Archives Of Toxicology[JOURNAL]
Sun
200 papers
Correction: From animal models to NAMs: a paradigm shift in developmental immunotoxicity testing.
Iulini M, de Bruijn V, Hurem S … +6 more , Nygaard UC, Kerdine-Römer S, Spruck C, Tigges J, Vandebriel R, Corsini E
Arch Toxicol · 2026 Jun · PMID 42295344 · Publisher ↗
Abstract loading — click title to view on PubMed.
Circadian regulation of hepatic detoxification: implications for drug-induced liver injury.
Wen R, Wang H, Wang S
Arch Toxicol · 2026 Jun · PMID 42295343 · Publisher ↗
The hepatic capacity for xenobiotic detoxification exhibits pronounced circadian rhythmicity. The molecular basis of this rhythm lies in the autonomous transcriptional-translational feedback loops constituted by clock-co...
The hepatic capacity for xenobiotic detoxification exhibits pronounced circadian rhythmicity. The molecular basis of this rhythm lies in the autonomous transcriptional-translational feedback loops constituted by clock-controlled genes (CCGs). These loops temporally regulate the expression of a vast array of drug-metabolizing enzymes (DMEs) and transporters, thereby determining the liver's detoxification efficacy at different times of day. Dysfunction of CCGs, such as reverse erythroblastosis virus α (Rev-erbα), brain and muscle ARNT-like 1 (Bmal1), circadian locomotor output cycles kaput (Clock), and period (Per), directly disrupts this metabolic timing and alters the liver's susceptibility to specific toxicants. Therefore, this review elaborates on the circadian characteristics of hepatic detoxification function, analyzes the complex network through which CCGs regulate hepatotoxicity, and further explores how external zeitgebers (e.g., light, food) and the timing of drug administration influence the outcomes of liver injury by either synchronizing or disrupting endogenous rhythms. These findings provide a theoretical basis for applying chronopharmacological principles to prevent and mitigate drug-induced liver injury through time-based intervention strategies, such as optimizing drug administration timing and managing lifestyle factors.
Defining early carcinogenic markers for the prediction of the hazard potential of mineral fibres in an in vitro human 3D bronchial model.
Almonti V, Mirata S, Passalacqua M … +9 more , Vernazza S, Tirendi S, Ferrando S, Risso B, Grasselli E, De Negri Atanasio G, Bassi AM, Gualtieri AF, Scarfì S
Arch Toxicol · 2026 Jun · PMID 42295342 · Publisher ↗
This study aimed to identify early carcinogenic markers to predict the hazard potential of mineral fibres using a human 3D bronchial model. Traditional 2D cell models inadequately mimic lung complexity, prompting the use...
This study aimed to identify early carcinogenic markers to predict the hazard potential of mineral fibres using a human 3D bronchial model. Traditional 2D cell models inadequately mimic lung complexity, prompting the use of more physiologically relevant 3D systems. We investigated the effects of crocidolite (CRO) and two size fractions of chrysotile (≤ and > 5 μm length: CHR S and CHR L) to elucidate early toxicological mechanisms and relate them to the IARC key characteristics (KCs) of carcinogens. Initial analyses (MTT, TEER, and histology) at 24-48 h showed a transient acute toxicity and tissue resilience, indicating limited predictive value at this time point. However, after 12 d of exposure, fibre-treated tissues exhibited persistent alterations corresponding to established IARC KCs, suggesting the early onset of cell transformation pathways. Key findings included: sustained inflammatory signalling, characterized by prolonged overexpression of IL-1β, IL-6, and IL-8; ii) persistent genotoxicity, marked by the prolonged nuclear positivity of γH2AX, indicating DNA double-strand breaks without significant cell death; and iii) induction of fibrotic and epithelial-to-mesenchymal transition (EMT) signals, including the increased expression of key markers such as TGF-β, VEGF, ZEB-2, N-Cadherin, Vimentin, and Mesothelin. These alterations correspond to IARC KCs 2, 6, and 8. They were observed within a short time frame of tissue treatment and could serve as reliable, early predictive endpoints for in vitro toxicological tests. We propose that integrating these specific KC-based biosignatures in 3D lung models with physicochemical fibre characterization may provide a robust framework for predictive assessment of inhalable fibre carcinogenicity.
Nanoplastic toxicity: an emerging blind spot in human risk assessment.
Parmar P, Rathod G
Arch Toxicol · 2026 Jun · PMID 42287387 · Publisher ↗
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NLRP3 inflammasome activation by particles and fibers: implications for human hazard assessment.
