Chem. Res. Toxicol. [JOURNAL]
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200 papers
Pubertal Exposure to Lambda-Cyhalothrin Disrupts Adrenal Steroidogenesis via Downregulation of AGTR1A/CYP11B2 and Apoptosis Induction.
Chen W, Liu X, Lin H … +3 more , Su M, Ge RS, Li H
Chem Res Toxicol · 2026 May · PMID 42066037 · Publisher ↗
Lambda-cyhalothrin (LCT) is a pyrethroid widely employed in agriculture. However, their effects on adrenal function during puberty remain unclear. The objectives of the study are to demonstrate LCT-mediated impairments o...
Lambda-cyhalothrin (LCT) is a pyrethroid widely employed in agriculture. However, their effects on adrenal function during puberty remain unclear. The objectives of the study are to demonstrate LCT-mediated impairments of adrenal steroidogenesis in rats. Male Sprague-Dawley rats were gavaged with LCT (0.25, 0.5, and 1 mg/kg) from postnatal days 28 to 58, and toxicity was analyzed. LCT exposure did not affect body weight but significantly reduced serum aldosterone at ≥0.25 mg/kg and corticosterone at ≥0.5 mg/kg, without altering ACTH levels. Histological assessment revealed no changes in zona glomerulosa thickness, but 1 mg/kg LCT significantly reduced the CYP11A1-positive zona fasciculata thickness. qPCR and Western blot analyses indicated selective downregulation of , , and transcripts, with corresponding decreases in AGTR1A, CYP11B2, and IGF1 protein expression, implicating disrupted hormone biosynthesis and adrenal growth signaling. In H295R cells, LCT at ≤1000 μM was noncytotoxic but suppressed aldosterone and cortisol secretion at 100 μM. This concentration also significantly inhibited AGTR1A and CYP11B2 expression, increased CASP3, and decreased BCL-2 levels, without changes in ROS generation or mitochondrial membrane potential, suggesting apoptosis induction through ROS- and MMP-independent pathways. Collectively, these findings reveal that LCT impairs adrenal endocrine development and function by downregulating key steroidogenic mediators and promoting apoptosis.
Next-Generation Sequencing Analysis of 8-Oxo-7,8-dihydroguanine in Human Mitochondrial DNA.
Zheng X, Fu P, Zhao Y … +4 more , Chen D, Peng Y, Dai X, You C
Chem Res Toxicol · 2026 May · PMID 42054583 · Publisher ↗
Oxidative damage to mitochondrial DNA is closely associated with the development of various human diseases. 8-Oxo-7,8-dihydroguanine (8-oxoG) is a vital biomarker of oxidative DNA damage with a putative role as an epigen...
Oxidative damage to mitochondrial DNA is closely associated with the development of various human diseases. 8-Oxo-7,8-dihydroguanine (8-oxoG) is a vital biomarker of oxidative DNA damage with a putative role as an epigenetic-like modification. Herein, we reported a high-throughput sequencing analysis of 8-oxoG modifications using a chemical labeling-based method and identified multiple 8-oxoG sites in human mitochondrial DNA. We also demonstrated that Y-box binding protein 1 (YBX1), an 8-oxoG-binding protein, is potentially involved in the transcriptional regulation of mitochondrial genes containing 8-oxoG modification sites. These findings provide a solid foundation for further understanding the biological consequences of 8-oxoG modification in mammalian cells.
A Structure-Based Platform for Predicting Chemical-Induced Parkinson's Disease.
Schoenmaker L, van der Veer EEM, Jiskoot DA … +3 more , Béquignon OJM, van Westen GJP, Jespers W
Chem Res Toxicol · 2026 May · PMID 42053241 · Publisher ↗
Current methods for determining the neurotoxic potential of (agro)chemicals are not comprehensive enough, as is suggested by the increased incidence of Parkinson's disease (PD) among people exposed to certain pesticides....
