Toxicology[JOURNAL]
Sun
200 papers
Integrative assessment of endocrine disruption: From in vitro mechanisms to species extrapolation - Highlights of the German Pharma-Tox Summit 2025.
Haßmann U, Gölz L, Geci R … +8 more , Stefanidis K, Brandt JL, North E, Feiertag K, Schopfer CR, Amann S, Melching-Kollmuss S, Landsiedel R
Toxicology · 2026 Feb · PMID 41389870 · Publisher ↗
Endocrine-disrupting chemicals (EDCs) are a growing focus in human and environmental risk assessment, as reflected by the new EU CLP hazard classes for endocrine disruptors. Within this context, the symposium "Cross-Spec...
Endocrine-disrupting chemicals (EDCs) are a growing focus in human and environmental risk assessment, as reflected by the new EU CLP hazard classes for endocrine disruptors. Within this context, the symposium "Cross-Species Extrapolation in Endocrine Disruption Assessments" was held at the 10th German Pharm-Tox Summit (GPTS) 2025 in Hannover (March 11-13), which formed part of the 91st annual meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT). The symposium assembled diverse lines of research addressing endocrine disruption from complementary angles. Contributions ranged from advanced experimental model systems, such as refined zebrafish embryo assays for thyroid hormone disruption, to high-throughput in silico and in vitro-based kinetic modelling frameworks that support quantitative in vitro to in vivo extrapolation and AOP-informed risk assessment. Clinical and translational perspectives were added by targeted LC-MS/MS profiling of steroid conjugates as biomarkers for adrenal tumours. Further talks expanded the mechanistic toolbox for thyroid disruption, including enzyme- and protein-binding-based in vitro assays, and highlighted metabolic endocrine disruptors that act beyond the EATS (estrogen, androgen, thyroid and steroidogenesis) pathways. A regulatory-oriented analysis of thyroid-related modes of action across vertebrate taxa underscored the importance of clearly defining domains of applicability for cross-species extrapolation. At the same time, the discussions revealed critical gaps, including still limited taxonomic applicability domains, incomplete regulatory coverage beyond established endocrine pathways and limited transparency in predictive tools. Together, these contributions illustrate how integrated experimental, computational and regulatory science can advance mechanism-based, animal-reduced assessment of endocrine disruptors.
Biological responses of human tracheobronchial mucociliary pseudo-epithelium repeatedly exposed at the air-liquid interface to PM indoor particles.
El Hajjar C, Pottier I, Lelong M … +2 more , Lecureur V, André V
Toxicology · 2026 Feb · PMID 41389869 · Publisher ↗
The PM fraction of representative indoor pollution (SRM® 2585) was repeatedly nebulized (1 and 6 μg/cm/day) on functional mucociliary pseudo-epithelia (NHBE cells differentiated at the Air Liquide Interface, ALI). Four c...
The PM fraction of representative indoor pollution (SRM® 2585) was repeatedly nebulized (1 and 6 μg/cm/day) on functional mucociliary pseudo-epithelia (NHBE cells differentiated at the Air Liquide Interface, ALI). Four consecutive daily exposures have been performed and the biomarkers were analyzed on day 4, 8 and 11. Exposures at the lower dose induced at day 4 a significant increase in cellular ROS and modulations of the expression of few genes associated with genotoxicity and oxidative stress. IL-6 expression was strongly upregulated accompanied by a delayed increased secretion in the basal medium, whereas IL-8 expression was downregulated. At the highest dose, a weak and transient decrease in epithelial cohesion was observed, as well as a potential alteration of the cilia. The mucus secretion tended to increase whereas expression of MUC5AC and MUC5B was downregulated. Co-exposure to macrophage mediators (produced by pre-exposure of human macrophages to the PM fraction of SRM® 2585) induced significant overexpression of MUC5AC, IL-6 and IL-8 in the pseudo-epithelium. Three genes involved in oxidative processes, distinct from those highlighted with PM alone, were modulated. Despite repeated exposures, the magnitude of the mucociliary pseudo-epithelial responses remained low overall. Trapping of PM in the mucus associated with efficient ciliary beating contributed to limit cellular responses. Thus, this physiological process must be considered for realistic in vitro toxicity assessments. Co-exposure protocol allowed to integrate the role of the innate immune system into the overall response of the lung tissue.
