Archives Of Toxicology[JOURNAL]
Sun
200 papers
Real-life nanoplastics induce endothelial dysfunction in primary human endothelial cells.
Martín-Pérez J, Morataya-Reyes M, Villacorta A … +7 more , Anguita-Solé C, Ferrer JF, Barguilla I, Alaraby M, Marcos R, Hernández A, García-Rodríguez A
Arch Toxicol · 2026 May · PMID 42086804 · Publisher ↗
Understanding how nanoplastics (NPLs) exposure affects vascular endothelium is essential for determining their potential cardiovascular risk. To this end, four different NPLs of similar nominal sizes (about 200 nm), but...
Understanding how nanoplastics (NPLs) exposure affects vascular endothelium is essential for determining their potential cardiovascular risk. To this end, four different NPLs of similar nominal sizes (about 200 nm), but different environmental relevance, have been used. They are: (i) spherical and monodisperse pristine polystyrene (PS), (ii) biodegradable polylactic acid (PLA), (iii) moderately irregular and polydisperse polytetrafluoroethylene (PTFE), and (iv) highly irregular and polydisperse polyethylene terephthalate (PET) derived from post-consumer bottles. To determine their hazardous risk, primary human umbilical vein endothelial cells (HUVECs) were used as a physiologically relevant model of the vascular endothelium. Results show that all NPLs were internalized by HUVECs, although uptake efficiency and intracellular distribution varied among polymers. None of the NPLs induced cytotoxicity or DNA damage at 25 µg/mL for 24 h. However, PTFE- and PET-NPLs elicited functional alterations consistent with endothelial dysfunction. PET-NPLs triggered IL-6 secretion and intracellular cholesterol accumulation, while both PTFE- and PET-NPLs significantly impaired cell migration, reducing wound closure. These findings reveal a clear gradient of biological impact, with irregular NPLs inducing stronger endothelial stress responses. By linking morphological realism to vascular inflammation, cholesterol dysregulation, and impaired migration, this study underscores the relevance of environmentally realistic NPLs into human health risk assessment frameworks.
The use of cultured human hepatocytes as a test system to evaluate cell proliferation as a key event in nongenotoxic carcinogenesis.
Cowie DE, Cohen SM, Goettel M … +8 more , Lake BG, Nadzialek S, Rooni U, Schutte ME, Tinwell H, Turiccki J, Yamada T, Strupp C
Arch Toxicol · 2026 May · PMID 42086803 · Publisher ↗
The objective of this study was to evaluate the applicability of replicative DNA synthesis (RDS) in cultured human hepatocytes as an in vitro model to evaluate the carcinogenicity of nongenotoxic chemicals and species di...
The objective of this study was to evaluate the applicability of replicative DNA synthesis (RDS) in cultured human hepatocytes as an in vitro model to evaluate the carcinogenicity of nongenotoxic chemicals and species differences. Investigations were performed with 39 cryopreserved human hepatocyte preparations from predominantly Caucasian male and female donors aged 10 months to 80 years and were conducted by two separate laboratories, which employed different culture conditions and methodology for evaluating effects on hepatocyte RDS. For all male and female human hepatocyte preparations of all ages examined, treatment with either epidermal growth factor (EGF) and/or hepatocyte growth factor (HGF) resulted in a stimulation of RDS. In contrast, the treatment of human hepatocytes with the constitutive androstane receptor (CAR) activators phenobarbital and CITCO and the peroxisome proliferator-activated receptor alpha (PPARα) activator WY-14,643 did not result in any increases in RDS. These findings are in agreement with previous studies where, unlike EGF and HGF, nongenotoxic CAR and PPARα activators are mitogenic agents in rodent but not in human hepatocytes. While some donor to donor variability was observed, the qualitative inducibility of RDS by EGF and/or HGF in human hepatocytes was not sex-, age-, or, based on a limited number of samples examined, ethnicity-dependent. These studies demonstrate that cultured cryopreserved human hepatocytes are an established, reproducible and relevant in vitro test system for investigating the nongenotoxic carcinogenic potential of chemicals and species differences, and worth progressing to formal validation according to OECD principles.
From raw data to meaningful information: a robust but flexible method to assess in vitro assay responses-lessons learned from a novel Dicentrarchus labrax estrogen screen test.
Slaby S, Duflot A, Maillet G … +6 more , Couteau J, Minier C, Allonier-Fernandes AS, Pinto PIS, Knigge T, Monsinjon T
Arch Toxicol · 2026 May · PMID 42086802 · Publisher ↗
Statistical analysis of in vitro assay data is a critical step towards a good interpretation of biological responses. However, it is still frequently undermined due to inappropriate statistical procedures, misinterpretat...