Current methods for determining the neurotoxic potential of (agro)chemicals are not comprehensive enough, as is suggested by the increased incidence of Parkinson's disease (PD) among people exposed to certain pesticides. Mechanism-based screening can address this shortcoming by predicting molecular initiating event activation, a precursor of the adverse outcome. However, a limited amount of protein-binding data has been collected on pesticides, meaning that for screening, an approach is required that is well suited for extrapolation to a wide variety of chemicals. Here, the group I metabotropic glutamate receptors (mGluRs) were taken as a case study because of their role in chemical-induced PD. Compounds with known activity for these receptors were docked into the allosteric binding site, interaction fingerprints (IFPs) were computed, and used to train classification models. Afterward, model enrichment was evaluated, feature importance was derived, and the applicability domain was analyzed. Both IFP-based mGluR models demonstrated good enrichment with the area under the Receiver Operating Characteristic Curve (ROC AUC) being 0.78 and 0.66. The interactions that were most important for model predictions were hydrogen bond formation with Asn760 for mGluR1 and aromatic interactions with Trp785 for mGluR5. The applicability domain varied depending on the training set but was consistently larger for IFPs than for Morgan fingerprints, a fragment-based descriptor. A virtual screen using the final models identified 132 potential mGluR binders, of which one, bifenthrin, had been previously found to bind in experiments. To promote the implementation of the screening technique presented here, a platform was created where users can make predictions using our models. All in all, these results highlight the potential of combining IFPs with machine learning and contribute to the shift toward mechanism-based toxicology.
Protein Adduction and Hepatotoxicity Induced by Stiripentol.
Lin Y, Jiang Z, Peng Y … +1 more , Zheng J
Chem Res Toxicol · 2026 May · PMID 42047167 · Publisher ↗
Stiripentol (STP) is a kind of effective antiepileptic medicine, but its hepatotoxicity has been documented. However, the cause of its hepatotoxicity remains unclear. In this study, we attempted to explain its hepatotoxi...
Stiripentol (STP) is a kind of effective antiepileptic medicine, but its hepatotoxicity has been documented. However, the cause of its hepatotoxicity remains unclear. In this study, we attempted to explain its hepatotoxicity from the perspective of protein adduction derived from STP. We proposed that STP could produce an electrophilic carbonium ion, which formed hepatic GSH conjugation and protein adduction, and the carbonium ion was produced through two pathways, spontaneous dehydration and sulfation catalyzed by sulfotransferases (SULTs). STP-derived glutathione (GSH) conjugate was found in chemical reaction systems involving STP and GSH, which indicates that STP can undergo spontaneous dehydration to produce a carbonium ion. Increased GSH conjugate was observed in mouse liver cytosol incubation supplemented with GSH in the presence of the sulfation cofactor 3'-phosphoadenosyl-5'-phosphosulfate, which indicates that sulfation metabolism by SULTs can accelerate the production of carbonium ions. GSH conjugation and protein adduction were found in the livers of STP-treated mice and mouse primary hepatocytes, and 2,6-dichloro-4-nitrophenol, an inhibitor of SULTs, displayed an inhibitory effect on them. Serum alanine aminotransferase and aspartate aminotransferase activities in STP-treated mice and cytotoxicity in mouse primary hepatocytes displayed dose- and concentration-dependent trends, respectively, as did protein adduction. L-Buthionine-sulfoximine co-treatment potentiated the protein adduction and the susceptibility of hepatocytes to the cytotoxicity of STP. These findings suggest that protein adduction is responsible for STP-induced hepatotoxicity, and GSH serves a detoxification function against protein adduction.
New Docking, Molecular Dynamics, and QSAR Models to Predict Disruption of Human and Rat Transthyretin Function by Per- and Polyfluoroalkyl Substances (PFAS).
Almeida NMS, Bolstad HM, Coffin S … +3 more , Majid S, Wilson AK, Soshilov AA
Chem Res Toxicol · 2026 May · PMID 42045079 · Full text
Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals that require an improved understanding of the toxicity mechanisms and the development of predictive models for risk assessment. One obse...
Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals that require an improved understanding of the toxicity mechanisms and the development of predictive models for risk assessment. One observed effect of PFAS exposure is a decrease in thyroxine (T) levels resulting from the direct displacement of T from a carrier protein, transthyretin (TTR), in a proposed adverse outcome pathway (AOP). In this study, the mechanism of thyroxine (T) displacement from human and rat TTRs was investigated by using structural approaches (i.e., docking and molecular dynamics) and quantitative structure-activity relationship (QSAR) models. A QSAR model was developed using the largest available binding data set and a two-tier approach that allowed inclusion of all data. Docking models that utilized a pharmacophore approach showed nearly perfect overlap with independently sourced crystal structures for perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS). Molecular dynamics simulations demonstrated similar PFAS binding modes in rat and human TTR, enabling interspecies toxicity comparisons. All models predicted moderate to strong binding of the novel PFAS 4,8-Dioxa-3-perfluorononanoic acid (ADONA) and hexafluoropropylene oxide dimer acid (GenX) to TTR, consistent with the limited toxicity and binding data for these chemicals. Predicted PFAS binding energies for rat TTR correlated well with the PFAS-associated decreases in T levels, supporting the AOP. The development of reliable predictive toxicity models for PFAS requires extensive validation, maximal use of available experimental data, and careful consideration of toxicokinetic differences in interchemical comparisons.
Early ADME and Preliminary Toxicity Studies of I-152, an -Acetyl-l-Cysteine/-Acetylcysteamine Conjugate.
Bartoccini F, Valeri A, Gregori M … +5 more , Masini S, Bruschi M, Goracci L, Fraternale A, Piersanti G
Chem Res Toxicol · 2026 May · PMID 42036895 · Full text
This study aimed to estimate the ADME properties and safety of I-152, a conjugate of -acetyl-l-cysteine (NAC) and -acetylcysteamine (also known as -acetyl-β-mercaptoethylamine; SMEA), linked by an amide bond. Its potent...
This study aimed to estimate the ADME properties and safety of I-152, a conjugate of -acetyl-l-cysteine (NAC) and -acetylcysteamine (also known as -acetyl-β-mercaptoethylamine; SMEA), linked by an amide bond. Its potent antioxidant and pro-glutathione effects make it of interest for a range of conditions linked to oxidative stress, such as infectious diseases and inflammation. I-152 was characterized in vitro for its stability in plasma, liver microsomes, and hepatocytes; its protein binding; and its AB BA (apical-to-basolateral and basolateral-to-apical) permeability using Caco-2 cells. Derisking and preliminary safety pharmacology assays were performed through a human ether-à-go-go-related gene assay (hERG) and in vitro cellular toxicity tests. The results demonstrated that I-152 is hydrolyzed in human plasma (half-life of about 9 min), human liver microsomes, and hepatocytes, as well as in rat liver microsomes and hepatocytes. In addition, I-152 was found to be permeable across the Caco-2 monolayer, indicating good intestinal absorption. Furthermore, I-152 did not produce detectable toxic effects at concentrations up to 1 mM in vitro assays using human keratinocytes, alveolar epithelial cells, and immortalized human embryonic kidney cells (HEK293T). These findings support further preclinical evaluation as a potential redox-modulating agent and thiol-based approach for viral infections and other conditions associated with oxidative stress.
Neuroprotection Against a Panel of Toxicants via a Novel Analog of the Natural Product Fraxinellone.
Bartman AE, Garcia-Mares MA, Preston SE … +5 more , Raeisi M, Peiris CD, Martin DBC, Lehmler HJ, Doorn JA
Chem Res Toxicol · 2026 May · PMID 42018735 · Full text
Humans are exposed to a myriad of environmental pollutants, with recent evidence indicating several of these toxicants serve as risk factors for neurodevelopmental disorders and neurodegenerative diseases. Given this, th...