Hexavalent chromium induced autophagy-dependent mTOR expression mediated by upregulation of HMGA2.
Li L, Dan M, Li S … +4 more , Cui X, Bao S, Luo S, Cao J
Toxicology · 2026 Feb · PMID 41386358 · Publisher ↗
High mobility group A2 (HMGA2) overexpression is often observed in cancers. Previously, we found that HMGA2 contributed to hexavalent chromium [Cr (VI)]-mediated autophagy. In this study, interestingly, Cr (VI) treatment...
High mobility group A2 (HMGA2) overexpression is often observed in cancers. Previously, we found that HMGA2 contributed to hexavalent chromium [Cr (VI)]-mediated autophagy. In this study, interestingly, Cr (VI) treatment triggered both autophagy and the mammalian target of rapamycin (mTOR) in vivo ( BALB/c mice, 0.5 and 1.5 mg/kg, p.o.) and in vitro (0.1, 0.2 and 0.4 μM in A549 and HELF cells), and both autophagy and mTOR were implicated in Cr (VI)-initiated cell growth. Autophagy and mTOR were both significantly induced by HMGA2 overexpression in vivo (BALB/c mice were intratracheal injected with 10 μg and 20 μg pcDNA3.1-HMGA2 plasmid complexes) and in vitro (A549 and HELF cells). Using the autophagy suppressor, 3-methyladenine (3MA, 2 mM), chloroquine (CQ, 10 μM), and knockdown of autophagy-related protein 4 homolog B (ATG4B) gene by siRNA, it was shown that Cr (VI)-provoked mTOR was reliant on autophagy. Furthermore, the results of the scratch assay indicated that HMGA2-mediated cell migration depends on autophagy, mTOR, and glycolysis. Chromatin immunoprecipitation assay elucidated elective binding of HMGA2 protein to the ATG4B promoter region, but not AKT1 and mTOR. Altogether, our findings demonstrated that both autophagy and mTOR could be induced by Cr (VI) and they were involved in Cr (VI)-caused cell growth and migration. HMGA2 mediated this effect by transcription regulation of ATG4B. These suggested that blocking the HMGA2-autophagy-mTOR axis could serve as an effective strategy to inhibit Cr (VI)-induced cell viability.
Chlorocholine chloride delays progenitor Leydig cell differentiation via PI3K/AKT pathway activation in rats.
Zhang H, Li Y, Wang X … +6 more , Kang C, Zhang Q, Liu D, Mao J, Xiao Q, Hao W
Toxicology · 2026 Feb · PMID 41380934 · Publisher ↗
Chlorocholine chloride (CCC) is a commonly used plant growth regulator. It was shown that CCC exposure could lead to decreased testosterone biosynthesis, delayed puberty onset, and damaged spermatogenesis in pubertal rod...
Chlorocholine chloride (CCC) is a commonly used plant growth regulator. It was shown that CCC exposure could lead to decreased testosterone biosynthesis, delayed puberty onset, and damaged spermatogenesis in pubertal rodents, but the underlying mechanism is still not well understood. The testosterone level is determined not only by the functional activity of Leydig cell but also by its number and maturational status. To identify the critical developmental stage at which CCC impairs Leydig cell maturation and elucidate its underlying mechanisms, pubertal rats were exposed to 0, 75, 137.5, and 200 mg/kg bw/day CCC from PND14 (progenitor Leydig cells, PLCs) to PND28 (immature Leydig cells, ILCs) and from PND28 to PND56 (adult Leydig cells, ALCs) respectively. The results showed that, for exposure from PLCs stage, CCC exposure at 137.5 and 200 mg/kg bw/day led to histopathological changes of rat testes and impaired Leydig cell lineage specification in rats. CCC exposure at 200 mg/kg bw/day significantly decreased the mRNA expression of Star, Lhcgr, Cyp17a1, and Hsd17b3. Hormonal measurement and proteomic analysis revealed that both the disruption of the hypothalamic-pituitary-testis axis and the aberrant activation of the PI3K/AKT signaling pathway contribute to the impairment of Leydig cell lineage specification. For exposure from ILCs stage, Leydig cell development was not affected, but serum and testicular testosterone levels decreased resulting from the down-regulation of StAR, CYP11A1, and HSD3B1. In conclusion, our study found that CCC exposure could delay the development process of rat Leydig cells by disruption of Leydig cell differentiation during early developmental stage, which might lead to decreased testosterone level.
