Toxicology Letters[JOURNAL]
Sun
200 papers
Corrigendum to "Bavachin induces liver injury and cell apoptosis by targeting Wnt/β-catenin/DRP1 signaling pathway mediated mitochondrial dysfunction" [Toxicol. Lett. 387 (2023) 1-13].
Yang Y, Zhou W, Wang Y … +4 more , Ge Y, Fan Z, Liu Q, Gao Y
Toxicol Lett · 2026 Jun · PMID 42156315 · Publisher ↗
Abstract loading — click title to view on PubMed.
Metal contamination in mice under conventional husbandry.
Fortmann C, Goeen T, Held N … +8 more , Froemmel S, Lichtl J, Kaifie A, Petersen C, Vieten G, Dingemann J, Bleich A, Jirmo AC
Toxicol Lett · 2026 Jun · PMID 42155691 · Publisher ↗
Metal release after implantation of medical metal implants can induce serious symptoms of hypersensitivity. A variety of immunologic reactions to metal particles has been demonstrated by a number of studies. To analyze t...
Metal release after implantation of medical metal implants can induce serious symptoms of hypersensitivity. A variety of immunologic reactions to metal particles has been demonstrated by a number of studies. To analyze the effect of metal abrasion in the thoracic cavity we aimed at developing a suitable mouse model. However, during the course of the study, high baseline concentrations of both chromium and nickel in conventional husbandry systems were observed. This finding necessitated modifications to the husbandry conditions. Groups of male C57BL/6 J mice were transferred into metal-free cages and fed a diet with reduced nickel and chromium content. After eight weeks, urinary concentrations of chromium and nickel were reduced, which was statistically significant in most groups for chromium and in one group for nickel. Due to their immunological impacts, we report the need to understand potential metal contaminations under conventional husbandry conditions in experimental set ups.
Mechanistic biomarkers in genotoxicity testing: A systematic mapping review of their integration with apical endpoints.
Nascimento NSO, Costa AO, Rebuiti BM … +1 more , Tagliati CA
Toxicol Lett · 2026 Jun · PMID 42155690 · Publisher ↗
Genetic toxicology plays a central role in regulatory safety assessment but remains largely dependent on a standardized battery of established genotoxicity assays. Increasing attention has been directed toward the integr...
Genetic toxicology plays a central role in regulatory safety assessment but remains largely dependent on a standardized battery of established genotoxicity assays. Increasing attention has been directed toward the integration of mechanistic information to improve biological interpretation and human relevance. This study presents a systematic mapping review (2020-2025) of biomarkers and methodological developments in genetic toxicology. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 1478 records were screened, resulting in 120 primary studies. The analysis showed that established genotoxicity assays, particularly the comet and micronucleus tests, remain dominant (91.7%), reflecting their continued role in regulatory hazard identification. However, 65% of the analyzed studies incorporated mechanistic components, indicating enhanced biological resolution. This mechanistic layer was primarily represented by targeted DNA damage response biomarkers (Level II) and systems-level omics-based or computational approaches (Level III), while 35% focused on technical optimization of established assays (Level I), including automation and high-throughput adaptations. Overall, the results indicate a dual structure in current genetic toxicology research, characterized by the sustained predominance of established regulatory assays alongside a heterogeneous integration of mechanistic and computational methodologies. Rather than replacing apical endpoints, these approaches primarily complement and refine the interpretation of genotoxicity data within weight-of-evidence frameworks. Integration of these biomarkers within Integrated Approaches to Testing and Assessment (IATA) may enhance mechanistic resolution in hazard evaluation, although regulatory maturity varies across platforms and application domains.
Erythrotoxicity of iron-doped cerium oxide nanoparticles is mediated by eryptosis.
Prokopiuk V, Lupan M, Grygorova G … +13 more , Posokhov Y, Maksimchuk P, Tryfonyuk L, Shevchenko N, Demchenko L, Kot K, Kurmangaliyeva S, Havranek O, Seminko V, Onishchenko A, Kot Y, Yefimova S, Tkachenko A
Toxicol Lett · 2026 Jun · PMID 42155689 · Publisher ↗
Iron doping has been reported to significantly modify the properties of metal oxide nanoparticles (NPs), including their interaction with cells and therefore toxicity. The present study explores the ability of Fe³ ⁺-dope...