Humans are exposed to a myriad of environmental pollutants, with recent evidence indicating several of these toxicants serve as risk factors for neurodevelopmental disorders and neurodegenerative diseases. Given this, there is a need for both interventional and protective strategies; however, of concern, the mechanistic targets of these environmental pollutants are variable or unknown in some cases. A prior report indicated that analogs of the natural product fraxinellone act as potent NRF2 activators, mitigating excessive reactive oxygen species (ROS) generation and Glu toxicity in vitro. Using one of the most effective fraxinellone analogs (i.e., analog 2) for NRF2 activation identified, we sought to determine the range of protection, in vitro, against a panel of neurotoxicants with varying mechanisms for adverse effects, including 6-hydroxydopamine (6-OHDA), organochlorine pollutants, and a fungicide. The data for analog 2 were compared to those for a structurally similar but inactive analog (i.e., analog 1). The dose-response for each toxicant with PC12 and SH-SY5Y cell lines was determined. Interestingly, the fraxinellone analog provided significant protection against all agents screened: 6-OHDA, dieldrin, benomyl, PCB52 hydroxy and sulfate metabolites, and rotenone. The extent to which the fraxinellone analog mitigated toxicity varied for each toxicant. In all cases, pretreatment with analog 2 significantly decreased total cellular ROS production, and in addition, generation of mitochondrial ROS via rotenone was mitigated. Furthermore, analog 2 provides some degree of restoration of cell viability following rotenone insult. In summary, our data indicate that an analog of the natural product fraxinellone potently inhibited ROS production and toxicity, thereby protecting cells against a panel of agents with varying mechanisms from adverse outcomes.
QSAR-ME Profiler 2025: A New Software for QSA(P)R Predictions Supported by Structural Analysis.
Chirico N, Sgariboldi A, Evangelista M … +1 more , Papa E
Chem Res Toxicol · 2026 May · PMID 42018473 · Full text
Quantitative structure-activity (property) relationships (QSA(P)Rs) are an alternative to / experiments. Over the past 20 years, QSA(P)Rs targeting various properties and activities have been developed by the QSAR resea...
Quantitative structure-activity (property) relationships (QSA(P)Rs) are an alternative to / experiments. Over the past 20 years, QSA(P)Rs targeting various properties and activities have been developed by the QSAR research unit at the University of Insubria. The new software QSAR-ME Profiler 2025 streamlines the application of these and other QSA(P)Rs and simplifies the evaluation of the predictions. It provides transparent outputs in tabular and graphical form and innovative solutions, compared to similar software, to quantify prediction uncertainty and applicability domain, while supporting the analysis of structural similarity, the application of customized models, and the compilation of QSAR prediction reporting format.
Modulation of ER Stress via cAMP Signaling: Protective Role of Rolipram in Paracetamol-Induced Liver Injury.
Palabiyik-Yucelik SS, Demirtas N, Aydemir Celep N … +3 more , Bozkurt A, Halici Z, Cadirci E
Chem Res Toxicol · 2026 May · PMID 42012056 · Full text
This investigation sought to assess the potential protective function of the phosphodiesterase-4 (PDE) enzyme inhibitor rolipram (ROL) against paracetamol (PARA) induced liver damage, as well as any potential underlying...
This investigation sought to assess the potential protective function of the phosphodiesterase-4 (PDE) enzyme inhibitor rolipram (ROL) against paracetamol (PARA) induced liver damage, as well as any potential underlying mechanism through modulation of endoplasmic reticulum (ER) stress via cAMP signaling. Fifty-six rats were randomly divided into 7 groups ( = 8). Following 24 h of fasting, animals received three different dosages of ROL (1.25, 2.5, and 5 mg/kg, i.p.) or -acetylcysteine (140 mg/kg, orally). One hour later, 2 g/kg PARA orally was administered to induce hepatotoxicity. The ELISA method was used to evaluate GSH, PDE4D, and cAMP levels in liver tissue, as well as PDE4D and cAMP levels in serum. In addition, serum levels of liver injury biomarkers, including ALT and AST, were measured. GRP78, IRE1, and CHOP mRNA expressions in tissue samples were assessed using the Real Time PCR technique. The liver tissue's histopathological parameters, including necrosis, bleeding, and mononuclear cell infiltration, were evaluated. The PARA group had higher serum and tissue PDE4 levels, lower cAMP and GSH levels, higher ALT and AST levels, and higher expressions of the ER stress markers GRP78, IRE1, and CHOP mRNA. Histopathological evaluation also revealed severe histopathological damage with PARA toxicity. These changes improved with dose dependent increase of ROL dose. It was evaluated that the protective effect of PDE4 enzyme inhibition on liver injury caused by PARA toxicity could be regulated by intracellular secondary communication signals and ER stress inhibition. These findings also suggested that these pathways might be studied in relation to other liver injuries.