Linking AhR and Nrf2 activation to neurotoxicity through adverse outcome pathway-based machine learning.
Yang J, Yan K, Li X … +5 more , Deng W, He M, Zhu H, Yan X, Yan B
Toxicology · 2026 Feb · PMID 41371571 · Publisher ↗
Chemical-induced neurotoxicity poses a challenge for safety assessment due to the complexity of central nervous system responses and the limitations of conventional assays. We developed an adverse outcome pathway (AOP)-g...
Chemical-induced neurotoxicity poses a challenge for safety assessment due to the complexity of central nervous system responses and the limitations of conventional assays. We developed an adverse outcome pathway (AOP)-guided machine-learning framework that links molecular initiating events, using the activation of the aryl hydrocarbon receptor (AhR) and Nrf2-mediated oxidative stress responses as examples, to neurotoxicity. A curated dataset was assembled from public sources and the literature, key molecular features such as nitrogen-containing groups were identified as structural alerts associated with neurotoxicity. Within this framework, AhR and Nrf2 activity information (measured or predicted) was integrated with structural fingerprints to enhance biological interpretability while maintaining robust predictive performance (e.g., AUC value > 0.80) in both cross-validation and external validation. The AOP-based model was further applied to virtual screening of 7576 compounds, with blood-brain barrier (BBB) permeability and applicability domain (AD) constraints ensuring reliable predictions. Molecular docking of 12 prioritized persistent organic pollutants (POPs) further supported these predictions, revealing strong binding affinities with AhR (up to -10.2 kcal/mol) and Nrf2 (up to -7.9 kcal/mol) through interactions such as hydrogen bonding and π-π stacking. Overall, this strategy highlights AOP-based machine learning as a powerful approach to connect structure, mechanism, and outcomes, thereby improving chemical risk assessment and prioritization.
Characterising a HepaRG liver microphysiological system for individual bile acid secretion and chemical induced disruptions.
Nitsche KS, Carmichael PL, Bakker W … +2 more , Bouwmeester H, Müller I
Toxicology · 2026 Feb · PMID 41349887 · Publisher ↗
Liver microphysiological systems (MPS) have gained increasing attention as human-relevant models for chemical safety assessments, particularly for studies with defined endpoints, such as cholestatic injury. In this study...
Liver microphysiological systems (MPS) have gained increasing attention as human-relevant models for chemical safety assessments, particularly for studies with defined endpoints, such as cholestatic injury. In this study, we built upon a previously established HepaRG-based liver MPS model using the OrganoPlate® 3-lane system. Our aim in this proof-of-concept study was to characterise the synthetic capacity and metabolic function, focusing on the bile acid secretion, under both basal and chemically treated conditions at three independent time points. Undifferentiated HepaRG cells were seeded into the perfusion channels coated with Matrigel and cultured under flow condition without the addition of dimethyl sulfoxide (DMSO). We monitored cell self-organisation, health, and maturation using microscopy, viability assays, albumin and individual bile acid secretion profiling, and gene expression analysis. To assess the metabolic competence and treatment responses regarding the bile acid secretion, the cells were exposed to rifampicin and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 48 h. Despite the absence of DMSO supplementation, HepaRG cells self-organised into maturing aggregates and demonstrated inducible CYP1A2 and CYP3A4 activity by day 3. Although the synthetic capacity was generally low, the model secreted all primary (conjugated) bile acids and exhibited clear time-dependent changes in the bile acid composition under treatment. These proof-of-concept findings highlight the potential of flow conditions to enable in situ HepaRG maturation and represent a promising step toward defining a potential context of use as a tool for cholestatic injury.
