled between the two model surfactants, particularly attributed to the complexities of the four surfactants mixture. Further research is suggested to address the mechanisms and implications involved with ENDS flavoring and additives on surfactant molecules in biological systems. Establishing well-informed regulations on ENDS consumption and distribution should be developed.
In Vitro Toxicity Assessment of Pre- and Post-incinerated Organomodified Nanoclays on Airway Epithelial and Lung Fibroblast Cells.
Stueckle TA, Jensen J, Coyle JP … +10 more , Wagner A, Derk R, Kornberg TG, Friend SA, Schreiner M, Ufelle AC, Agarwal S, Gupta RK, Dinu CZ, Rojanasakul LW
Chem Res Toxicol · 2025 Oct · PMID 40970902 · Publisher ↗
The use of two-dimensional organomodified nanoclays (ONCs) to improve nanocomposite properties continues to grow. Recent evidence suggests that airborne nanoclays in occupational environments pose an inhalation hazard; h...
The use of two-dimensional organomodified nanoclays (ONCs) to improve nanocomposite properties continues to grow. Recent evidence suggests that airborne nanoclays in occupational environments pose an inhalation hazard; however, health risks and the underlying mechanisms remain undefined. In vivo studies evaluating pre- and post-incinerated ONC exposures found that cytotoxicity, inflammation, and fibrotic signaling responses are coating- and incineration status-dependent. We hypothesized that physicochemical property differences associated with coating presence/absence and incineration status of nanoclays will elicit changes in key events (KE) in exposed human small airway epithelial (SAECs) and normal lung fibroblast (NHLF) cells that contribute to pulmonary lung fibrosis. Using multiplex high-throughput screening strategies, SAEC and NHLF cells were acutely exposed (0-20 μg/cm) to pristine nanoclay (CloisNa), an ONC (Clois30B), their incinerated byproducts (I-CloisNa and I-Clois30B), and crystalline silica (CS), to evaluate how ONC characteristics influence several KE in the pulmonary fibrosis adverse outcome pathway. In vitro exposure to pre-incinerated nanoclay induced organic coating-dependent cytotoxicity in SAECs. CloisNa caused disruption of mitochondrial membrane potential, which coincided with loss in viability in both cell types. Clois30B exposure caused dose-dependent SAEC cytotoxicity, micronuclei formation, and mitochondrial hyperpolarization in SAECs and NHLFs. Incinerated nanoclays were noncytotoxic but elicited a SAEC mitochondrial radical and pro-inflammatory response. Direct in vitro exposure to NHLFs exhibited particle-dependent increased live cell count, reactive oxygen species production, and α-smooth muscle actin expression. Nanoclay-exposed NHLFs (0.6 μg/cm) possessed elevated collagen I levels while the same mass dose in vivo (300 μg/lung) favored elevated fibronectin and collagen III deposition for CloisNa and CS. In conclusion, organic coating presence and incineration status influenced nanoclays' effects on cellular interaction, membrane integrity, inflammation, fibroblast activation, and collagen accumulation in exposed cell models. Although pre-incinerated nanoclay exposure promoted collagen accumulation in vitro, it was a poor predictor of in vivo model reticular fiber deposition.
Association between Occupational Cadmium Exposure and Markers of Kidney Injury: A Systematic Review and Meta-Analysis.
Kalahasthi R, Nagaraju R, Balachandar R … +2 more , Upadhyay K, Bagepally BS
Chem Res Toxicol · 2025 Oct · PMID 40955464 · Publisher ↗
Cadmium (Cd)-induced nephrotoxicity is a well-known phenomenon; however, several observational studies have used various biomarkers to monitor kidney injury in occupationally exposed populations. The markers used in thes...