Correction to "1,4-Benzoquinone (PBQ) Induced Toxicity in Lung Epithelial Cells Is Mediated by the Disruption of the Microtubule Network and Activation of Caspase-3".
Das A, Chakrabarty S, Choudhury D … +1 more , Chakrabarti G
Chem Res Toxicol · 2026 May · PMID 42008718 · Publisher ↗
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Complex Reactivity of Bisphenol A Diglycidyl Ether (BADGE) with DNA.
Berenguer M, Béal D, Breton J … +1 more , Douki T
Chem Res Toxicol · 2026 May · PMID 41988877 · Publisher ↗
Bisphenol A diglycidyl ether (BADGE) is a diepoxide product used in the synthesis of epoxy resins. Its genotoxic properties were strongly suggested by its ability to induce mutations and micronuclei, but the exact nature...
Bisphenol A diglycidyl ether (BADGE) is a diepoxide product used in the synthesis of epoxy resins. Its genotoxic properties were strongly suggested by its ability to induce mutations and micronuclei, but the exact nature of the underlying DNA damage remains to be established. For this purpose, we first applied cellular tests (the Comet assay and 53BP1 immunostaining) to show that direct induction of strand breaks was not the favored genotoxic pathway for BADGE. Consequently, we investigated the formation of DNA adducts using UHPLC coupled with tandem mass spectrometry (UHPLC-MS/MS) analysis following enzymatic hydrolysis. Analyses using single-stage mass spectrometry, product ion scan, and neutral loss monitoring showed that BADGE readily formed monoadducts with DNA bases. The structural assignments were confirmed by the results of accurate thermal degradation studies, which showed that BADGE reacted with DNA like other aliphatic epoxides. We also obtained unambiguous evidence that the reaction of BADGE with DNA led to the formation of biadducts between nonadjacent bases. This was explained by the transient formation of monoadducts bearing a BADGE moiety with an unreacted epoxide group. A sensitive quantitative UHPLC-MS/MS assay was then developed for the detection of BADGE adducts in cellular DNA. All the adducts identified in isolated DNA were also detected in cellular DNA. The proportions between the monoadducts were similar, but the relative yield of biadducts was lower in cellular than in isolated DNA. A time-course study of the level of adducts in DNA also showed that BADGE adducts were substrates for the cellular repair machinery. The present results definitively show that BADGE is a DNA-damaging chemical. The detected adducts represent novel biomarkers of the genotoxicity of BADGE.
Correction to "Cigarette Smoke Extract Induces Disruption of Structure and Function of Tubulin-Microtubule in Lung Epithelium Cells and ".
Das A, Bhattacharya A, Chakrabarti G
Chem Res Toxicol · 2026 May · PMID 41987493 · Publisher ↗
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Mixture Toxicity in Human Health: Integrating One Health, Exposomics, and Modern Risk Assessment Strategies.
Domingo JL, Nadal M
Chem Res Toxicol · 2026 May · PMID 41985101 · Full text
Human and environmental health are critically threatened by combined exposures to multiple chemical toxicants, including industrial chemicals, heavy metals, pesticides, endocrine-disrupting chemicals (EDCs), and per- and...
Human and environmental health are critically threatened by combined exposures to multiple chemical toxicants, including industrial chemicals, heavy metals, pesticides, endocrine-disrupting chemicals (EDCs), and per- and polyfluoroalkyl substances (PFAS). These substances interact biologically, producing additive, synergistic, or antagonistic effects that conventional single-substance risk assessments fail to predict. This leads to a systematic underestimation of health risks, particularly for vulnerable populations. Despite robust evidence on mixture toxicity, major regulatory frameworks such as the US Toxic Substances Control Act (TSCA) and the EU's REACH program continue to assess chemicals in isolation. This review synthesizes current science on toxicant interactions and critiques global regulatory shortcomings, underscoring the real-world consequences through case studies on PFAS, heavy metals, and pesticide mixtures. It advocates for a paradigm shift, proposing reforms that integrate emerging tools like exposomics and computational toxicology with holistic frameworks such as One Health. We highlight pioneering regulatory efforts, including Canada's mandate for cumulative risk assessments under CEPA and the EU's development of mixture assessment factors (MAFs), as essential models for progress. Our recommendations include mandating science-based mixture assessments, harmonizing global standards, and implementing equity-driven policies to align regulations with the reality of multichemical exposures.