Statistical analysis of in vitro assay data is a critical step towards a good interpretation of biological responses. However, it is still frequently undermined due to inappropriate statistical procedures, misinterpretation, insufficient statistical power-often resulting from small sample sizes-or poorly defined methodologies, in case of standardized tests. In line with practices commonly adopted in clinical studies and more recently in biomonitoring research, the use of thresholds for interpreting results may improve the robustness of conclusions. This work presents the application of a methodology for defining thresholds using a normal distribution-based approach. As a case study, these thresholds were applied to analyze data obtained from the DLES test (Dicentrarchus labrax estrogen screen test), an in vitro screening tool designed to detect interactions between chemicals and nuclear estrogen receptors in D. labrax. The results were subsequently compared with methods derived from the OECD TG 455, as well as with non-parametric statistical analyses. By applying normal distribution-based thresholds, data analysis was simplified and the reliability of the DLES test results was increased, especially when compared with hypothesis tests. Also, this was especially true when studying non-model species, for which standard reference substances are rarely available. However, special attention should be paid to the size of the initial dataset used to define the thresholds. The methodology implemented here could provide insight for other in vitro assays. Overall, this article encourages the reflection on approaches to in vitro data analysis.
Mitochondrial lipid remodeling in sepsis-associated acute kidney injury: a cardiolipin-centered convergence framework.
Ma T, Zhai P, Ning S … +4 more , Shi Y, Chen Y, Xu D, Li Y
Arch Toxicol · 2026 Jul · PMID 42084613 · Publisher ↗
Sepsis-associated acute kidney injury (S-AKI) is a frequent and severe complication of sepsis in which metabolic dysfunction and inflammatory activation develop in parallel and reinforce each other. Although mitochondria...
Sepsis-associated acute kidney injury (S-AKI) is a frequent and severe complication of sepsis in which metabolic dysfunction and inflammatory activation develop in parallel and reinforce each other. Although mitochondrial dysfunction is widely recognized in S-AKI, the structural mechanisms linking mitochondrial bioenergetic failure to innate immune signaling remain incompletely understood. Emerging evidence suggests that mitochondrial lipid remodeling-particularly alterations in cardiolipin (CL)-may represent a structural interface connecting these processes. As a signature phospholipid of the inner mitochondrial membrane, cardiolipin supports cristae architecture, stabilizes respiratory chain supercomplexes, and maintains efficient oxidative phosphorylation. In renal tubular epithelial cells, which depend heavily on mitochondrial oxidative metabolism, disruption of cardiolipin homeostasis may have particularly profound consequences. Under septic stress, oxidative injury and dysregulated lipid remodeling alter cardiolipin composition and distribution, contributing to respiratory chain instability, impaired ATP production, and increased reactive oxygen species generation. In parallel, cardiolipin oxidation or externalization can transform mitochondrial membranes into signaling platforms that promote inflammasome activation and mitochondrial danger-associated molecular patterns (mtDAMPs) release. In this review, we propose a cardiolipin-centered framework that integrates mitochondrial bioenergetic failure with inflammatory amplification in S-AKI. By positioning mitochondrial lipid remodeling at the intersection of metabolism and innate immunity, this framework highlights mitochondrial lipid homeostasis as a potential mechanistic node and therapeutic entry point in septic kidney injury.
Developing adverse outcome pathways underlying CAR activation-induced liver injuries using HepG2 spheroid model.
Jin C, Ma Y, Chen L … +11 more , Kong X, Zhang C, Zhang M, Ma W, Zhu X, Guo H, Jiang L, Li X, Tian Y, Yu D, Jin Y
Arch Toxicol · 2026 May · PMID 42067649 · Publisher ↗
The constitutive androstane receptor (CAR) plays a key role in hepatic xenobiotic responses, yet its toxicity mechanisms remain unclear due to limitations in current models. This study employed a HepG2 spheroid model to...
The constitutive androstane receptor (CAR) plays a key role in hepatic xenobiotic responses, yet its toxicity mechanisms remain unclear due to limitations in current models. This study employed a HepG2 spheroid model to systematically delineate chemical-induced liver injuries that are induced by CAR activation. By assessing the expression levels of metabolizing enzymes and functional biomarkers, the advantages of the 3D culture were shown as superior to 2D culture. Immunofluorescence confirmed CAR cytoplasmic localization in untreated status, and activation-induced transnucleic-activation upon exposure. Transcriptomics demonstrated the 3D-HepG2's superiority for hepatic studies involving metabolizing pathways. Knockdown experiments demonstrated CAR's critical role in hepatotoxicity that were induced by acetaminophen (5, 10, and 20 mM) and 2,2',4,4'-tetrabromodiphenyl ether (100, 150, and 200 μM). The detection of early DNA damage markers and liver injury indicators revealed that CAR mediates aristolochic acids (25, 50, and 100 μM)-induced DNA damage. Lipidomics was firstly applied to the 3D-HepG2, proving its superiority for researching hepatic lipid metabolism. Further, the detection of lipid droplet formation and key enzyme alterations proved that CAR mediates lipid accumulation that was induced by perfluorooctanoic acid (100, 150, and 300 μM) and nonylphenol (15, 30, and 45 μM). Eventually, adverse outcome pathways were constructed linking CAR activations to chemical-induced hepatotoxicity, dyslipidemia, and DNA damage, respectively. The present study provides scientific insights for studies concerning exogenous chemicals-induced liver injuries.