Cadmium (Cd)-induced nephrotoxicity is a well-known phenomenon; however, several observational studies have used various biomarkers to monitor kidney injury in occupationally exposed populations. The markers used in these studies are found to be varied in sensitivity and are site-specific, and experts have the opinion that a single marker cannot predict the degree of kidney injury in human biomonitoring studies. Therefore, the current systematic review consolidates existing evidence to identify the association between Cd exposure and markers of potential sites of renal dysfunction/damage. Thirty (30) studies with 1980 chronic Cd exposure by occupations and 1292 unexposed were included in the review. The pooled mean difference of Cd exposure was as follows: blood Cd, 6.45 (5.18 to 7.71) μg/L; urine Cd, 4.52 (3.54 to 5.5) μg/g creatinine. Cd exposure was associated with impaired glomerular function (higher serum creatinine, serum β2 microglobulin, and lower creatinine clearance rate), tubular reabsorption (higher urinary β2 microglobulin and retinol binding protein), and injury (higher urinary -acetyl-β-d-glucosaminidase and kidney injury molecule-1). However, the included studies exhibited high levels of heterogeneity. From the data, it is highly evident that biomarkers such as urinary -acetyl-β-d-glucosaminidase, and retinol binding protein are found to be more sensitive than conventional clinical renal functional markers such as serum creatinine, urinary albumin, and protein levels, which are found to be within acceptable limits among the Cd-exposed group. Considering the rising disease burden of chronic kidney disease of unknown origin, Cd exposure-associated renal dysfunction and damage is a public health concern. Therefore, the review also discussed emerging biomarkers with higher sensitivity for early detection that can be adopted in occupational biomonitoring studies as early markers to prevent/delay the progression of kidney disease among the working population. Prospero Registration ID: CRD42022380923.
CYP2A6 Activity and Deuterated 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) Metabolism in Cigarette Smokers.
von Weymarn LB, Thomson NM, Le Marchand L … +1 more , Murphy SE
Chem Res Toxicol · 2025 Oct · PMID 40952945 · Publisher ↗
Smoking is the leading cause of lung cancer. Differences in CYP2A6-catalyzed nicotine metabolism affect smoking dose and intensity, which, in turn, can affect lung cancer risk. CYP2A6 also catalyzes the bioactivation of...
Smoking is the leading cause of lung cancer. Differences in CYP2A6-catalyzed nicotine metabolism affect smoking dose and intensity, which, in turn, can affect lung cancer risk. CYP2A6 also catalyzes the bioactivation of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). To determine the contribution of CYP2A6 to the metabolic activation of NNK, a group of Japanese American and Native Hawaiian smokers with little or no CYP2A6 activity was recruited to smoke [pyridyl-D]-NNK-containing cigarettes for a week. [Pyridyl-D]-4-hydroxy-4-(3-pyridyl)butanoic acid (D-hydroxy acid), the urinary product of NNK α-hydroxylation, the major bioactivation pathway, was quantified in these individuals and in an equal number of smokers with "normal" CYP2A6 activity. In expectation of low D-hydroxy acid levels, a sensitive nanoflow LC-MS/MS assay was developed. CYP2A6 activity was measured as the plasma ratio of 3'-hydroxycotinine to cotinine, which is the nicotine metabolite ratio (NMR). The average concentration of D-hydroxy acid in 24 h urine samples over 3 days was 20 ± 14 fmol/mL in low NMR (<0.05) smokers ( = 8) 33 ± 18 fmol/mL ( = 0.056) in "normal" NMR (>0.3) smokers ( = 8). The total D-hydroxy acid excreted by the low NMR group was half that of the higher NMR group (29.1 ± 16.8 59.7 ± 45.3 pmol/24h, = 0.048). These data support the role of CYP2A6 in the metabolic activation of NNK. However, it is unlikely that more modest differences in CYP2A6 activity, for example, as might be seen across smokers of European ancestry, would significantly impact NNK bioactivation. The influence of CYP2A6 activity on nicotine metabolism and the associated carcinogen uptake is likely the primary influence of CYP2A6 activity on a smoker's risk of lung cancer, not a modest effect on the metabolic activation of NNK, one of several lung carcinogens in tobacco smoke.