Iron doping has been reported to significantly modify the properties of metal oxide nanoparticles (NPs), including their interaction with cells and therefore toxicity. The present study explores the ability of Fe³ ⁺-doped CeO NPs with the varying content of Fe ions (3, 5, and 10 at%) to stimulate eryptosis, a controllable cell death pathway of mature erythrocytes, as an attempt to shed light on hemocompatibility of iron-doped CeO NPs. Overall erythrotoxicity of iron-doped CeO NPs was evaluated by investigating their ability to trigger spontaneous hemolysis and affect osmotic fragility of rat erythrocytes. Eryptosis of erythrocytes exposed to iron-doped and non-doped CeO NPs for 24 h was evaluated by the state-of-the-art flow cytometry-based annexin V staining. Mechanisms involved in iron-doped CeO NP-induced eryptosis were evaluated by 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) and caspase-3 assays, as well as the fluorescent O1O (2-(2'-hydroxy-phenyl)-5-phenyl-1,3-oxazole), NR12S, Fluo-3 AM, BODIPY™ 581/591 C11, and BioTracker Far-red Fe Live Cell imaging probes. Dose-dependent effects of iron-doped CeO NPs on hemolysis, osmotic fragility, and eryptosis were revealed. Eryptosis triggered by iron-doped CeO NPs was found to be oxidative stress-mediated, cation channel-driven, and caspase-dependent. Oxidative stress and alterations of lipid membranes demonstrated by the tested NPs could be attributable to their direct •OH generation and peroxidase-like activity, as well as Fe-mediated Fenton reaction at the surface of Fe³⁺-doped CeO₂ NPs (presumably due to Fe³⁺/Fe²⁺ redox cycling). Importantly, non-doped CeO NPs did not promote eryptosis. Nor they stimulated generation of ROS and Ca influx. The presence of iron was found to mediate phosphatidylserine externalization, caspase activation, and changes in lipid membranes of erythrocytes. Notably, Fe³⁺-doped CeO NP-induced eryptosis was independent of p38 MAPK and CK1α. Iron-doped CeO NPs trigger eryptosis, an effect mediated by iron. Iron doping is a promising modification of CeO NPs, which can modulate their toxicity and widen their pharmaceutical profile.
A generic physiologically based kinetic model for the domestic cat (Felis catus): Model characterisation, validation and reporting using the OECD reporting template.
Spyropoulos F, Di Nicola MR, Tarazona JV … +2 more , Lautz LS, Dorne JLCM
Toxicol Lett · 2026 Jun · PMID 42134645 · Publisher ↗
Domestic cats (Felis catus) are among the most popular pets in the world, with the global domestic cat population generally estimated to exceed 600 million and potentially approach 1 billion when feral populations are in...
Domestic cats (Felis catus) are among the most popular pets in the world, with the global domestic cat population generally estimated to exceed 600 million and potentially approach 1 billion when feral populations are included. As hypercarnivores, cats exhibit unique metabolic deficiencies, particularly in phase II conjugation enzymes (e.g., glucuronidation, glycine conjugation), which impair elimination of phenolic xenobiotics including pharmaceuticals, feed additives, and contaminants. Consequently, the European Food Safety Authority (EFSA) Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) recommends an additional default uncertainty factor (UF) of 5 for such compounds. Physiologically based kinetic (PBK) modelling offers a mechanistic approach to refine these default factors using chemical-specific kinetic data and such models for the domestic cat are not currently available to the scientific and risk assessment community. Hence, this manuscript focuses on the development and validation of a generic PBK model for the species Felis catus according to the six-step process from the template of the Organisation for Economic Cooperation and Development (OECD) guidance document on characterisation, validation and reporting of PBK models for regulatory purposes. The model integrates meta-analysed physiological parameters from the peer-reviewed literature and 11 perfusion limited compartments. The model has been validated using chemical-specific inputs for 15 pharmaceuticals using in vitro and in vivo clearances to compare in vivo to in vivo and in vitro to in vivo predictions with the available experimental data for plasma maximum concentration (Cmax) and area-under-the-curve (AUC) values in blood after oral and intravenous exposure. Impact of bioavailability on model performance has also been assessed using conservative default values and reported or estimated values. In addition, global sensitivity analysis using the Sobol method identified the muscle:blood partition coefficient as the dominant parameter influencing model output variance. Overall, the generic PBK cat model performed well and most predictions accounting for bioavailability using in vitro derived clearance yielded 86% of Cmax predictions and 64% of AUC predictions were within 2-3-fold of the experimental data as recommended by the OECD. Future applications and refinements of the model with regard to NGRA of food and feed chemicals are highlighted.
Multi-platform In Silico assessment of selected a-series (Novichok) nerve agents: Physicochemical, toxicological, and mechanistic insights.
Kanavou I, Anastasiou S, Chalaris M
Toxicol Lett · 2026 Jun · PMID 42114727 · Publisher ↗
A multi-platform in silico framework was developed to characterize five selected A-series (Novichok) nerve agents-A-230, A-232, and A-234 (each evaluated using Ellison- and Mirzayanov-type structural representations) [1,...