Busch M, Bredeck G, Bouwmeester H … +1 more , Schins RPF
Arch Toxicol · 2026 Jun · PMID 42287386 · Publisher ↗
The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been shown to be involved in the manifestation of adverse effects following exposure to occupational, dietary and environmental particulate ma...
The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been shown to be involved in the manifestation of adverse effects following exposure to occupational, dietary and environmental particulate matter. In this review, we summarize knowledge on NLRP3 inflammasome activation by particles and fibers in vitro and in vivo, outline dominant activation mechanisms and discuss the link to human diseases. While the association between NLRP3 activation and development of diseases is well established for occupational exposure to mineral dusts like asbestos and quartz, the health effects of low-level exposure to environmental particulate pollutants, such as micro- and nanoplastics, desert dust or novel nanocomposites remain to be unraveled. Based on the combined literature of well-studied and emerging particles, we emphasize the relevance of testing for NLRP3 activation in the hazard assessment of novel particulate materials.
Recent advances in multidimensionally regulated nanozyme-integrated biosensors for rapid and ultrasensitive foodborne mycotoxin detection.
Sun C, Wang Q, Chen Z … +4 more , Du W, Wu T, Dong B, Wang R
Arch Toxicol · 2026 Jun · PMID 42287385 · Publisher ↗
Mycotoxins pose great risks to global food safety and human public health. Traditional instrumental detection suffers from high equipment costs and complicated procedures, whereas natural enzyme-based rapid assays are re...
Mycotoxins pose great risks to global food safety and human public health. Traditional instrumental detection suffers from high equipment costs and complicated procedures, whereas natural enzyme-based rapid assays are restricted by poor structural stability and excessive production costs. These drawbacks greatly limit their practical application in routine food monitoring. Combining unique nanostructural features and intrinsic enzyme-mimicking activity, nanozymes exhibit superior stability and adjustable catalytic properties, emerging as advanced functional materials for mycotoxin analysis. Accordingly, nanozyme-based biosensors have become a rapidly developing research hotspot. This review comprehensively summarizes five-year research advances of four mainstream nanozyme categories. Multi-dimensional regulation of structures, surface properties and chemical compositions can effectively improve their catalytic performance. Based on biorecognition, catalytic signal regulation and quantitative output, colorimetric, fluorescent and electrochemical biosensing platforms are well established for ultra-sensitive detection of typical mycotoxins, with detection limits reaching picogram and femtogram levels. Future directions include rational nanozyme design, sensing innovation, intelligent detection and industrial translation, which will facilitate full-chain mycotoxin monitoring and strengthen food safety management.
Fenitrothion induces sex-specific glucose metabolism dysregulation in rats by targeting PK/glycolysis in males and IDH3/TCA cycle in females.
Guo Y, Gu D, Okeke ES … +6 more , Feng W, Chen Y, Mao G, Yang L, Zhao T, Wu X
Arch Toxicol · 2026 Jun · PMID 42287384 · Publisher ↗
Fenitrothion (FNT) is a widely used organophosphorus insecticide, and its potential health hazards have raised increasing public concern. However, the mechanisms underlying FNT-induced glucose metabolic dysregulation rem...
Fenitrothion (FNT) is a widely used organophosphorus insecticide, and its potential health hazards have raised increasing public concern. However, the mechanisms underlying FNT-induced glucose metabolic dysregulation remain poorly understood. Here, Sprague-Dawley rats were exposed to FNT (0.37, 3.7 or 37 mg/kg bw/day) for 28 days, resulting in hyperglycemia, hyperphagia, and impaired glucose tolerance at the 3.7 and 37 mg/kg doses. Multi-omics analysis revealed that inhibition of PK and IDH3 constitutes a key toxic event following FNT exposure. In males, FNT suppressed the PI3K-AKT and ChREBP pathways while activating the cAMP-PKA and AMPKα pathways, thereby downregulating Pk expression and impairing glycolysis. In females, FNT inhibited the PI3K-AKT and AMPKα-PGC1α pathways, downregulating Idh3 expression, ultimately impeding TCA cycle. These sex-specific alterations cooperatively suppressed glycolysis and oxidative metabolism, thereby causing hepatic energy imbalance, hyperglycemia, and glucose homeostasis disruption. These findings uncover novel molecular mechanisms linking FNT exposure to glucose metabolic dysregulation, providing insights into pesticide-associated risks of hyperglycemia and insulin resistance. Overall, this study highlights the endocrine-disrupting potential of organophosphorus pesticides.
Metabolism-dependent induction of DNA and chromosome damage by orally administered carbamazepine in adult male C57BL/6J mice, Cyp2b being major activating enzymes.