Characterizing the Conversion of Benzene Exposure Urinary Biomarker 6-Hydroxy-2,4-cyclohexadienyl Mercapturic Acid (Pre-PhMA) to Phenyl Mercapturic Acid (PhMA) for Human Biomonitoring Applications.
Bowman BA, Goldy DW, Roberson BJ … +4 more , Woodruff CA, Blount BC, Chambers DM, Bhandari D
Chem Res Toxicol · 2026 May · PMID 41983587 · Full text
Urinary phenyl mercapturic acid (PhMA) is a specific biomarker of benzene exposure that has been widely used in biomonitoring of the general population and in occupational exposure studies. However, previous research has...
Urinary phenyl mercapturic acid (PhMA) is a specific biomarker of benzene exposure that has been widely used in biomonitoring of the general population and in occupational exposure studies. However, previous research has identified significant interlaboratory variation in urinary PhMA concentrations due to differences in the acidity of the sample treatment conditions. This variation arises from the need to convert the benzene's precursor metabolite 6-hydroxy-2,4-cyclohexadienyl mercapturic acid (pre-PhMA) to PhMA. In this study, we systematically examined the influence of sample treatment pH on this reaction across various acidic treatment conditions representative of the reported PhMA assays. The resulting pre-PhMA and PhMA levels were quantified using an established liquid chromatography-tandem mass spectrometry assay. PhMA levels increased with more acidic treatment conditions until pH -0.6 when PhMA formation was the greatest at 53.1% formation of the total pre-PhMA. The formation of PhMA was dependent on sample treatment pH. Thus, a quadratic regression was modeled on PhMA formation vs pH across all acid types. The resulting regression model ( = 0.874 × pH - 12.146 × pH + 41.99, = 0.978) can be used to determine the extent of PhMA formation for a specific treatment pH, improving the ability to compare PhMA results among studies with different analytical methods or to absolute health-based cutoffs such as the biological exposure index. To explain the incomplete PhMA formation, we utilized gas chromatography-mass spectrometry to identify and quantify the formation of benzene as a major byproduct of the acid-derived dehydration of pre-PhMA. Further, base-derived dehydration of pre-PhMA to PhMA was performed to validate the benzene formation mechanism observed with acid dehydration.
PFDA Influences the Structure of the Globular Milk Protein, α-Lactalbumin: Implications for Its Ability to Bind a Physiologically Crucial Cofactor.
Wilson DL, Ramirez Orozco RS, Vukovic L … +1 more , Narayan M
Chem Res Toxicol · 2026 Jun · PMID 41983548 · Publisher ↗
Perfluorodecanoic acid (PFDA) ingestion is associated with liver, immune, developmental, and reproductive effects. Nevertheless, the molecular mechanisms underlying PFDA toxicity remain poorly understood. For example, de...
Perfluorodecanoic acid (PFDA) ingestion is associated with liver, immune, developmental, and reproductive effects. Nevertheless, the molecular mechanisms underlying PFDA toxicity remain poorly understood. For example, despite its established presence in human milk, cow milk, and infant formula, its molecular interactions with constituent proteins and their consequences require further study. Here, we report the outcomes associated with the interaction between PFDA and α-lactalbumin (ALAC), a calcium-binding whey protein essential for nutrition and lactose production. Absorbance and Trp fluorescence data reveal PFDA-dependent changes consistent with interactions that perturb the native disposition of the optically active chromophores. Deconvolution of the amide I region of PFDA: protein IR spectra suggest dose-dependent distortions of PFDA in helical and sheet topologies. Ca-binding kinetics suggest that the "forever" chemical compromised metal-ion binding to the protein in a dose-dependent manner, reflecting impaired metal-dependent structural stabilization from the molten-globule-like apo-state to the native and biologically active holo-state. Molecular dynamics simulations identified two preferential PFDA binding regions enriched in hydrophobic and positively charged residues and showed that local rearrangements in ALAC's unstructured N-terminus coils can generate tightly bound PFDA states with favorable interaction energies. Combined, these results reveal a coherent molecular mechanism in which PFDA anchors to the ALAC surface, disrupts secondary structure organization, and weakens Ca binding. Considering ALAC's role in early infant nutrition and human health, these findings provide a mechanistic insight into how PFAS exposure may compromise protein function in the postnatal environment.