Quantitation by Liquid Chromatography-Nanoelectrospray Ionization-High Resolution Tandem Mass Spectrometry of Methyl and Ethyl DNA Adducts in Oral Cells from Cigarette Smokers and Nonsmokers of the Shanghai Cohort Study.
Cheng G, Luedtke MW, Wang R … +3 more , Yuan JM, Balbo S, Hecht SS
Chem Res Toxicol · 2025 Oct · PMID 40934370 · Full text
We used liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry (LC-NSI-HRMS/MS) to quantify DNA adducts released from human oral cell DNA upon neutral thermal hydrolysis followed by ac...
We used liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry (LC-NSI-HRMS/MS) to quantify DNA adducts released from human oral cell DNA upon neutral thermal hydrolysis followed by acid hydrolysis. The assay was applied to 80 buccal cell samples selected from those collected in the Shanghai Cohort Study, a prospective epidemiology study of 18,244 Chinese men 45-64 years old who resided in Shanghai, China when the samples were collected in 2001-2003. The DNA adducts quantified were 3-methyladenine (3-Me-Ade), 3-ethyladenine (3-Et-Ade), and 7-ethylguanine (7-Et-Gua). The method used hydrolysis of DNA samples containing the stable isotope labeled internal standards, solid phase extraction for adduct enrichment, and analysis by LC-NSI-HRMS/MS. Accuracy and precision of the analytical method were established with detection limits of 10-20 amol on column. Median levels of 3-Me-Ade -187 adducts/10 nucleotides in smokers and 129 adducts/10 nucleotides in nonsmokers; and 7-Et-Gua -49 adducts/10 nucleotides in smokers and 21 adducts/10 nucleotides in nonsmokers─were significantly higher in smokers than in nonsmokers (both values <0.01). Levels of 3-Et-Ade -50 adducts/10 nucleotides in smokers and 43 adducts/10 nucleotides in nonsmokers - were not significantly different. These results demonstrate the applicability of a highly sensitive LC-NSI-HRMS/MS method for the analysis of human oral cell DNA for adducts released by neutral thermal and acid hydrolysis and show the significant effects of cigarette smoking on levels of 3-Me-Ade and 7-Et-Gua in this DNA. This is apparently the first study to characterize 3-Me-Ade in intact DNA isolated from any human tissue.
Overview of Tools to Evaluate Human Health Toxicity, Ecotoxicity, and Toxicokinetic Profiles in the Hazard Assessment of Chemicals Used in Cosmetics.
Lancia P, Louazzani M, Gros L … +3 more , Ginestar J, Fioravanzo E, Baleydier A
Chem Res Toxicol · 2025 Oct · PMID 40925860 · Publisher ↗
The development of alternative methods to animal testing has gained momentum over the years, including the rapid growth of methods, which are faster and more cost-effective. A large number of tools have been published,...
The development of alternative methods to animal testing has gained momentum over the years, including the rapid growth of methods, which are faster and more cost-effective. A large number of tools have been published, focusing on Read-Across, (quantitative) Structure-Activity Relationship ((Q)SAR) models, and Physiologically Based Pharmacokinetic (PBPK) models. All of these methods play a crucial role in the risk assessment for cosmetics. However, despite the continuous efforts of various working groups, these methods are not always accepted by regulatory authorities around the world due to a lack of standardization and transparency in their development and application. This study aimed to identify tools that can predict key properties relevant to the hazard assessment of cosmetic ingredients, aiming to streamline decision-making and assist toxicologists in efficiently selecting and integrating predictions. Eighty-four tools were identified based on their predictive capabilities, covering physicochemical parameters, toxicological/ecotoxicological endpoints, and toxicokinetic properties using different computational methods, e.g., (Q)SARs; Read-Across. Additional criteria were also considered for QSAR models, helping toxicologists integrate them into risk assessment processes: (1) definition of the Applicability Domain (AD), (2) model performance, and (3) nearest neighbors of the target substance. Based on these criteria, the models were classified as either useful for screening or suitable for a Weight of Evidence (WoE) approach. Finally, this study highlights the growing number of computational tools available for assessing various endpoints relevant to cosmetic safety. The number of tools continues to increase, and regular reviews are necessary. A deeper understanding of these tools will facilitate their use by toxicologists and improve their acceptance for regulatory purposes from different cosmetic authorities.