Sun H, Chen M, Zhu S … +3 more , Xu K, Wang Y, Liu Y
Arch Toxicol · 2026 Jun · PMID 42287383 · Publisher ↗
Carbamazepine is a commonly applied anti-neurosis drug, which meanwhile severely pollutes the global environment. It induced DNA/chromosome damage and gene mutations in vitro following metabolic activation, however, evid...
Carbamazepine is a commonly applied anti-neurosis drug, which meanwhile severely pollutes the global environment. It induced DNA/chromosome damage and gene mutations in vitro following metabolic activation, however, evidence for its genotoxicity in intact mammalians remains absent. In this study, 6-week old male C57BL/6J mice were exposed to carbamazepine by gastric gavage at doses of 8, 20, and 50 mg/kg/d for 7 consecutive days, followed by a micronucleus test in bone marrow polychromatic erythrocytes, a comet assay in hepatocytes, and Western blot assay of hepatic proteins, including a phosphorylated histone 2AX (γ-H2AX, indicator of double-strand DNA breaks), aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), and several Cyp enzymes. In some experiments, ticlopidine (4 mg/kg/d, specific inhibitor of Cyp2b) was used as a modulator. The results demonstrated no obvious toxicity of carbamazepine to the liver or bone marrow, while it induced micronucleus formation in the bone marrow and hepatic DNA damage (indicated by positive comet assay results and elevated γ-H2AX protein) at 20 and/or 50 mg/kg/d doses, all of which were nevertheless abolished or alleviated by ticlopidine. Meanwhile, carbamazepine induced hepatic AhR and CAR at 50 mg/kg/d, and PXR, Cyp2b10 and Cyp3a11 at doses ≥ 20 mg/kg/d, with no effect on Cyp1a2; furthermore, coexposure of ticlopidine blocked the induction of PXR, Cyp3a11 and Cyp2b10 by carbamazepine, while enhanced that of AhR. This study provides evidence for the genotoxicity of carbamazepine in mammalians in vivo, its dependence on Cyp2b activity, and the activation of relevant nuclear receptor/Cyp-regulating pathway.
Cigarette smoke extract (CSE) reduces expression of functional TRPV4 channels in primary human bronchial epithelial cells differentiated at an air liquid interface (ALI) in vitro.
Müller I, Alt P, Gudermann T … +2 more , Kiefmann M, Dietrich A
Arch Toxicol · 2026 Jun · PMID 42287382 · Publisher ↗
Primary human bronchial epithelial cells (pHBECs) of the airways of smokers are chronically exposed to cigarette smoke, which may induce chronic obstructive pulmonary disease (COPD) ranked fourth among the most common gl...
Primary human bronchial epithelial cells (pHBECs) of the airways of smokers are chronically exposed to cigarette smoke, which may induce chronic obstructive pulmonary disease (COPD) ranked fourth among the most common global causes of death. Using an established protocol for differentiation of pHBECs to a pseudostratified epithelium at an air liquid interface (ALI), we analyzed functional expression of transient receptor potential vanilloid 4 (TRPV4) proteins after application of cigarette smoke extract (CSE), which upregulated seven smoke exposure regulated genes (SERGs). TRPV4 protein expression in the plasma membrane and localization next to the cilia of ciliated cells was reduced, while cell barrier function was not altered after chronic exposure to CSE for 28 days compared to untreated control cells. Accordingly, TRPV4-mediated Ca influx was blocked in pHBECs after CSE exposure. Moreover, Os-9 protein, which after binding mediates protection from degradation of TRPV4 protein by polyubiquitination, was significantly less expressed in pHBECs upon CSE exposure. Most interestingly, overexpression of OS-9 in pHBECs rescued reduced TRPV4 protein levels induced by CSE. Our study identifies a novel molecular mechanism of toxicity by CSE interfering with TRPV4 and OS-9 expression in pHBECs, which may blaze the trail for new therapeutic options in COPD.
Mechanistic investigation of the hepatotoxicity and potential carcinogenicity of microcystin-LR, -LA, and -RR in the HepaRG cell line model.
Silva EZM, Kiessig S, Suciu I … +5 more , Mathias C, de Lourdes Marzo-Solano M, Pestana CB, Marx-Stoelting P, Leme DM
Arch Toxicol · 2026 Jun · PMID 42259957 · Publisher ↗
Microcystins (MCs) are cyanobacterial toxins found in water and food and are suspected to pose significant health risks, particularly to the liver. To gain insight into the mechanisms of hepatotoxicity and the potential...