A multi-platform in silico framework was developed to characterize five selected A-series (Novichok) nerve agents-A-230, A-232, and A-234 (each evaluated using Ellison- and Mirzayanov-type structural representations) [1,2] together with A-242 and A-262-through integrated physicochemical, toxicological, and biological-activity prediction. Four complementary computational platforms (ACD/Labs Percepta, OECD QSAR Toolbox, EPA T.E.S.T., and PASS Online) were combined within a reproducible workflow to support Structure-Property-Toxicity Relationship (SPTR) interpretation across eight modeled structures (n = 8). Predicted partitioning behavior indicated moderate lipophilicity (logP (GALAS) ≈ 0.5-1.7) together with very low vapor pressure (0-0.05 mmHg at 25 °C), consistent with condensed-phase persistence and contact-driven exposure rather than sustained vapor dispersion. QSAR-derived LD₅₀ values and dermal permeability coefficients varied across structural variants, demonstrating that predicted acute toxicity is not governed by a single descriptor. PASS-derived probabilities indicated elevated neurotoxicity likelihoods, while cholinergic activity probabilities showed stronger association with polarity-related descriptors (TPSA) than with lipophilicity alone. Principal Component Analysis (PC1 ≈ 81%, PC2 ≈ 13%) showed that descriptor variance was primarily driven by polarity-permeability balance rather than toxicity magnitude alone. Composite hazard ranking integrating inverse LD₅₀, permeability, and neurotoxicity probability identified structural variants combining higher predicted permeability and elevated activity probabilities as comparatively higher within the modeled set. All findings are restricted to the studied compounds and represent computational predictions rather than experimental measurements, providing a transparent and regulatory-aligned framework for comparative, non-experimental hazard assessment under Chemical Weapons Convention constraints.
Mixed exposure to brominated flame retardants adversely affects vaccine-induced antibody titers: Risk prioritization and benchmark dose modeling.
Zhao Z, Zhang C, Chen X … +15 more , Yan Y, Jiao H, Wang X, Yan R, Wang Y, Liu M, Yue X, Sui Y, Li X, Wang S, Sun R, He Q, Song D, Ji L, Li D
Toxicol Lett · 2026 Jun · PMID 42097324 · Publisher ↗
The association between brominated flame retardant (BFRs) exposure and measles, mumps, and rubella vaccine (MMR) antibody responses was investigated using the National Health and Nutrition Examination Survey (2003-2004)....
The association between brominated flame retardant (BFRs) exposure and measles, mumps, and rubella vaccine (MMR) antibody responses was investigated using the National Health and Nutrition Examination Survey (2003-2004). Using multivariate linear regression and restricted cubic spline (RCS) model, we found significant inverse association between single BFR exposure (BB-153 and BDE-100) and mumps antibody levels (P < 0.05). Mixed BFR exposure synergistically reduced antibody levels across mumps and rubella vaccines, with BB-153 identified as the dominant contributor for mumps (PIP = 0.460). Benchmark dose modeling revealed immunotoxicity thresholds for a 10% antibody reduction: BB-153 (BMDL = 46.73 pg/g serum) for mumps, BDE-153 (BMDL = 258.27 pg/g serum) for rubella. While the exposure levels of most people in this study were below these thresholds, dose-response trends were still observed at sub-threshold concentrations. Enrichment analyses via Comparative Exploratory functional enrichment analysis suggested that BFR exposure may be associated with immune-related pathways. However, these findings are hypothesis-generating and do not represent definitive mechanistic evidence. Further experimental studies are needed to validate these potential biological mechanisms. Sensitivity analyses confirmed robust associations, and independent toxic effects were observed in females. This is the first study to examine the relationship between BFR exposure and MMR vaccine effects, highlighting the need for enhanced monitoring and a revised framework for assessing immunotoxicity.
Toxicological potential of nanomaterials by concentration-dependent transcriptomics of human cells.
Fang W, Tian M, Gou X … +2 more , Xia P, Zhang X
Toxicol Lett · 2026 Jun · PMID 42092645 · Publisher ↗
Biological pathways altered by nanomaterials can be used to predict potential hazards to humans and wildlife. However, the impacts of particle size, charge, and chemical composition of nanomaterials on biological pathway...