Implementation of growth curves in a generic physiologically based kinetic model with a case study of perfluorooctanesulfonic acid (PFOS) in beef cattle, sheep, and chicken.
Inauen D, Lautz LS, Hendriks AJ … +1 more , Gehring R
Arch Toxicol · 2026 May · PMID 42067648 · Publisher ↗
Perfluorooctanesulfonic acid (PFOS) is an environmental contaminant with a long half-life in animals. Risk assessment of PFOS in livestock and food tissue can be conducted with physiologically-based kinetic (PBK) models....
Perfluorooctanesulfonic acid (PFOS) is an environmental contaminant with a long half-life in animals. Risk assessment of PFOS in livestock and food tissue can be conducted with physiologically-based kinetic (PBK) models. For fast-growing livestock, changes in body weight affect the kinetics of PFOS primarily through tissue dilution, which needs to be considered when using a PBK model. A generic PBK model was used to predict tissue concentrations of PFOS in cattle, sheep, and chickens. The primary excretion routes were feces and urine, which were affected by enterohepatic circulation and saturable tubular reabsorption, respectively. Animal weight gain was modeled using the sigmoidal Richards curve. Model performance was validated by comparing simulations, with or without growth, to independent literature data. Blood and plasma concentrations of independent cattle and chicken data were accurately predicted. Liver and kidney concentrations were overpredicted by up to five-fold and three-fold, respectively, in cattle, and twelve-fold for liver in chickens. Liver concentrations in sheep were accurately predicted. Muscle concentrations were overpredicted in cattle by up to three-fold. Predictions using constant body weights differed from the growth PBK predictions by up to 80%, 12%, and 60% in cattle, sheep, and chicken tissue, respectively. Integration of growth in the PBK model led to improved accuracy in concentration predictions. Tissue concentration predictions could be improved using reliable partition coefficient estimates. The presented model closed gaps in previously developed models by integrating growth and PFOS-specific processes such as enterohepatic circulation and tubular reabsorption.
A review of machine learning in toxicology: current practices and reporting gaps.
Kappenberg F, Stolte M, Sauer L … +7 more , Duda JC, Lau M, Schürmeyer L, Zhou H, Schwender H, Schorning K, Rahnenführer J
Arch Toxicol · 2026 Apr · PMID 42059907 · Publisher ↗
In recent years, machine learning and artificial intelligence approaches have been increasingly applied in the context of toxicological risk assessment. Many published overview, review, and comment papers discuss advanta...
In recent years, machine learning and artificial intelligence approaches have been increasingly applied in the context of toxicological risk assessment. Many published overview, review, and comment papers discuss advantages, disadvantages, success stories, and open challenges for the application of machine learning models in toxicology. Machine learning methods using information from in vitro experiments can help to avoid animal experiments, thus allowing for larger numbers of experiments to be conducted. Drawbacks of machine learning models are the lack of mechanistic interpretability and the need for large amounts of high-quality data. In this work, we present a literature review of papers indexed in PubMed or published in the journal Computational Toxicology in the years 2022 to 2024, to assess the usage of machine learning methods in toxicology as well as the practices in reporting of methods and corresponding results. We do not address the suitability or the performance of methods, which is impossible to assess objectively without reanalysis on raw data, but focus on common practices and gaps in reporting. Major results are that many different machine learning methods are used in toxicology, often with appropriate internal validation. However, in only half of the cases, interpretation methods are used to address the problem that these models often make predictions as a black box. Moreover, there are very frequent gaps in reporting, in particular related to handling of missing values, and availability of data and code. Thus, this review can serve as a starting point for further tailored methodological research and guidance.
Cylindrospermopsin toxicokinetics: in silico ADMET modeling, rat and human liver microsome metabolism, and UHPLC-MS/MS metabolite characterization.
Cascajosa-Lira A, Guzmán-Guillén R, Cameán AM … +2 more , Jos A, Prieto AI
Arch Toxicol · 2026 Apr · PMID 42050195 · Publisher ↗
Cylindrospermopsin is a potent cyanobacterial toxin of growing global concern due to its environmental persistence and broad toxicological profile. Despite increasing evidence of its toxic effects, knowledge of its toxic...