Microcystins (MCs) are cyanobacterial toxins found in water and food and are suspected to pose significant health risks, particularly to the liver. To gain insight into the mechanisms of hepatotoxicity and the potential carcinogenicity of MCs, this study investigated the effects of MC-LR, -LA, and -RR (congeners differing in cellular uptake and detoxification efficiency) on PP2A activity, cell proliferation, and gene expression profiling focused on toxicity pathways and carcinogenesis in HepaRG cells. The three MCs similarly inhibited PP2A activity; however, only MC-LR and -LA significantly increased cell proliferation. Gene expression profiles (mRNA) revealed strong, similar treatment effects induced by MC-LR and -LA (R2 = 0.66), whereas -RR affected fewer genes, showing weak correlations with the other two congeners (-LRx-RR - R = 0.31; -LAx-RR - R = 0.06). Moreover, MC-LR and -LA, but not -RR, affected several liver-enriched toxicity pathways, which correlate most closely to hepatocellular/liver carcinoma, cholestasis, and fibrosis. All congeners altered carcinogenesis-related miRNA expression, but no consistent pattern was observed among them. Overall, the present findings reinforce the congener-specific toxicity of MCs, likely driven by differences in toxicokinetics among congeners. Furthermore, the findings indicate that MC-induced liver effects also involve PP2A-independent mechanisms, as MC-LR/-LA and -RR elicited markedly different biological responses despite comparable PP2A inhibition. Finally, the study demonstrates the applicability of the NAM-based approach for evaluating liver effects (hepatocytes) in the MC family and, as structurally different congeners were investigated, provides data that could be used for read-across and grouping.
Multi-omics study to elucidate molecular mechanism of polyhexamethylene guanidine phosphate (PHMG-p)-induced pulmonary damage in mice.
Lee JD, Kim HY, Im JE … +11 more , Lee H, Park J, Park K, Kang K, Jeong HG, Chae S, Hwang D, Han BS, Cho WS, Kim S, Kim KB
Arch Toxicol · 2026 Jun · PMID 42259956 · Publisher ↗
Polyhexamethylene guanidine phosphate (PHMG-p), a cationic disinfectant previously used in humidifiers, has been linked to severe pulmonary diseases in Korea. This study aimed to elucidate the molecular mechanisms underl...
Polyhexamethylene guanidine phosphate (PHMG-p), a cationic disinfectant previously used in humidifiers, has been linked to severe pulmonary diseases in Korea. This study aimed to elucidate the molecular mechanisms underlying PHMG-p-induced lung toxicity using an integrated multi-omics approach. BALB/c mice were intratracheally instilled with PHMG-p (0, 0.03, 0.1 mg/kg, twice weekly for 4 weeks). Histopathology revealed dose-dependent pulmonary lesions, including inflammatory infiltration, alveolar wall hyperplasia, and fibrosis. Transcriptomic profiling identified 213 and 1,506 differentially expressed genes (DEGs) in the low- and high-dose groups, respectively, with enriched pathways related to immune activation, cytokine signaling, and cellular stress responses. Proteomic analysis detected 148 and 1,168 differentially expressed proteins (DEPs), many of which overlapped with DEGs and were associated with chemokine signaling, protein refolding, and ion transport dysregulation. Metabolomic profiling of serum samples identified dose-responsive alterations in amino acid and energy metabolism, with notable increases in glutamate, leucine, serine, and related metabolites. Integrated omics analysis revealed consistent up-regulation of CDKN1A, HSP90AA1, HSPA1A, HSPA8, and HSPH1, and down-regulation of FPR1, suggesting their roles as potential biomarkers of PHMG-p-induced pulmonary injury. Pathway convergence indicated activation of inflammatory and fibrotic remodeling processes, as well as metabolic reprogramming involving glutamate and branched-chain amino acid pathways. These findings provide mechanistic insight into PHMG-p-induced lung toxicity and highlight multi-omics signatures that may serve as biomarkers for monitoring or predicting pulmonary damage caused by cationic polymer biocides.
Aging in a highly polluted world: challenges and solutions to prevent Alzheimer's disease.
Domingo JL
Arch Toxicol · 2026 Jun · PMID 42259955 · Publisher ↗
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder globally and a leading cause of disability and death among the elderly. As populations age worldwide, the epidemiological burden of AD is expected...