Mitotoxic effects of the melanin-concentrating hormone receptor 1 (MCHr1) antagonist AZD1979 are influenced by mitochondrial DNA variation in HepG2 cybrids.
Jensen RL, Kiy RT, Jolly CE … +2 more , Williams DP, Chadwick AE
Toxicology · 2026 Feb · PMID 41349886 · Publisher ↗
AZD1979 is a melanin-concentrating hormone receptor 1 (MCHr1) antagonist, which was developed for obesity treatment, but clinical development was halted due to unanticipated liver toxicity. Mitochondrial DNA (mtDNA) vari...
AZD1979 is a melanin-concentrating hormone receptor 1 (MCHr1) antagonist, which was developed for obesity treatment, but clinical development was halted due to unanticipated liver toxicity. Mitochondrial DNA (mtDNA) variation influences hepatic energy metabolism and may underlie individual susceptibility to drug-induced mitotoxicity. Transmitochondrial cybrids offer a model to assess the impact of mtDNA variation on drug response against a constant nuclear background. This study assessed the mitotoxic potential of AZD1979 in HepG2 wild-type (WT) cells and HepG2 transmitochondrial cybrids representing distinct mtDNA haplogroups from the H and J haplogroup lineages. A 2-hour acute metabolic switch assay was performed in HepG2 WT cells and transmitochondrial cybrids to identify mitochondrial toxicity, with confirmatory Seahorse extracellular flux analysis. AZD1979 was identified as a potent mitotoxicant in HepG2 WT cells, inducing mitochondrial dysfunction prior to cell death. AZD1979 caused reductions in basal respiration, ATP-linked respiration, and spare respiratory capacity, and inhibited complex I-driven respiration. Cybrids displayed haplogroup-specific differences in susceptibility. Haplogroup J2b1g showed the highest sensitivity, while J1c1e, despite lacking spare respiratory capacity, was less susceptible. These findings highlight the role of mtDNA in shaping individual responses to mitochondrial toxicants and that transmitochondrial cybrid models could support early assessment of mitochondrial liability.
AhR/ROS-mediated endoplasmic reticulum stress contributes to PFOSA-induced cardiac defects.
Wang K, Chen H, Chen P … +3 more , Wu L, Jiang Y, Chen T
Toxicology · 2026 Feb · PMID 41338066 · Publisher ↗
Perfluorooctane sulfonamide (PFOSA), an immediate precursor of perfluorooctane sulfonate (PFOS), is widely detected in the environment. Recent studies have indicated that the aryl hydrocarbon receptor (AhR) mediates PFOS...
Perfluorooctane sulfonamide (PFOSA), an immediate precursor of perfluorooctane sulfonate (PFOS), is widely detected in the environment. Recent studies have indicated that the aryl hydrocarbon receptor (AhR) mediates PFOSA-induced cardiac defects; however, the precise mechanisms remain unclear. Given that genes involved in endoplasmic reticulum stress (ERS) are enriched in zebrafish larvae following PFOSA exposure, we hypothesized that AhR mediates PFOSA-induced cardiac defects through ERS. In this study, we observed a dose-dependent increase in the ERS markers Grp78 and Chop in the hearts of zebrafish larvae exposed to PFOSA. Furthermore, PFOSA-induced ERS activated the PERK branch of the unfolded protein response (UPR), while inhibition of either AhR or reactive oxygen species (ROS) significantly attenuated PFOSA-triggered ERS and PERK branch activation. The results further demonstrated that PFOSA-induced ERS and PERK activation led to 1) mitochondrial calcium overload through the Ip3r/Grp75/Vdac1 complex, and 2) downregulation of PGC-1α resulting from CHOP overexpression. Collectively, these events resulted in apoptosis in the zebrafish embryonic heart. AhR/ROS-dependent ERS, PERK branch activation, and mitochondrial damage were also observed in rat embryonic cardiomyocytes exposed to PFOSA. In conclusion, our findings indicate that PFOSA induces ERS and activates the PERK branch through the AhR/ROS axis, leading to mitochondrial damage via calcium overload and PGC-1α suppression, ultimately resulting in apoptosis and cardiac defects. Overall, these results highlight the fundamental role of ERS in the cardiac developmental toxicity of PFOSA.