Cylindrospermopsin is a potent cyanobacterial toxin of growing global concern due to its environmental persistence and broad toxicological profile. Despite increasing evidence of its toxic effects, knowledge of its toxicokinetics remains limited. This study integrates in silico ADMET predictions with in vitro microsomal assays using human and sex-stratified rat liver microsomes to characterize CYN biotransformation. In silico predictions indicated low intestinal absorption, improbable blood-brain barrier (BBB) penetration, minimal binding to plasma proteins, and very limited CYP450-mediated metabolism. However, several potential phase II conjugation routes were identified, with certain metabolites predicted to display altered toxicological properties compared with the parent compound. Complementary in vitro studies in microsomes confirmed the high metabolic stability of CYN, with only modest decreases in toxin concentration observed during incubation (8-15% decrease). Notably, biotransformation was more evident under phase II conditions, particularly glucuronidation and amino acid conjugation. Novel metabolites were detected for the first time by Ultra-High Performance Liquid Chromatography (UHPLC-/MS/MS), including conjugates with cysteine, glycine, taurine, and arginine, as well as with fatty acids. No significant quantitative differences were observed between sexes or species, although qualitative variability in metabolite profiles was detected. These findings provide new insights into the metabolic fate of CYN, underscore the importance of conjugation reactions in its detoxification, and support the application of integrative computational and experimental approaches to improve cyanotoxin risk assessment.
ChemSkin DB 2.0: a comprehensive reference chemical database for skin corrosion and irritation.
Lee M, Lim KM
Arch Toxicol · 2026 Apr · PMID 42050194 · Publisher ↗
We previously developed ChemSkin DB listing 100 reference chemicals to aid the development of new approach methodologies (NAMs) for skin irritation. However, ChemSkin DB is insufficient for NAMs addressing the full spect...
We previously developed ChemSkin DB listing 100 reference chemicals to aid the development of new approach methodologies (NAMs) for skin irritation. However, ChemSkin DB is insufficient for NAMs addressing the full spectrum of skin hazards, i.e., skin corrosion and irritation. To address this gap, ChemSkin DB was expanded with 134 reference chemicals to ChemSkin DB 2.0 as a harmonized reference database aligning skin corrosion and irritation data with UN GHS criteria. A total of 234 unique substances were consolidated and assigned to reference categories under a precautionary decision framework. ChemSkin DB 2.0 contains normalized in vivo metrics and model-specific in vitro viability values obtained with OECD TG 431 and 439 In Vitro Skin Corrosion and Irritation Tests: Reconstructed Human Epidermis (RhE) Test Methods, ensuring transparency and regulatory traceability. Especially, performance evaluation demonstrated substantial agreement across OECD TG 431 RhE models for corrosion identification. In contrast, OECD TG 439 irritation RhE models showed moderate to substantial agreement, with variability in specificity linked to the single-threshold structure of irritation classification. Chemical category stratification further revealed chemical class-dependent performance patterns across both endpoints, highlighting the influence of mechanistic diversity on model reliability. Collectively, ChemSkin DB 2.0 provides a severity-stratified, regulatory-aligned reference resource that supports transparent model development and evaluation, and improved consistency in skin hazard assessment.
Assessment of cytotoxicity and genomic instability induced by coal-derived nanoparticles in V79 and HaCaT Cells.
Miranda-Guevara A, Martínez-López W, León-Mejía G … +19 more , Moreno OF, Pacheco-Londoño L, Tapia JR, Torres Cantillo FJ, Palma MF, Hernández P, Liddle P, Mechoso B, López M, Lafon-Hughes L, Villarreal L, Benech JC, Puga R, Vargas JE, Fragoso-Castilla P, Quintana-Sosa M, da Silva J, Henriques JAP, Acosta-Hoyos A
Arch Toxicol · 2026 Apr · PMID 42050193 · Publisher ↗
Coal is a major global energy resource, but its extraction raises significant environmental and health concerns. Mining activities release large amounts of particulate matter, including nanoparticles (NPs), into the envi...
Coal is a major global energy resource, but its extraction raises significant environmental and health concerns. Mining activities release large amounts of particulate matter, including nanoparticles (NPs), into the environment. These NPs are hazardous due to their content of polycyclic aromatic hydrocarbons (PAHs), metals, oxides, and other compounds capable of disrupting cellular and molecular processes. This study evaluated the cytotoxic and genotoxic effects of coal-derived NPs on V79 and HaCaT cell lines, focusing on their impact on DNA stability and the mechanisms responsible for cellular damage. NPs were isolated using an acid-based separation method and applied to cells at concentrations of 50, 150, and 300 μg/mL. Atomic force microscopy (AFM) provided topographical characterization, while dynamic light scattering (DLS) confirmed their tendency to agglomerate. Scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS) confirmed NP morphology and elemental composition, including carbon, oxygen, iron, calcium, silicon, aluminum, and copper. Cytotoxicity was assessed using resazurin and sulforhodamine B assays, and genotoxicity was evaluated using the comet assay, micronucleus test, and γH2AX immunostaining. Results showed a clear dose-dependent effect, with coal NPs inducing genomic instability and increased cell mortality, mainly through apoptosis. These findings highlight the importance of characterizing coal-derived NPs to better assess their environmental and health risks, particularly regarding respiratory diseases.