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder globally and a leading cause of disability and death among the elderly. As populations age worldwide, the epidemiological burden of AD is expected to more than double by 2050, surpassing 150 million affected individuals. While genetic susceptibility, particularly the apolipoprotein E ε4 (APOE4) allele, modulates individual risk, most AD cases are late-onset and shaped by complex interactions between genetic background and modifiable environmental exposures. Environmental pollution has emerged as a critical and potentially preventable contributor to this burden. The 2024 Lancet Commission on Dementia Prevention, Intervention, and Care has identified 14 modifiable risk factors, with air pollution explicitly included. Drawing on evidence from human epidemiological cohorts, experimental animal models, and in vitro neuronal/glial systems, the present review aims to synthesize mechanistic evidence linking environmental pollutant classes to AD-relevant neuropathology. The review examines the growing body of evidence linking major categories of environmental pollutants (ambient particulate matter, heavy metals, pesticides, PFAS, and emerging contaminants including microplastics and nanoplastics) to AD risk and pathogenesis. Special attention is given to studies showing that the characteristic neuropathological features of AD may emerge in children and young adults chronically exposed to heavily polluted urban environments, which highlights critical concerns about when and how these changes develop throughout life. Shared mechanistic pathways through which environmental pollutants promote neurodegeneration are discussed, including neuroinflammation, oxidative stress, blood-brain barrier disruption, tau kinase dysregulation, epigenetic reprogramming, and gut-brain axis dysbiosis. The review also examines the amplifying role of biological aging on neurotoxic vulnerability and proposes a comprehensive, multi-level prevention framework addressing individual exposure reduction, clinical risk identification, and population-level policy interventions.
Diazinon-induced oxidative stress and organ toxicity in rodent models: a narrative review of mechanistic pathways, biomarkers and antioxidant interventions.
Liu R, Wu B
Arch Toxicol · 2026 Jun · PMID 42259954 · Publisher ↗
Diazinon (DZN) is a widely used organophosphorus insecticide whose toxicity has traditionally been attributed to acetylcholinesterase inhibition after metabolic activation to diazoxon. However, a growing body of rodent e...
Diazinon (DZN) is a widely used organophosphorus insecticide whose toxicity has traditionally been attributed to acetylcholinesterase inhibition after metabolic activation to diazoxon. However, a growing body of rodent evidence indicates that this mechanism alone does not adequately explain the breadth and persistence of DZN-induced organ injury, particularly under subacute and subchronic exposure conditions. This narrative review synthesizes current evidence on the toxicokinetic, mechanistic and organ-specific basis of DZN-induced oxidative stress in rodent models, with emphasis on biomarker behaviour and the protective effects of antioxidant and pharmacological interventions. Relevant studies were identified from PubMed/MEDLINE, Scopus and Web of Science up to December 2025, with inclusion limited to in vivo rodent and rodent-derived ex vivo studies that assessed oxidative or nitrosative stress endpoints alongside organ injury or functional outcomes. Across the reviewed literature, DZN consistently increased reactive oxygen and nitrogen species, lipid peroxidation and protein oxidation, while depleting glutathione and disrupting antioxidant defenses such as superoxide dismutase, catalase and glutathione peroxidase. These redox disturbances were closely associated with inflammatory activation, mitochondrial dysfunction, and oxidative DNA damage and tissue injury in the liver, kidney, cardiovascular system, brain, reproductive organs, pancreas, adipose tissue and blood. Time-course and correlation data further indicate that oxidative stress develops rapidly, may precede or coincide with peak cholinesterase inhibition, and often persists beyond the overt cholinergic phase, supporting a partially dissociated but mechanistically intertwined oxidative axis. Intervention studies show that antioxidants, phytochemicals and selected pharmacological agents can attenuate DZN-induced redox imbalance and ameliorate biochemical and histopathological damage, although protection is typically incomplete. Overall, the evidence positions oxidative stress as a central cross-organ mechanism of DZN toxicity rather than a secondary by-product of cholinergic injury. A more standardized and translationally integrated research framework is now needed to refine biomarker selection, improve hazard characterisation and guide the development of adjunctive strategies for organophosphate-related toxicity.
Will there ever be an in vitro assay that is predictive for human hepatotoxicity?
Thompson DC
Arch Toxicol · 2026 Jun · PMID 42259953 · Publisher ↗
Advances in novel alternative methods (NAMs)-including in silico modeling, hepatic co-cultures, 3D models such as spheroids and organoids, and microphysiological liver platforms-have greatly improved our ability to study...