Temozolomide-Derived AIC Is Incorporated into Purine Synthesis in Glioblastoma.
Sowers ML, Baljinnyam T, Herring JL … +7 more , Chang-Gu B, Hackfeld LC, Tang H, Hatch S, Valdes P, Zhang K, Sowers LC
Chem Res Toxicol · 2025 Oct · PMID 40925600 · Full text
Glioblastoma (GBM) is a lethal brain tumor with limited therapeutic options. Temozolomide (TMZ), a standard-of-care chemotherapeutic agent, exerts its cytotoxicity by alkylating DNA, which triggers a DNA damage response...
Glioblastoma (GBM) is a lethal brain tumor with limited therapeutic options. Temozolomide (TMZ), a standard-of-care chemotherapeutic agent, exerts its cytotoxicity by alkylating DNA, which triggers a DNA damage response and depletes ATP and NAD. However, TMZ also releases the byproduct 4-amino-5-imidazole carboxamide (AIC), which is believed to be a benign metabolite. We considered the possibility that AIC from TMZ could enter the de novo purine synthesis pathway, contributing to AMP and NAD synthesis and thus potentially antagonizing the anticancer activity of TMZ. The purpose of this article is to determine if AIC from TMZ can be incorporated into cellular purines. Using mass spectrometry with isotope-labeled TMZ, we demonstrate that the AIC derived from TMZ is incorporated into AMP and NAD in glioblastoma cell lines. Further, we performed an analysis of publicly available transcriptomic data from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Our analyses demonstrate that de novo purine synthesis is upregulated in GBM relative to the normal brain. Collectively, our findings demonstrate that a drug metabolite of TMZ, AIC, can be incorporated into de novo purine synthesis, which is upregulated in GBM.
Ultrasensitive Direct Chemical Analysis of Human Hair Using Proton Transfer Reaction Time-of-Flight Mass Spectrometry (PTR-TOF-MS) for Nontargeted Exposure Profiling.
Neville AC, Jarma DA, Blomdahl DC … +3 more , Lin CH, Kinney KA, Misztal PK
Chem Res Toxicol · 2025 Oct · PMID 40919832 · Full text
Exposure to air pollution plays a significant role in human health. Current methods of measuring human exposure are often limited to outdoor measurements, are time intensive, or are unable to accurately measure certain c...
Exposure to air pollution plays a significant role in human health. Current methods of measuring human exposure are often limited to outdoor measurements, are time intensive, or are unable to accurately measure certain classes of compounds. This study proposes human hair as a promising indicator of pollution exposure. We present a novel method of hair analysis involving thermal extraction and detection of semivolatile organic compounds using a Vocus 2R proton transfer reaction time-of-flight mass spectrometer (Vocus PTR-TOF-MS). The hair samples were subjected to a temperature ramp spanning three different temperatures: 60 °C, 90 °C, and 120 °C. A hierarchical clustering approach was used to create "clustergrams", dendrograms comprising chemical fingerprints of the hair samples at each different temperature. Each clustergram grouped the chemicals in the samples by similarity, allowing the determination of potential sources of exposure. Multivariate factor analysis revealed the presence of phthalates and their corresponding metabolites, confirming that this method can detect biomarkers associated with pollution exposure. This method enables the rapid and sensitive detection of a wide spectrum of toxicologically relevant compounds in human hair, providing an initial screening tool for measuring human exposure and assessing health risks.
N-Doped Graphene for Biomedical Applications: A Comparative Biocompatibility Assessment of Green and Chemical Exfoliation.