The immunogenic potential of AZD1402 (Elarekibep) T-cell epitopes in healthy volunteers and drug-exposed clinical trial participants.
Farrell L, Bates SM, Walker A … +10 more , Ogese M, Meng X, Piper S, Mo J, Saide K, Hornberg J, Close D, Wallace I, Betts CJ, Naisbitt DJ
Arch Toxicol · 2026 Apr · PMID 42050192 · Publisher ↗
AZD1402 (Elarekibep) is a novel anticalin with engineered IL-4Rα antagonist binding properties that was under development for inhaled treatment of asthma. Structural similarity to tear-lipocalin is thought to limit immun...
AZD1402 (Elarekibep) is a novel anticalin with engineered IL-4Rα antagonist binding properties that was under development for inhaled treatment of asthma. Structural similarity to tear-lipocalin is thought to limit immunogenicity risk; however, a range of treatment-emergent hypersensitivity-like adverse events were observed in a clinical study. This study aimed to (i) explore the activation of drug-exposed human T-cells with AZD1402- and tear lipocalin-derived peptides, (ii) characterise any T-cell epitopes contained within AZD1402 and (iii) define the nature of any response. Peripheral blood mononuclear cells (PBMC) from AZD1402-exposed study participants, alongside AZD1402-naïve donors, were cultured with AZD1402 and AZD1402-derived overlapping 18mer peptides. Proliferation and cytokine secretion were measured. T-cell clones were generated to characterise the diversity of T-cell epitopes and reactivity against equivalent tear-lipocalin peptides. AZD1402 contained multiple epitopes located in engineered "hotspot" regions of the molecule that activated PBMC and MHC class II-restricted CD4 + T-cell clones from both study participants and AZD1402-naïve donors. T-cell stimulatory peptides contained amino acid substitutions generated through mutagenesis to create AZD1402 target binding properties; similar T-cell epitopes were not found in tear-lipocalin. Detection of T-cell clones responsive towards AZD1402 and AZD1402-derived peptides provides evidence that immunogenic epitopes are formed naturally through processing of the AZD1402. These data describe a recall immunogenicity risk associated with AZD1402 and provide a framework by which to explore the immunogenic potential of modified sequences within anticalin or other large molecule therapeutics.
The role of oxidative stress and antioxidant therapy in cisplatin neurotoxicity: preclinical evidence in the last decade.
Dos Santos NAG, Dos Santos JM, Dos Santos AC
Arch Toxicol · 2026 Jun · PMID 42050191 · Full text
Cisplatin remains one of the most effective chemotherapeutic agents for the treatment of several tumors. However, its use is limited by dose-dependent and cumulative neurotoxicity, which affects the peripheral nervous sy...
Cisplatin remains one of the most effective chemotherapeutic agents for the treatment of several tumors. However, its use is limited by dose-dependent and cumulative neurotoxicity, which affects the peripheral nervous system, hypothalamus, prefrontal cortex, cerebellum, retina and optic nerve. Currently, there is no neuroprotective strategy against cisplatin-induced neurotoxicity. Studies in the last decade have consolidated the role of oxidative stress as a central molecular event in cisplatin-induced neurotoxicity. A wide array of antioxidant-based strategies from natural compounds to repurposed drugs has been investigated in animal models as neuroprotective agents. In general, these compounds act directly through free radical scavenging, or indirectly, by activating the Nrf2 pathway, which induces the expression of antioxidant defense enzymes. This review approaches the role of oxidative stress in preclinical studies on cisplatin-induced neurotoxicity from the last decade, and evaluates the most promising antioxidant interventions, with the focus on cognitive impairment, peripheral neuropathy, ocular toxicity, anxiety and depression. The link between cisplatin neurotoxicity and neurodegenerative diseases as well as the emerging novel therapeutic strategies to replace cisplatin chemotherapy are discussed. The need for future studies in tumor-bearing animal models to investigate interferences with the antitumor efficacy of cisplatin is pointed out as a critical requirement for clinical translation.
Integrating high-fidelity hiPSC-cardiomyocytes with AI-driven modeling for enhanced proarrhythmic risk assessment.
Kim SB, Lee J, An J … +7 more , Cho A, Lee KH, Choi H, Han C, Pramudito MA, Lim KM, Woo DH
Arch Toxicol · 2026 Apr · PMID 42050190 · Publisher ↗
Cardiotoxicity remains the leading driver of drug attrition; however, its prediction remains suboptimal when conventional hERG assays and animal models are used. Human induced pluripotent stem cell-derived cardiomyocytes...