A Method to Calibrate Chemical-Agnostic Quantitative Adverse Outcome Pathways on Multiple Chemical Data.
Zhou Z, Sahlin U
Chem Res Toxicol · 2026 May · PMID 41979413 · Full text
Quantitative Adverse Outcome Pathways (qAOPs) can support next-generation risk assessment by integrating new approach methods (NAMs) for deriving points of departure. To be useful, a qAOP should be chemical-agnostic. How...
Quantitative Adverse Outcome Pathways (qAOPs) can support next-generation risk assessment by integrating new approach methods (NAMs) for deriving points of departure. To be useful, a qAOP should be chemical-agnostic. However, existing qAOP studies often pool multichemical data without adequately addressing cross-chemical heterogeneity. Consequently, pathway relationships become obscured by heterogeneity-induced variations, thereby compromising model reliability and generalizability. We developed a calibration approach to address this challenge by leveraging hierarchical structures to systematically separate chemical-specific heterogeneity from the underlying pathway effects. Chemical-specific deviations are explicitly modeled as random effects, enabling the extraction of pathway-level parameters that represent core mechanistic relationships independent of the individual chemical properties. We demonstrated through a simulation study that performance differences between models with and without hierarchical calibration can reveal the magnitude of the heterogeneity in the data. When heterogeneity is substantial, an uncalibrated qAOP should not be considered truly chemical-agnostic in practice, as it confounds pathway-level effects with chemical-specific variations. Finally, we demonstrated the application of this calibration approach through deriving points of departure to a case study of nonmutagenic liver tumor qAOP.
Dermal Toxicity of Nanoparticles: A Review of Recent Progress.
Rayhan MA, Ahmed S, Bhuiya MS … +2 more , Shakil MS, Uddin S
Chem Res Toxicol · 2026 May · PMID 41975249 · Publisher ↗
Nanoparticles (NPs) have gained attention as dermal drug delivery vehicles for several skin diseases, including the theranostic application of skin cancer. In recent times, the use of NP-based therapeutics has expanded t...
Nanoparticles (NPs) have gained attention as dermal drug delivery vehicles for several skin diseases, including the theranostic application of skin cancer. In recent times, the use of NP-based therapeutics has expanded to prevent and treat skin infections, protect against UV rays, and aid in scar reduction by accelerating skin cell repair. Despite their therapeutic benefits, the short- and long-term dermal toxicity of NPs poses concerns for clinical applications of NP-based dermal drug delivery. Intentional or unintentional contact of inorganic or organic NPs can lead to skin irritation, photosensitivity, or inflammation via the production of inflammatory cytokines (e.g., IL-5, IL-13, IL-17, and TNF-α) and proinflammatory cytokines (e.g., IL-6, IL-1β, and TNF-α). Additionally, both inorganic and organic NPs can cause collagen depletion. More importantly, genotoxic events can occur with their topical application. In this review, we will report on the dermal application of different NPs and highlight their biodegradability and safety concerns to guide the development of next-generation treatment modalities.
Neutralization Kinetics and Transport Define the Dermal Decontamination Window for Warfare and Industrial Toxicants.
Simon L, Kulkarni I
Chem Res Toxicol · 2026 May · PMID 41968522 · Full text
Chemical warfare agents that are moderately to highly volatile can readily permeate the skin, posing an acute systemic toxicity risk. Effective decontamination depends on how intervention timing and chemical reactivity j...