Papanikolaou E, Athinodorou AM, Patila M … +15 more , Zygouri P, Spyrou K, Subrati M, Alatzoglou C, Dounousi E, Gournis DP, Kotoulas KT, Xie M, Burrows AD, Cave G, Peschos D, Tsamis K, Lakkas L, Stamatis H, Simos YV
Chem Res Toxicol · 2025 Sep · PMID 40910196 · Full text
Graphene-based nanomaterials have transformed biomedical applications due to their exceptional physicochemical properties, and nitrogen (N)-doping further enhances the electrocatalytic activity of graphene. Driven by the...
Graphene-based nanomaterials have transformed biomedical applications due to their exceptional physicochemical properties, and nitrogen (N)-doping further enhances the electrocatalytic activity of graphene. Driven by the demand for safer and more sustainable nanomaterials, in this work, we compared eco-friendly produced - doped graphene (bD) with conventionally synthesized - doped graphene (cD) in three different cell lines. Across all cell types and assays, cD was more toxic than bD. In NIH/3T3 fibroblast cells, cD activated the Nrf2 signaling pathway, whereas in HaCaT keratinocytes, it triggered oxidative stress responses and increased the apoptotic population. High doses of cD also affected THP-1-derived macrophages by inducing apoptosis and arresting the cell cycle in the G0/G1 phase. Although high doses of bD were also cytotoxic, overall, its effects were milder than cD. Our results confirm that green exfoliation of - doped graphene retains its desirable biomedical properties while enhancing its biocompatibility, making bD a safer choice for future biomedical applications.
Heating Coil Corrosion by E-Liquid Containing Nicotine Lactate Salt and In Vitro and In Vivo Evaluation of Nickel Leachate in E-Liquid and E-Cigarette Aerosol.
Dong Z, Pang Q, Ling Q … +11 more , He C, Wu G, Wei S, Deng W, Liu C, Qian J, Fu Y, Hai T, Chen Z, Yun L, Rong X
Chem Res Toxicol · 2025 Sep · PMID 40907005 · Publisher ↗
Nicotine lactate salt is one of the commonly used nicotine salts in electronic cigarette (e-cigarette) formulations, including products that have received Marketing Granted Orders through the FDA's Premarket Tobacco Prod...
Nicotine lactate salt is one of the commonly used nicotine salts in electronic cigarette (e-cigarette) formulations, including products that have received Marketing Granted Orders through the FDA's Premarket Tobacco Product Application (PMTA) evaluation in the US. However, full-life cycle evaluation on nicotine lactate salt remains limited, especially its leaching reactions with heating elements and the potential to influence aerosol composition. This study investigated the chemical effects of nicotine lactate salt on e-cigarette heating coils and potential toxicological consequences of nickel (Ni) leachates using in vitro cells and animal models. The results showed that immersion of heating coils in e-liquid (PG:VG 6:4) containing 2% nicotine lactate salt resulted in a significant increase in Ni concentration in the e-liquid over a period of 4 weeks, with levels rising over time as compared to the nicotine benzoate group. A commercially available disposable e-cigarette (liquid capacity: 9.4 mL; power output: 11 W) was utilized. Similarly, aerosol generated from the e-liquid containing 2% nicotine lactate salt exhibited elevated Ni levels. In vitro cytotoxicity exposure to the Beas-2B, SH-SY5Y, and HepG2 cell lines indicated that the aerosol generated from 2% nicotine lactate e-liquid showed higher toxicity than that of the 2% nicotine benzoate e-liquid, with more pronounced Ni accumulation in cells. In vivo inhalation using C57BL/6J mice demonstrated significant Ni accumulation in mice exposed to the aerosol produced from nicotine lactate salt, particularly in the liver. The corrosion of heating coils of nicotine lactate salt e-liquid was attributed to combined electrochemical and acidic corrosion mechanisms. In conclusion, our findings provide valuable insights into the material compatibility and potential toxicological implications for nicotine lactate-based e-liquids in electronic nicotine delivery systems. More research is needed to fully assess the implications of these preclinical findings.
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