Advances in novel alternative methods (NAMs)-including in silico modeling, hepatic co-cultures, 3D models such as spheroids and organoids, and microphysiological liver platforms-have greatly improved our ability to study human hepatic biology and reduce reliance on animal testing. However, whether such systems can predict human hepatotoxicity remains doubtful. Low-incidence, idiosyncratic liver injury typically arises from patient-specific factors and complex immune interactions that are not captured in simplified or genetically limited in vitro settings. Temporal constraints, limited biomarker diversity, and inconsistent validation further hinder predictive claims. Even a "perfect" in vitro liver model would still represent the biology of a single donor, comparable to a clinical study with one subject. These systems are invaluable for mechanistic and metabolic investigations but should be regarded as investigative-not predictive-tools for hepatotoxicity risk assessment.
Electronic cigarette aerosols disrupt airway barrier function via MMP-dependent E-cadherin cleavage: findings from cell culture and murine models.
Beaumont AL, Ozeki SG, Lee CE … +3 more , Chatburn RL, Bowler RP, Rezaee F
Arch Toxicol · 2026 Jun · PMID 42247188 · Full text
Electronic cigarette (e-cigarette) use continues to rise, yet the toxicological mechanisms by which inhaled aerosols impair airway epithelial integrity remain poorly defined. E-cadherin, a key adherens junction protein r...
Electronic cigarette (e-cigarette) use continues to rise, yet the toxicological mechanisms by which inhaled aerosols impair airway epithelial integrity remain poorly defined. E-cadherin, a key adherens junction protein required for epithelial cohesion, can undergo proteolytic cleavage to generate soluble E-cadherin (sE-cad), a mediator of epithelial barrier dysfunction and inflammation. We hypothesized that e-cigarette aerosol exposure promotes MMP-dependent E-cadherin cleavage, resulting in sE-cad release and epithelial barrier disruption. Using differentiated primary normal human bronchial epithelial (NHBE) cells, 16HBE cells, and a murine whole-body exposure model, we examined epithelial injury induced by physiologically relevant aerosols generated with a programmable puffing system. Air Factory salt e-liquid was used at 18 mg/mL nicotine for in vitro studies and 36 mg/mL for in vivo exposures. Immunoblotting demonstrated increased sE-cad levels in apical supernatants and bronchoalveolar lavage fluid. Aerosol exposure upregulated MMP-2, MMP-9, and MMP-12 expression. E-cigarette aerosol exposure significantly reduced transepithelial electrical resistance, increased FITC-dextran permeability, and disrupted airway epithelial barrier structure, indicating impaired barrier integrity and function. These effects were attenuated by pretreatment with the MMP inhibitor fisetin, which preserved barrier function and junctional protein localization. Fisetin treatment significantly reduced e-cigarette-induced sE-cad release and was associated with a marked reduction in MMP-9 expression, whereas MMP-2 and MMP-12 levels were not altered, identifying MMP-9 as a key mediator of E-cadherin cleavage. Collectively, these findings establish MMP-dependent E-cadherin cleavage as a mechanistic driver of e-cigarette-induced epithelial barrier dysfunction and identify sE-cad as a potential early biomarker and therapeutic target for aerosol-induced airway injury.
Mitochondrial dynamics in environmental neurotoxicity: beyond oxidative stress toward spatial and functional reorganization.
Yu X, Lin W, Hu W … +2 more , Long D, Zhao W
Arch Toxicol · 2026 Jun · PMID 42240671 · Publisher ↗
Environmental stressors are widely recognized as key drivers of neurotoxicity, yet their underlying mechanisms are still predominantly interpreted within a damage-centered framework focused on mitochondrial dysfunction,...
Environmental stressors are widely recognized as key drivers of neurotoxicity, yet their underlying mechanisms are still predominantly interpreted within a damage-centered framework focused on mitochondrial dysfunction, particularly oxidative stress and bioenergetic impairment.This perspective, primarily based on measurements of oxidative stress and bioenergetic impairment, cannot fully explain the spatial heterogeneity and selective vulnerability that define neuronal injury. Increasing evidence indicates that mitochondrial dynamics, including fission-fusion balance, intracellular transport, and quality control, function as an integrated regulatory system that actively organizes mitochondrial networks. Through the coordination of spatial distribution, functional renewal, and damage segregation, these processes shape how neurons respond to environmental challenges. Rather than serving as passive indicators of injury, mitochondrial dynamics determine whether cells maintain adaptive compensation or progress toward irreversible degeneration. In this review, we summarize how environmental stressors disrupt mitochondrial biology and propose mitochondrial dynamics as a central axis linking environmental exposure to neuronal fate. This perspective shifts the focus from static descriptions of dysfunction to dynamic regulation of mitochondrial networks and provides a conceptual framework for understanding heterogeneous neurotoxic outcomes while highlighting new opportunities for therapeutic intervention.