Chemical warfare agents that are moderately to highly volatile can readily permeate the skin, posing an acute systemic toxicity risk. Effective decontamination depends on how intervention timing and chemical reactivity jointly shape dermal absorption, evaporation, and neutralization. While earlier finite-dose models characterized dermal uptake, they lacked decontaminant reactivity and failed to quantify how neutralization competes with diffusion and surface clearance. This work presents a unified, dimensionless framework integrating diffusion, evaporation, and reactive neutralization. The system behavior is governed by two dimensionless groups: a surface-loss number () that captures combined evaporation and interfacial reaction and a Damköhler number () that quantifies bulk neutralization relative to diffusion. Analytical solutions yield characteristic time constants describing the relative rates of absorption, surface clearance, and neutralization. Three distinct kinetic regimes emerge: (i) low (<3), where slow internal reaction leaves surface loss as the primary clearance mechanism; (ii) intermediate (3-8), characterized by competitive transport and reaction rates; and (iii) high (>8), where rapid bulk neutralization renders surface-based interventions progressively less effective. The framework identifies a critical decontamination window during which the applied decontaminant neutralizes the agent faster than it can enter the bloodstream, thereby minimizing systemic exposure. Implemented as open-source Python software, this tool can help emergency responders and regulatory agencies predict decontamination windows for chemical warfare agents and industrial toxicants.
Mechanism-Based Inactivation of CYP2C19 by Anwuligan Resulting in Changes in Pharmacokinetic Properties of Amitriptyline.
Cheng X, Cheng Z, Dai J … +6 more , Yang D, Zhang Q, Tang H, Peng Y, Li W, Zheng J
Chem Res Toxicol · 2026 May · PMID 41968488 · Publisher ↗
The worldwide consumption of traditional herbal preparations has risen markedly in recent years, raising increasing toxicological concern regarding drug-drug interactions. A major mechanistic basis for these interactions...
The worldwide consumption of traditional herbal preparations has risen markedly in recent years, raising increasing toxicological concern regarding drug-drug interactions. A major mechanistic basis for these interactions is the ability of specific phytochemicals to inhibit cytochrome P450 enzymes, thereby altering xenobiotic metabolism at the molecular and enzymatic levels. Anwuligan (ANL), a bioactive compound isolated from nutmeg and Schisandra chinensis, has attracted considerable pharmacological interest, yet its inhibitory potential toward P450 enzymes remains poorly defined. In this study, we systematically investigated the effects of ANL on CYP2C19 and evaluated its pharmacokinetic interaction with amitriptyline. Enzyme kinetics revealed that ANL is a mechanism-based inhibitor of CYP2C19, and NAC trapping assays indicated that an -quinone intermediate generated during its metabolism is the key species responsible for irreversible enzyme inactivation. pharmacokinetic studies in rats showed that ANL pretreatment increased amitriptyline exposure, with and AUC increased by 1.4-fold and ∼30%, respectively, and CL/F reduced by 24%. In contrast, nortriptyline exposure decreased, with reductions in (39%) and AUC (29-34%). These results demonstrate CYP2C19 inhibition by ANL and its potential to cause clinically relevant drug-drug interactions.
Quantitative Proteomic Profiling of Bronchoalveolar Lavage-Derived Extracellular Vesicles in a Murine Asthma Model.
Hutchins Z, Chen X, Siddique AE … +5 more , Thorne PS, Salem AK, Cho JL, Adamcakova-Dodd A, Wang Y
Chem Res Toxicol · 2026 May · PMID 41958033 · Publisher ↗
Extracellular vesicles (EVs) are key mediators of intercellular communication and immune regulation; however, their proteomic composition in allergic asthma remains poorly understood. We performed tandem mass tag (TMT)-b...
Extracellular vesicles (EVs) are key mediators of intercellular communication and immune regulation; however, their proteomic composition in allergic asthma remains poorly understood. We performed tandem mass tag (TMT)-based quantitative proteomic analyses of bronchoalveolar lavage fluid (BALF) and BALF-derived EVs in a murine house dust mite (HDM) model of allergic airway inflammation. HDM challenge elicited significant upregulation of Th2-associated proteins (CLCA1, FCGBP, CHIL3, CHIL4, and RETNLA), which is consistent with hallmark features of asthma. EPX and CKM were detected exclusively in BALF-derived EVs, demonstrating that EVs can selectively carry disease-relevant proteins. Our results underscore EV's cargo-mediated mechanisms in asthma pathogenesis.
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