Cardiotoxicity remains the leading driver of drug attrition; however, its prediction remains suboptimal when conventional hERG assays and animal models are used. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer a human-relevant alternative that aligns with the CiPA initiative and ICH E14/S7B guidelines. This study validated an integrated platform that combines high-purity hiPSC-CMs with Artificial Intelligence (AI) to enhance the accuracy of predicting drug-induced proarrhythmic risk. Phenotypic characterization of the hiPSC-CMs demonstrated high cardiac differentiation efficiency (cTnT + > 95%) and a predominant ventricular-like identity (MLC-2 V + , 78-84%), ensuring biological relevance for ventricular arrhythmia assessment. Electrophysiological data from 28 CiPA reference compounds were collected via Multielectrode Array (MEA) to train multiple machine learning models. The Artificial Neural Network outperformed the other architectures, achieving a superior ROC-AUC of 0.982. The utility of the platform was evaluated using 12 anticancer agents. Although most drugs showed dose-dependent reductions in impedance-based viability, four compounds (Idarubicin, Erlotinib, Sunitinib, Cyclophosphamide) did not exhibit overt structural cytotoxicity. However, MEA analysis revealed significant functional perturbations, including FPDcF prolongation, in sunitinib- and erlotinib-treated samples after long-term treatment. The AI model subsequently classified these two agents as high-to-intermediate risk for Torsades de Pointes (TdP), thereby quantifying their time-dependent proarrhythmic liabilities. These findings show the platform's ability to detect hidden functional cardiotoxicity, often missed by standard viability assays. The AI-hiPSC-CM system offers a high-throughput, early-stage safety screening tool that bridges in vitro data and clinical outcomes with a standardized risk assessment framework.
Impact of glyphosate and its mixture with 2,4-D and dicamba on gut biochemical function, intestinal barrier integrity and microbiome composition in adult rats with prenatal commencement of exposure.
Mesnage R, Ferguson S, Nechalioti PM … +6 more , Cercelaru L, Hbous MA, Docea AO, Tsatsakis A, Kouretas D, Antoniou MN
Arch Toxicol · 2026 Apr · PMID 42050189 · Publisher ↗
Intensive use of glyphosate-based herbicides in genetically modified (GM) and non-GM agriculture has resulted in widespread glyphosate-resistant weeds. In response, the agricultural biotechnology industry has launched GM...
Intensive use of glyphosate-based herbicides in genetically modified (GM) and non-GM agriculture has resulted in widespread glyphosate-resistant weeds. In response, the agricultural biotechnology industry has launched GM crops tolerant to glyphosate plus 2,4-D and glyphosate plus dicamba. Consequently, people are increasingly exposed to mixtures of these herbicides, yet no studies have been conducted to assess health risks. Intestinal structure and integrity, as well as gut microbiome composition and function, are recognised contributors to disease. Therefore, we investigated the effects of glyphosate alone and in combination with 2,4-D and dicamba on gut structure and function. Pregnant Wistar rats were administered via drinking water from gestation day 6 with glyphosate at the European Union (EU) no observed adverse effect level (NOAEL: 50 mg/kg bw/day) and acceptable daily intake (ADI: 0.5 mg/kg bw/day), and with an ADI mixture of glyphosate (0.5 mg/kg bw/day), 2,4-D (0.02 mg/kg bw/day) and dicamba (0.3 mg/kg bw/day). Offspring continued this regimen for 13 weeks post-weaning. Large and small intestinal tissues and gut content were isolated and analysed for inflammation, gut epithelial integrity, oxidative stress, microbiota composition and histopathology. The glyphosate NOAEL and, to a greater degree, the glyphosate, dicamba, 2,4-D mixture resulted in increased gut inflammation and permeability, associated with oxidative stress and altered microbial composition. Histological analysis confirmed structural alterations and inflammation in large and small intestine. Effects were more pronounced in large intestine and females. Our results identify exposure to glyphosate alone and a mixture of glyphosate, 2,4-D and dicamba as risk factors for gut structure and function dysbiosis.
Lipidomic and machine learning analysis reveals enantioselective mechanisms of hexaconazole-induced lipid metabolism disorder in 3T3-L1 preadipocytes.
Zhang J, Yang T, Li Z … +3 more , Yang Q, Huang Z, Sun D
Arch Toxicol · 2026 Apr · PMID 42050188 · Publisher ↗
Lipid metabolism disorder is known to promote fat accumulation and increase the risk of metabolic syndrome. Hexaconazole (Hex) has been reported to disrupt lipid homeostasis while its mechanism of action and enantioselec...
Lipid metabolism disorder is known to promote fat accumulation and increase the risk of metabolic syndrome. Hexaconazole (Hex) has been reported to disrupt lipid homeostasis while its mechanism of action and enantioselective behavior remain unclear. Therefore, this study investigated the effects of Hex enantiomers on lipid metabolism in 3T3-L1 preadipocytes. The results showed Hex induced lipid droplet accumulation, total cholesterol (TC) content enhancement, along with the up-regulation of lipogenic genes and down-regulation of lipolytic genes in an enantioselective manner as (−)-Hex > Rac-Hex> (+)-Hex. Lipidomic analysis revealed the significant alterations in lipids of phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and ceramide (Cer) by Hex exposure leading to the interference of glycerophospholipid and sphingolipid metabolism. Machine learning suggested that (−)-Hex achieved the highest binding affinity with phosphatidic acid phosphatase (PLPP1) resulting in the activation of PLPP1-PA/DAG signaling pathway. This study elucidated the potential mechanism of lipid disruption by Hex, providing a theoretical basis for assessing the enantiomer-specific health risks of triazole pesticides.