The in vitro alkaline comet assay with liver models as a complementary tool for genotoxicity assessment of N-nitrosamines.
Djuari MA, Londenberg A, Bassan A … +12 more , Cross K, Elenschneider L, Escher SE, Fahrer J, Fangmann J, Felske C, Frötschl R, Haas B, Johnson GE, Vogel M, Whomsley R, Ziemann C
Arch Toxicol · 2026 Jun · PMID 42228136 · Publisher ↗
N-nitrosamine (NA) impurities in pharmaceuticals represent "cohort of concern" compounds under ICH M7(R2), due to their mutagenic/carcinogenic potential, involving cytochrome P450 (CYP)-mediated metabolic activation. Inc...
N-nitrosamine (NA) impurities in pharmaceuticals represent "cohort of concern" compounds under ICH M7(R2), due to their mutagenic/carcinogenic potential, involving cytochrome P450 (CYP)-mediated metabolic activation. Increasing interest in mammalian cell-based genotoxicity/mutagenicity assays prompted our assessment of the in vitro alkaline comet assay regarding its predictive power for NAs. Here, precision-cut liver slices (PCLiS), primary human hepatocytes (PHH), primary rat hepatocytes (PRH), and HepG2 cells with rat or hamster S9-mix were investigated as in vitro model systems. Metabolic competence was characterized beforehand. For performance evaluation, a panel of known-mutagenic [N-nitroso-dimethylamine (NDMA), N-nitroso-diethanolamine, N-nitroso-methylaniline, S-N-nitroso-nornicotine, N-methyl-N-nitroso-2-propanamine] and reported non-mutagenic (methyl-t-butylnitrosamine, N-nitrosoproline) was tested, together with Nitrosamine Drug Substance-Related Impurities [N-nitrosodesloratadine, N-nitrosofolic acid, N-nitrosofluoxetine (NFluo)] at a concentration range of 0.005-10 mM. After 2 h (PCLiS, PHH and PRH) or 4 h (HepG2), NDMA concentration-dependently induced DNA strand breaks in all in vitro models. Sensitivity/specificity of the various liver cell models for prediction of carcinogenic NAs were 100%/50% (HepG2 with hamster S9-mix), 50%/100% (PHH, PRH), and 50%/50% (HepG2 with rat S9-mix), respectively. Benchmark dose modeling indicated a higher relative in vitro comet assay response for NFluo compared to NDMA in all cell systems. In conclusion, the in vitro comet assay represents a sensitive and/or specific tool for complementing regulatory in vitro tests in prediction of mutagenic NAs. However, further optimization work is needed, using expanded training sets of compounds and thorough validation of liver cell models, before the in vitro comet assay could be incorporated in the standard battery for genotoxicity testing.
PPAOT predictor: ARKA-RASTR strategy-driven rodent acute oral toxicity prediction for pyrazole and pyrrolidine scaffolds-based chemicals with intelligent mechanistic interpretation.
Xu J, Chen S, Ren T … +5 more , Li F, Zhang N, Zhao L, Zhong R, Sun G
Arch Toxicol · 2026 Jun · PMID 42228135 · Publisher ↗
Pyrazole and pyrrolidine represent two classes of high-frequency nitrogen-containing "privileged scaffolds" in drug discovery and industrial chemicals; however, their potential acute toxicity poses significant challenges...
Pyrazole and pyrrolidine represent two classes of high-frequency nitrogen-containing "privileged scaffolds" in drug discovery and industrial chemicals; however, their potential acute toxicity poses significant challenges to clinical translation and industrial application. This study aims to establish systematic prediction models for the acute oral toxicity of the two scaffolds in rats and mice, strictly adhering to OECD guidelines. Based on experimental data for 552 compounds collected from PubChem, we calculated 2D molecular descriptors and systematically compared the performance of several modeling strategies, traditional 2D-QSTR, q-RASTR, Hybrid-ARKA, and ARKA-RASTR and six machine learning (ML) algorithms. The results demonstrated that the ARKA-RASTR framework yielded the most superior performance. It not only outperformed other methods in external validation but also effectively overcame the internal stability issues often associated with conventional q-RASTR approaches, with all validation metrics exceeding the most stringent international standards. In terms of mechanistic interpretation, this study innovatively employed the ARKA-RASTR model for intelligent physical mechanism analysis, dynamically linking variable importance to specific toxicity intensity ranges, thereby significantly enhancing model interpretability. Finally, the optimized models were applied to the virtual screening of 18,000 real world compounds lacking experimental values. Through applicability domain (AD) assessment, we provided prioritized lists of the top ten potential high- and low-toxicity candidates for each scaffold. We also developed an online web-based predictor: PPAOT (Pyrazole-Pyrrolidine-Acute Oral Toxicity), enabling one-stop toxicity prediction. By leveraging advanced data fusion strategies, this study offers robust tools and clear guidance for the early safety assessment and structural optimization of nitrogen-containing heterocyclic drugs and chemicals.