Biological pathways altered by nanomaterials can be used to predict potential hazards to humans and wildlife. However, the impacts of particle size, charge, and chemical composition of nanomaterials on biological pathways in the cellular system are largely unknown. Here, the biological pathway profiles of ten typical metal oxide nanomaterials were obtained in A549 cells by using concentration-dependent transcriptomic analysis with reduced human transcriptome (RHT) technology. We further analysed the influence of particle size, charge, and chemical composition on the biological pathways affected by nanomaterials. All pathways activated by the ten metal oxide nanomaterials were related to inflammation, DNA damage, and apoptosis; however, the transcriptomic potencies of this group of materials differed by more than two orders of magnitude. Furthermore, nanomaterials with similar chemical compositions, particle sizes, and charges are more likely to cluster together based on profiles of altered pathways. In addition, small-sized manganese oxide nanomaterials are more likely to interfere with metabolic, cell component, and developmental pathways, whereas high-charge manganese oxide nanomaterials are more likely to activate pathways such as stress response, DNA damage, and hormone signalling. Concentration-dependent transcriptomic analysis can provide information on the biological pathways and associated potency, which can then provide references for future nanomaterial toxicity assessment and green metal oxide nanoparticle design.
Tributyltin exposure disrupts intestinal barrier and enteric nervous system in the ileum of Wistar rats.
Marinsek GP, Oliveira ICCDS, Tagliamento MA … +4 more , Villas Boas LC, de Castro ÍB, Silva RCBD, de Britto Mari R
Toxicol Lett · 2026 May · PMID 42070756 · Publisher ↗
Tributyltin (TBT) is a lipophilic compound known to damage biological membranes and is associated with neurotoxic and inflammatory effects. This study evaluated the impact of TBT (20 ng/g and 600 ng/g) on the gastrointes...
Tributyltin (TBT) is a lipophilic compound known to damage biological membranes and is associated with neurotoxic and inflammatory effects. This study evaluated the impact of TBT (20 ng/g and 600 ng/g) on the gastrointestinal tract (GIT) barrier and morphology and enteric nervous system (ENS) of Wistar rats exposed for 30 days via gavage. We observed a significant reduction in goblet cell density in the group 20 ng/g, and an increase in goblet cells in the group 600 ng/g. There was also an increase in intraepithelial lymphocytes (IELs) in both exposed groups, indicating an activated immune response and potential tissue injury. In the enteric nervous system, neuronal metabolism decreased without affecting overall neuronal density, in the group 20 ng/g, while the group exposed to 600 ng/g showed an increase in total neuronal density with the maintenance of metabolic activity. TBT exposure also induced an increase in peroxiredoxin-2 (Prx2) in both groups and altered occludin expression. Integrated biomarker response (IBR) analysis confirmed that TBT disrupted intestinal homeostasis and neuronal integrity, affecting cellular functions and causing immunological and oxidative dysfunctions.
Tacrolimus-accelerated renal interstitial injury in subtotal nephrectomized rats and its pharmacological modulation by everolimus.
Nakayama Y, Kamikawa S, Masuda S
Toxicol Lett · 2026 May · PMID 42061595 · Publisher ↗
Tacrolimus, a calcineurin inhibitor widely used in clinical practice, is associated with chronic nephrotoxicity, particularly under conditions of reduced renal reserve. However, experimental models that efficiently repro...
Tacrolimus, a calcineurin inhibitor widely used in clinical practice, is associated with chronic nephrotoxicity, particularly under conditions of reduced renal reserve. However, experimental models that efficiently reproduce tacrolimus-accelerated renal injury within a short time frame remain limited. In this study, we established an in vivo model to evaluate tacrolimus-associated renal injury using subtotal (5/6) nephrectomized rats. Low-dose tacrolimus was administered for two weeks starting four weeks after surgery, and the effects of concomitant everolimus treatment were examined as a pharmacological modulator. Renal function was assessed by plasma creatinine and urinary albumin parameters, and renal injury was evaluated by histological analyses and protein expression profiling. Tacrolimus administration significantly exacerbated renal dysfunction and structural injury in nephrectomized rats, as evidenced by increased plasma creatinine levels, albuminuria, and enhanced interstitial fibrosis. Concomitant everolimus treatment was associated with partial attenuation of these functional and histopathological changes. The present study demonstrates the establishment of a tacrolimus-accelerated renal injury model under conditions of reduced renal reserve. Everolimus co-treatment was associated with partial attenuation of renal injury under the experimental conditions used.
Benzothiazole and 2-mercaptobenzothiazole impair reproduction by disrupting sperm function in Caenorhabditis elegans.
Zhao Q, Cao Z, Zhang J … +3 more , Wang X, Dai L, Du H
Toxicol Lett · 2026 May · PMID 42049079 · Publisher ↗
Benzothiazoles (BTs), derived primarily from tire wear particles, are ubiquitous contaminants that pose significant environmental hazards and health risks. This study evaluated the effects of benzothiazole (BTH) and 2-me...