Comparison of ex vivo placenta perfusion and in vitro BeWo b30 cell models for assessing transfer of developmental and reproductive toxic compounds.
Roelofsen D, Spriggs S, Nicol B … +5 more , van den Broek P, Muller I, van Hove H, Russel F, Greupink R
Arch Toxicol · 2026 Apr · PMID 42050187 · Publisher ↗
There is an increasing interest in the prediction of exposure for risk assessment, as next generation risk assessment (NGRA) encompasses an exposure-led approach. Within the field of developmental and reproductive toxico...
There is an increasing interest in the prediction of exposure for risk assessment, as next generation risk assessment (NGRA) encompasses an exposure-led approach. Within the field of developmental and reproductive toxicology (DART), data on placental transfer is essential for estimating foetal exposure. However, human-relevant data is often limited or unavailable. Ex vivo human placenta perfusion is considered the gold standard in placental transfer research, but it is hampered by a low success rate, limited availability of tissue, and the inability to allow high throughput data collection. BeWo b30 cells can offer a high-throughput, lower-tier alternative to collect human-relevant placental transfer data. Here, thalidomide, valproic acid, amoxicillin, and antipyrine were tested in both model systems. A comparison matrix was derived to evaluate a set of shared placenta transfer parameter values obtained for each compound in the two systems. Transfer index (TI), relative transfer rate, initial transfer rate, and apparent permeability (Papp) were calculated for both experimental set-ups. The relative transfer rates in BeWo b30 cells and TIs of the placenta perfusions were highly comparable, with only a mean difference factor of 1.1. In addition, for the initial transfer rate and Papp values we found differences between the placenta perfusion and BeWo b30 experiments of an average factor of 4.5 and 2.4, respectively. Which parameter to calculate and extract from experimental data is determined by the underlying scientific question, e.g., whether a qualitative/relative or quantitative/absolute assessment of placental transfer is required. Nevertheless, the Papp values derived from both systems are particularly useful for parameterizing physiological-based kinetic (PBK) models and estimating foetal exposure following maternal external exposure, especially within NGRA.
The role of cytotoxicity in the process of carcinogenesis.
Schwarz M, Epe B, Wohak LE … +2 more , Voss C, Hartwig A
Arch Toxicol · 2026 Apr · PMID 42050186 · Publisher ↗
Enhanced cancer prevalence findings restricted to high, cytotoxic dose levels in long-term animal cancer studies are generally assumed to be a consequence of-indirect or secondary-mutational effects, e.g. DNA damage medi...
Enhanced cancer prevalence findings restricted to high, cytotoxic dose levels in long-term animal cancer studies are generally assumed to be a consequence of-indirect or secondary-mutational effects, e.g. DNA damage mediated by generation of reactive oxygen species (ROS) or replication errors occurring during regenerative cell proliferation. An alternative explanation is provided by recent findings suggesting that cell lysis caused by cytotoxic doses of non-genotoxic agents may give rise to tumor promotion by selective growth stimulation of pre-existing (already mutated) dormant tumor precursor cells. This growth stimulation is assumed to be mediated by damage-associated molecular pattern (DAMP) signaling ("sterile inflammation"). Here, we discuss the differing views on cancer findings observed only at high cytotoxic doses in particular with respect to the implications for the risk assessment of the agents.
Pulmonary responses to polyacrylic acid with and without carboxyl groups following intratracheal instillation in rats.
Morimoto T, Izumi H, Nishida C … +13 more , Tomonaga T, Nakamura Y, Higashi Y, Wang KY, Kojima T, Sakurai K, Moriyama A, Takeshita JI, Higashi H, Tahara M, Yamasaki K, Yatera K, Morimoto Y
Arch Toxicol · 2026 Apr · PMID 42050185 · Publisher ↗
Polyacrylic acid (PAA) is a widely used organic polymer synthesized from acrylic acid monomers. Its viscosity and water absorbency can be modified through cross-linking, making it suitable for various applications, inclu...