Associations of serum per- and polyfluoroalkyl substances (PFAS) mixture with the risk of chronic diseases: evidence from single‑ , multi-pollutant, and machine learning models.
Li M, Sheng L, Ding Z … +10 more , Yu G, Chen Y, Chen Q, Shao W, Liu B, Du M, Gu D, Chen S, Xin J, Wang M
Arch Toxicol · 2026 Jun · PMID 42228134 · Publisher ↗
Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals commonly found in consumer products. Despite growing concern over their health effects, their associations with chronic diseases in humans are still unc...
Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals commonly found in consumer products. Despite growing concern over their health effects, their associations with chronic diseases in humans are still unclear. We included 10,093 participants to examine the associations between 8 PFAS and 40 chronic diseases. Multivariable logistic regression and restricted cubic spline (RCS) models were applied to evaluate linear and nonlinear associations, and mixture effects were further assessed using weighted quantile sum regression (WQS), quantile-based g-computation (q g‑comp), and Bayesian kernel machine regression (BKMR). Overall, we identified 16 significant PFAS-chronic disease associations after false discovery rate (FDR) correction, involving 7 PFAS and 6 chronic diseases. Specifically, each 1 ng/mL increase in perfluoroundecanoic acid (PFUnA) was associated with higher odds of heart attack (OR = 1.32, P = 0.032), coronary heart disease (OR = 1.31, P = 0.040), and non-melanoma cancer (OR = 1.22, P = 0.046). Non-linear analyses showed that, 6 PFAS were significantly associated with colorectal cancer. PFAS mixture analyses consistently indicated increased risks of cardiovascular diseases, hypertension, high cholesterol, and metabolic dysfunction. Perfluorononanoic acid (PFNA) was identified as the dominant contributor to the positive mixture effect (31.8-52.7%), as evidenced by several machine learning methods. Our findings provide important evidence of associations between PFAS exposure and multiple chronic diseases, and may contribute to the development of precision management strategies for chronic diseases prevention.
N-Ethylpentedrone: first hair detection and human metabolic profiling across multiple biological matrices using UHPLC-HRMS, molecular networking and in silico prediction.
Pasquet A, Pelletier R, Rouah R … +5 more , Panter T, Loiseau M, Porée FH, Gicquel T, Guerard P
Arch Toxicol · 2026 Jun · PMID 42228133 · Publisher ↗
N-ethylpentedrone (NEP) is a New Psychoactive Substance (NPS) of the cathinone class that has raised public health concerns, scheduled by both the United Nations Office on Drugs and Crime and the European Union Drugs Age...
N-ethylpentedrone (NEP) is a New Psychoactive Substance (NPS) of the cathinone class that has raised public health concerns, scheduled by both the United Nations Office on Drugs and Crime and the European Union Drugs Agency, since 2024. We report here a fatal case involving a 29-years-old man who used NEP in a chemsex context. Three plastic bags containing off-white to beige powders and crystals were found near the body. Proton and carbon nuclear magnetic resonance spectrometry (H and C NMR) and ultra-high performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) analyses confirmed all three bags contained NEP with purity above 98%. UHPLC-HRMS data analyses using molecular networking and in silico prediction allowed to propose NEP metabolic profile in peripheral and cardiac blood, bile, gastric fluid, urine and hair. We described here six Phase I metabolites, and we proposed NEP (CHNO) as the principal biomarker in NEP intake, metabolites M4 (CHNO) and M1 (CHNO) serving as biomarkers of consumption, as all of which were detected in all postmortem body fluid samples as well as in hair. Predominant metabolic pathways involved keto-reduction, N-dealkylation, hydroxylation, and oxidation, while no Phase II metabolites were detected under the applied analytical conditions. NEP was quantified at 18 mg/L and 20 mg/L in peripheral and cardiac blood, respectively, and 654-755 pg/mg in hair. These exceptionally high concentrations in biological fluids indicate an acute NEP intoxication, while hair analyses confirm repeated exposure over several months, consistent with chronic use. In summary, the identification of these metabolites in various postmortem body fluid matrices and in hair will improve our understanding of potential drug consumption markers and contribute to better monitoring and detection of N-ethylpentedrone use and abuse.
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