Benzothiazoles (BTs), derived primarily from tire wear particles, are ubiquitous contaminants that pose significant environmental hazards and health risks. This study evaluated the effects of benzothiazole (BTH) and 2-mercaptobenzothiazole (MBT) on reproductive toxicity by using the model organism Caenorhabditis elegans. Synchronized L1 larvae were exposed to BTH or MBT at 0, 0.1, 1, 10, and 50 μg/L for 60 h. Germline apoptosis, oogenesis, sperm activation, and sperm migration were tested in parental worms, and some reproductive endpoints were further examined in non-exposed F1 offspring. Our findings demonstrate that BTs at environmentally relevant concentrations induced germline apoptosis and inhibited oogenesis. Furthermore, in male worms, sperm activation and migration were significantly disrupted in parental worms, where increased failure rates of sperm activation were also observed in non-exposed F1 generation. Transcriptomic analysis showed substantial alterations in the expression of spermatogenesis-related genes, with enrichment of pathways involved in spermatid differentiation. Our findings show that BTs disrupt germ cell development and sperm function in C. elegans, with parental exposure linked to measurable reproductive defects in offspring, underscoring potential long-term environmental health risks of tire wear particles.
Systemic inflammation moderate the association between urinary polycyclic aromatic hydrocarbon metabolites and hypertensive adults.
Liu J, Zhou Z, Zhu X … +9 more , Guan G, Li F, Cui Q, Hui R, Wang J, Wu R, Zhao Z, Pang H, Zhu L
Toxicol Lett · 2026 May · PMID 42019582 · Publisher ↗
BACKGROUND: This study aims to investigate the mediation effects of the systemic inflammation on the association between urinary polycyclic aromatic hydrocarbons (PAHs) metabolites and hypertension in general US populati...
BACKGROUND: This study aims to investigate the mediation effects of the systemic inflammation on the association between urinary polycyclic aromatic hydrocarbons (PAHs) metabolites and hypertension in general US population. METHODS: This cross-sectional study analyzed 9 urinary PAHs metabolites from the 2003-2012 National Health and Nutrition Examination Survey (NHANES). Quantile g-computation (QG-C) were applied to assess the association between PAHs mixture exposure and hypertension prevalence. The associations among PAHs (exposure), hypertension (outcome), and inflammatory markers (C-reactive protein, alkaline phosphatase, white blood cell count, neutrophil count, and monocyte count; mediators) were investigated using mediation analysis. RESULTS: Among the 6846 participants, 2473 (36.1%) were diagnosed with hypertension. The mean of systolic and diastolic BP were 138.6 (20.4) and 72.7 (16.0) mmHg in the hypertensive group, and 115.8 (10.9) mmHg and 69.0 (10.0) mmHg in the non-hypertensive group. The mixture of urinary PAHs metabolites was significantly associated with increased prevalence of hypertension, with β = 0.124 (95% CI: 0.04, 0.20) for every quantile increase. Urinary 1-PHE (36.48%), 2-FLU (27.64%) and 1-PYR (26.64%) had the greatest positive contribution to the overall effect. Mediation analysis revealed that inflammatory markers play a mediating role in the associations between PAHs metabolites (2-FLU, 3-PHE, 1-PHE, 2-PHE, 1-PYR, and 9-FLU) and hypertensive adults. CONCLUSIONS: Our study demonstrated that mixture exposure to PAHs is associated with the prevalence of hypertension in US adult population, which might be primarily driven by 1-PHE, 2-FLU and 1-PYR. Furthermore, we have observed that systemic inflammation plays a significant mediating role in this associations.
Corrigendum to "Acanthoic acid protectsagainst ethanol-induced liver injury: Possible role of AMPK activation and IRAK4 inhibition" [Toxicol. Lett. 281 (2017) 127-138].
Yao YL, Han X, Song J … +5 more , Zhang J, Li YM, Lian LH, Wu YL, Nan JX
Toxicol Lett · 2026 May · PMID 42002432 · Publisher ↗
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A stimulating effect induced by Bisphenol A bis (diphenylphosphate) in HepG2 cells via vascular endothelial growth factor (VEGF)/VEGF receptor axis.
An J, Yi Y, Li N … +4 more , Lin M, Zhong Y, Ren G, Shang Y
Toxicol Lett · 2026 May · PMID 41990979 · Publisher ↗
With the widespread distribution and increasing detection levels of Bisphenol A bis (diphenylphosphate) (BDP) in environment, toxicity risk assessment on BDP has become indispensable issue. So far, available toxicologica...