Polyacrylic acid (PAA) is a widely used organic polymer synthesized from acrylic acid monomers. Its viscosity and water absorbency can be modified through cross-linking, making it suitable for various applications, including shampoos, food products, and pharmaceuticals. However, several reports have suggested that PAA has high potential for pulmonary injury, especially if exposed during product manufacturing processes. To elucidate which specific physicochemical properties of PAA lead to pulmonary disease development, we intratracheally instilled PAA with different physicochemical properties in rats. We compared the lung responses of standard PAA containing carboxyl groups (COOH) and specially manufactured COOH-removed PAA. Male F344 rats were intratracheally instilled with COOH-removed PAA at two doses (0.2 mg, 1.0 mg/rat), standard PAA with COOH at one dose (1.0 mg/rat), or distilled water (control group). Inflammatory and fibrotic responses in the lungs were examined at 3 days, 1 week, 1 month, 3 months, and 6 months post-exposure. PAA with COOH group exhibited persistent pulmonary inflammation and fibrosis, whereas the COOH-removed PAA showed no detectable signs of either condition. Comprehensive analyses of lung tissue mRNA revealed significantly increased Spp1 expression in the PAA with COOH group compared with the COOH-removed PAA group. Comprehensive analyses of microRNAs in bronchoalveolar lavage fluid extracellular vesicles revealed decreased expression of miR-23a-3p and miR-24-3p, which are associated with pulmonary fibrosis. Analysis of human datasets provided additional support for our animal findings. Our results indicate that the COOH in PAA is involved in lung inflammation and fibrosis through specific changes in gene expression.
Recent advances in the mechanism of deoxynivalenol-induced hepatotoxicity and protective strategies.
Zhu K, Duan J, Zhuang Y … +3 more , Shi H, Chen X, Liu A
Arch Toxicol · 2026 Apr · PMID 42047702 · Publisher ↗
Deoxynivalenol (DON) is a type B trichothecene mycotoxin produced by fusarium species, which widely contaminates grains and feed, posing a serious threat to human and animal health, with the liver as one of its key targe...
Deoxynivalenol (DON) is a type B trichothecene mycotoxin produced by fusarium species, which widely contaminates grains and feed, posing a serious threat to human and animal health, with the liver as one of its key target organs. This review summarises in vivo and in vitro studies indicating that DON induces liver injury through multiple synergistic mechanisms, among which ferroptosis has attracted increasing attention; other core mechanisms include ribosomal stress response triggered by ribosomal function inhibition, reactive oxygen species (ROS) burst and lipid peroxidation (LPO), inflammatory cascades, and various forms of programmed cell death. In terms of protective mechanisms, the innovative potential of diverse protective strategies is highlighted: natural compounds exert significant hepatoprotective effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway, inhibiting nuclear factor-kappa B kinase subunit beta (NF-κB) inflammatory signalling, and interfering with ferroptosis, while probiotic microorganisms, nanomaterials, epigenetic modulators, and physicochemical methods also show considerable detoxification capacity. Despite significant progress, future research should focus on the cumulative effects of long-term low-dose exposure and the combined toxicity of multiple mycotoxins, with emphasis on species specificity and dose dependency. Centering on the "GPX4-ferroptosis" axis, this review integrates research data to establish a comprehensive evidence chain, elucidate the "target-mechanism-consequence" logic of DON-induced hepatotoxicity, and provide a crucial theoretical basis for understanding its mechanisms and developing effective prevention and control strategies.
Cardiovascular toxicity of ethyl maltol exposure: a comprehensive investigation from virtual screening to experimental validation.
Chen Q, Fu L, Wang H … +9 more , Cen X, Long L, You H, Tan Q, Chen X, Liu Y, Li H, Xu Y, Chen Y
Arch Toxicol · 2026 Apr · PMID 42047701 · Publisher ↗
Ethyl maltol is a ubiquitous synthetic flavor enhancer. Despite its widespread use in foods, beverages, and electronic cigarettes, and its potential for environmental dispersion, its long-term cardiovascular safety remai...
Ethyl maltol is a ubiquitous synthetic flavor enhancer. Despite its widespread use in foods, beverages, and electronic cigarettes, and its potential for environmental dispersion, its long-term cardiovascular safety remains unevaluated. Here, we employed an integrative strategy commencing with network toxicology and machine learning to identify pivotal molecular targets. The interaction between ethyl maltol and the key target was scrutinized via molecular docking and dynamics simulations. Cardiovascular toxicity was subsequently validated through in vivo and in vitro experiments, incorporating transcriptomic and single-cell RNA sequencing analyses. HMOX1 was identified as the central target. Molecular simulations confirmed stable binding between ethyl maltol and HMOX1. In mice, ethyl maltol exposure (5, 10, 20 mg/kg) induced anemia, platelet activation, reduced hindlimb perfusion, and impaired endothelium-dependent vasodilation, concomitant with upregulated vascular adhesion molecules. In human endothelial cells, ethyl maltol (10, 20, 40 μM) suppressed cell viability and triggered HMOX1 expression, NLRP3 inflammasome activation, and NF-κB signaling. Mechanistically, ethyl maltol appears to subvert the typically protective HMOX1 response into a driver of chronic vascular inflammation and adhesion. This study unveils a previously unrecognized cardiovascular risk associated with ethyl maltol, mediated through HMOX1-driven inflammatory dysregulation. It establishes a translatable paradigm for the safety assessment of prevalent food additives and environmental contaminants.
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