With the widespread distribution and increasing detection levels of Bisphenol A bis (diphenylphosphate) (BDP) in environment, toxicity risk assessment on BDP has become indispensable issue. So far, available toxicological information about BDP is still limited. In this study, a hormesis-like effect of BDP in HepG2 cells was observed and potential mechanism was investigated. BDP (<2 μM) promoted proliferation ability and stimulated the migration and invasion ability of HepG2 cells as evidenced by increased viability, accelerated colony formation, hasted scratch healing, down-regulated E-cadherin, and up-regulated matrix metalloproteinase (MMP-9) and mouse double minute 2 homolog (MDM2) proteins. However, high doses of BDP (>20 μM) exhibited completely opposite effects to that of lower dose. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis was involved in the stimulating effect induced by 0.2 μM of BDP through activation of the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway and extracellular regulated protein kinases (ERK)/p38 mitogen activated protein kinase (MAPK) cascades, and there was a bidirectional regulation between the latter two pathways. Our results demonstrated the network of VEGF/VEGFR, Akt/mTOR, and ERK/p38 MAPK pathways involving in BDP-induced stimulating effect on proliferation, migration and invasion ability of HepG2 cells, which providing a novel insight on toxicology risk assessment of BDP.
The mitochondrial fission-mitophagy axis drives neuronal S-phase arrest and hippocampal damage in co-exposure to polystyrene nanoplastics and lead.
Li Q, Zhang Y, Hu Y … +8 more , Liu Z, Cui S, Wei D, Yue L, Du Q, Liu T, Huang D, Qi Y
Toxicol Lett · 2026 May · PMID 41990978 · Publisher ↗
Smaller polystyrene nanoplastics (PS-NPs) can act as vectors for co-existing environmental heavy metals like lead (Pb). The complex neurological health risks posed by these co-exposures are concerning, but their combined...
Smaller polystyrene nanoplastics (PS-NPs) can act as vectors for co-existing environmental heavy metals like lead (Pb). The complex neurological health risks posed by these co-exposures are concerning, but their combined neurotoxicity mechanism remains unclear. This study investigated the individual and combined toxic impacts of PS-NPs (5 mg/kg in mice, 50 μg/mL in HT22 cells) and Pb (100 mg/L in mice, 10 μg/mL in HT22 cells) on hippocampal neurons, and explored the underlying mechanisms. The results show that PS-NPs facilitate Pb accumulation in the mouse hippocampus and HT22 cells via clathrin-mediated endocytosis. Co-exposure to Pb and PS-NPs, but not either alone, synergistically induced hippocampal neuronal damage, manifesting as synaptic loss and memory deficits in mice, and triggered S-phase cell cycle arrest alongside oxidative stress in HT22 cells. Mechanistically, Pb+PS-NPs caused mitochondrial dysfunction and shifted mitochondrial dynamics towards excessive fission, evidenced by upregulated DRP1/p-DRP1 and downregulated MFN1/2, and activated PINK1/Parkin-mediated mitophagy. Crucially, inhibition of this mitochondrial fission-mitophagy axis by Mitochondrial Division Inhibitor 1 or cyclosporin A attenuated mitochondrial damage, rescued S-phase arrest, and alleviated hippocampal neuronal injury. Our findings unveil a novel pathway wherein the mitochondrial fission-mitophagy axis drives neuronal cell cycle arrest and cognitive impairment, providing new insights into the risks of combined pollutant exposure.
Snake venom-induced tissue damage as a paradigm of redox imbalance, ferroptosis, and inflammaging.
Dahiya R, Singh AP, Rawat A
Toxicol Lett · 2026 May · PMID 41974208 · Publisher ↗
Snakebite envenomation remains a major cause of illness globally, resulting in complex local and systemic toxic effects. Although the biochemical functions of individual snake venom components have been extensively studi...
Snakebite envenomation remains a major cause of illness globally, resulting in complex local and systemic toxic effects. Although the biochemical functions of individual snake venom components have been extensively studied, the cellular mechanisms underlying progressive tissue damage and organ dysfunction remain less well understood. This review compiles contemporary mechanistic evidence associating notable venom toxin families, such as phospholipase A₂, snake venom metalloproteinases, and three-finger toxins, with oxidative stress-induced cellular damage. Mounting evidence highlights mitochondrial dysfunction, iron release, and lipid peroxidation as central drivers of redox imbalance. New evidence supporting the idea that ferroptotic cell death plays a role in venom-induced disease is compared to more traditional types of cell death. This shows how iron-dependent oxidative injury can lead to long-term tissue damage. The review also examines how oxidative mechanisms interact with innate immune activation, endothelial dysfunction, and microvascular injury to cause organ-specific toxicity, particularly in the liver, kidneys, heart, and nervous system. This overview does not suggest a singular, unifying pathogenic pathway; instead, it emphasises representative mechanistic vignettes that influence the progression and severity of snake venom-related injury. A deeper understanding of the interactions among these pathways may enhance future research and facilitate the development of innovative strategies to improve the effectiveness of traditional antivenom therapy.
Influence of hepatic steatosis on antiseizure drug metabolism: in vitro evidence from differentiated HepaRG cells.
Plissonneau V, Gicquel T, Legrand Brault ER … +3 more , Jost J, Massart J, Le Daré B
Toxicol Lett · 2026 May · PMID 41965184 · Publisher ↗
BACKGROUND: Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) could impair hepatic drug metabolism by altering cytochrome P450 and conjugating enzyme activities, potentially affecting the pharm...
BACKGROUND: Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) could impair hepatic drug metabolism by altering cytochrome P450 and conjugating enzyme activities, potentially affecting the pharmacokinetics and toxicity of antiseizure drugs (ASDs). OBJECTIVE: To investigate the impact of in vitro steatosis on the cytotoxicity and hepatic metabolism of six ASDs (carbamazepine, phenytoin, lamotrigine, levetiracetam, felbamate and sulthiame) in differentiated HepaRG cells. METHODS: HepaRG cells were exposed to fatty acid overload, oleic acid (300 µM) and stearic acid (150 µM), to induce steatosis and incubated with each ASD for 48 h. Cytotoxicity was assessed, and metabolic profiling was performed using liquid chromatography coupled with high resolution mass spectrometry. RESULTS: Steatotic conditions did not significantly increase cytotoxicity for any ASD. However, steatosis significantly reduced the formation of carbamazepine-10,11-epoxide (consistent with impaired CYP3A4 activity) and decreased production of levetiracetam's major metabolite L057 (likely via reduced carboxylesterase activity). No significant metabolic changes were observed for phenytoin, lamotrigine, felbamate or sulthiame. CONCLUSIONS: Hepatic steatosis selectively alters the metabolism of carbamazepine and levetiracetam in vitro without enhancing short-term cellular toxicity. These findings raise concerns about possible modifications in drug exposure, efficacy and tolerability in patients with MASLD, and underscore the need for further in vivo and clinical studies.
Targeting PCSK9 suppresses NF-κB-mediated M1 polarization in alveolar macrophages and lung injury induced by low-dose systemic PM2.5 exposure.
Wang C, Zhang W, Liu Y … +1 more , Guo Y
Toxicol Lett · 2026 May · PMID 41962642 · Publisher ↗
BACKGROUND: Fine particulate matter (PM2.5) exposure is a major environmental risk factor for pulmonary inflammation and injury, in which alveolar macrophages (AMs) play a central role. Proprotein convertase subtilisin/k...
BACKGROUND: Fine particulate matter (PM2.5) exposure is a major environmental risk factor for pulmonary inflammation and injury, in which alveolar macrophages (AMs) play a central role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is recognized for its role in cholesterol metabolism and cardiovascular inflammation; however, its involvement in PM2.5-induced lung injury remains unexplored. AIM: This study aims to elucidate the role of PCSK9 in mediating AMs M1 polarization and lung injury following low-dose systemic PM2.5 exposure. METHODS: Using in vitro PM2.5-exposed AMs (MH-S cell line) models and in vivo mouse whole-body exposure systems (56-day subacute injury and 112-day chronic fibrosis models), we employed genetic knockdown (shRNA, AAV-shPCSK9) and pharmacological inhibition (SBC-115076) approaches to validate PCSK9 function. Conditioned medium co-culture experiments were performed to assess alveolar epithelial cell (MLE-12) injury. M1 polarization was evaluated by flow cytometry (CD86), western blot (iNOS), and ELISA (TNF-α, IL-1β, IL-6). NF-κB pathway activation was assessed by phosphorylation of p65 and IκBα. RESULTS: PM2.5 exposure (20 μg/mL, 24 h) upregulated PCSK9 expression by 4.7-fold and increased the proportion of CD86⁺ M1 macrophages from 3.38% ± 0.52% in controls to 33.41% ± 3.63%. Genetic knockdown of PCSK9 reduced the CD86⁺ population to 15.75% ± 1.45% (P < 0.01 vs. PM2.5 alone) and suppressed secretion of TNF-α, IL-1β, and IL-6 by 68%, 55%, and 62%, respectively (all P < 0.01). Pharmacological inhibition with SBC-115076 (10 μM) similarly attenuated M1 polarization, with CD86⁺ cells reduced to 8.69% ± 1.34% (P < 0.01), and decreased TNF-α, IL-1β, and IL-6 levels by 66.94%, 58.73%, and 60.24%, respectively (all P < 0.01). Mechanistically, PCSK9 knockdown reduced phosphorylation of p65 and IκBα by 77.76% and 87.85% (P < 0.01), effects partially reversed by an NF-κB agonist. Conditioned medium from PM2.5-primed AMs decreased MLE-12 cell viability by 50.9% (P < 0.01) and increased apoptosis, with TUNEL⁺ cells rising from 3.62% ± 1.09-43.03% ± 5.24% (P < 0.01); these effects were abrogated by PCSK9 knockdown. In vivo, intranasal AAV-shPCSK9 reduced PM2.5-induced lung injury and decreased BALF levels of TNF-α, IL-1β, and IL-6. In the 112-day chronic model, SBC-115076 (10 mg/kg) reduced collagen deposition, with Masson's trichrome-positive area decreasing from 25.02% ± 3.71% in the PM2.5 group to 8.98% ± 1.26% (P < 0.01), and downregulated fibrotic markers α-SMA and fibronectin by 60% and 55%, respectively (P < 0.01). CONCLUSION: PCSK9 acts as a critical mediator of low-dose PM2.5-induced lung injury by driving AMs M1 polarization via NF-κB activation, highlighting its potential as a therapeutic target for mitigating air-pollution-related respiratory diseases.
From cellular toxicity and inflammation to human safety: An integrated in vitro-in silico assessment of 5-hydroxymethylfurfural (HMF).
Faustino DC, Santos LO, Feitosa BAC … +8 more , Cedro MA, Borges-Silva W, Nonaka CKV, Souza BSF, Daleprane JB, Gondim LFP, Guedes CES, Matos LCP
Toxicol Lett · 2026 May · PMID 41937002 · Publisher ↗
5-Hydroxymethylfurfural (HMF) is a heat-induced food contaminant whose toxicological relevance remains under debate. This study integrates in vitro assays, in silico modelling, and probabilistic exposure assessment to ch...
5-Hydroxymethylfurfural (HMF) is a heat-induced food contaminant whose toxicological relevance remains under debate. This study integrates in vitro assays, in silico modelling, and probabilistic exposure assessment to characterize the risk associated with HMF. Differentiated 3T3-L1 cells, a metabolic and inflammation-responsive model, were exposed to concentrations of HMF (1-1000 µg/ml). Cell viability remained above 95% up to 16 µg/ml, which was defined as the in vitro NOAEL. Acute exposure (150 µg/ml, 12 h) markedly upregulated IL-6, TNF-α, IFN-γ, and TGF-β, indicating activation of pro-inflammatory pathways likely mediated by oxidative stress. In vitro-in vivo extrapolation (IVIVE) converted the cellular NOAEL into oral equivalent doses, ranging from 1.067 to 12.935 µg/kg bw/day, depending on the pharmacokinetic assumptions. Monte Carlo simulation (100,000 iterations) predicted mean dietary exposures (µg/kg bw/day) of 541 for adults, 605 for adolescents, and 223 for infants. Margin of exposure (MOE) estimates placed 50-56% of adults and adolescents in an intermediate-risk category, while 43-49% fell within the high-risk range (MOE < 10), and Infants within the low-risk range. These findings highlight the pro-inflammatory potential of HMF in adipocytes and support the value of combining in vitro data with probabilistic modelling to refine human dietary risk assessment.
Bisphenol S and high-fat diet drive structural and inflammatory remodeling of the colon in C57Bl/6 male mice.
de Luca BG, Alexandre-Santos B, Gama E Souza KM … +11 more , Barreto-Reis E, Paula Alves AP, de Souza Carvalho-Laureano T, Sepúlveda-Fragoso V, Diniz LG, Stockler-Pinto MB, Dos Santos CM, de Carvalho DP, Miranda-Alves L, Frantz EDC, Magliano DC
Toxicol Lett · 2026 May · PMID 41933810 · Publisher ↗
Bisphenol S (BPS) is an emerging environmental contaminant with endocrine-disrupting properties capable of triggering early gastrointestinal alterations linked to intestinal remodeling. This study investigated the effect...
Bisphenol S (BPS) is an emerging environmental contaminant with endocrine-disrupting properties capable of triggering early gastrointestinal alterations linked to intestinal remodeling. This study investigated the effects of BPS and a high-fat diet (HFD) on colon remodeling in male mice. Forty animals were divided into four groups: standard chow (SC), SC+BPS (SCB), HFD, and HFD+BPS (HFB). After 12 weeks, biometric parameters and colon morphology were analyzed. Both BPS and HFD induced weight gain, adiposity, and reductions in colon length, crypt depth, and mucus-positive area. Altered tight junction protein expression (decreased Occludin, and increased Claudin-2) suggested impaired epithelial barrier integrity. Higher TLR-4 expression and serotonin-secreting cells supported the presence of local inflammation. The combination of BPS and HFD did not potentiate these effects. Chronic exposure to BPS, even at low doses, promotes adverse colon remodeling comparable to that induced by HFD, and might compromise barrier integrity, and enhance local inflammation. These findings raise concerns about BPS safety and highlight the need for stricter regulation of bisphenol analogues in food packaging.
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