Ceritinib-ibuprofen synergistic hepatotoxicity: Insights from real-world data and liver organoid models.
Tan S, Yang Y, Ma L … +6 more , Zuo X, Rao J, Pu Y, Cheng F, Gu Z, Zhang J
Toxicology · 2026 Jan · PMID 41326256 · Publisher ↗
Ceritinib, a next-generation anaplastic lymphoma kinase inhibitor used to treat non-small cell lung cancer, has been increasingly associated with drug-induced liver injury (DILI), especially in the context of drug-drug i...
Ceritinib, a next-generation anaplastic lymphoma kinase inhibitor used to treat non-small cell lung cancer, has been increasingly associated with drug-induced liver injury (DILI), especially in the context of drug-drug interactions (DDIs). To elucidate the hepatotoxic risk of ceritinib in combination therapies, we conducted a real-world pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) and experimentally validated the results using human liver organoids. Disproportionality analysis revealed that ceritinib administered in combination therapy was more likely to induce DILI than its monotherapy, with the strongest correlation observed for ceritinib combined with ibuprofen (reporting odds ratio [ROR] = 12.01). Ibuprofen and acetaminophen (a classic DILI-associated drug with an ROR of 5.82) were selected for further combination studies using the liver organoid model. Both ceritinib-ibuprofen and ceritinib-acetaminophen combinations exhibited synergistic hepatotoxicity in organoids, with ceritinib-ibuprofen demonstrating a more pronounced effect, as demonstrated by the Bliss independence model based on organoid cell viability data. Mechanistically, ibuprofen possibly exacerbates ceritinib-induced hepatotoxicity by suppressing CYP3A4 activity, thereby impairing ceritinib metabolic clearance and enhancing its hepatotoxicity. Together, these findings provide a multidimensional understanding of DILI risks associated with ceritinib combination therapies. By integrating pharmacovigilance signals with physiologically relevant in vitro validation, this study highlights the utility of the human liver organoids for elucidating the mechanisms of hepatotoxicity insights and supporting safer prescribing practices, especially when ceritinib is co-administered with non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen in real-world clinical settings.
A next generation physiologically-based kinetic model for quantitative in vitro to in vivo extrapolation of cisplatin-induced nephrotoxicity in humans.
Romano Olmedo KGJ, Chen J, Rietjens IMCM … +1 more , Kramer NI
Toxicology · 2026 Jan · PMID 41326255 · Publisher ↗
Animal-based toxicity tests inadequately predict human nephrotoxicity, hence the call for human-based new approach methodologies. Nephrotoxic chemicals often accumulate in the proximal tubule as transporters on the polar...
Animal-based toxicity tests inadequately predict human nephrotoxicity, hence the call for human-based new approach methodologies. Nephrotoxic chemicals often accumulate in the proximal tubule as transporters on the polarized membrane of these cells can actively take-up chemicals. The aim of the present study was to develop next generation human physiologically-based kinetic (PBK) models to simulate plasma and kidney concentrations and predict the nephrotoxicity of i.v.-administered cisplatin as the model compound. The PBK models were used to predict nephrotoxic doses of this chemotherapeutic by quantitative in vitro to in vivo extrapolation (QIVIVE) of literature available concentration-response relationships of cytotoxicity in renal cell lines. Two forms of the PBK model were developed: one with a simple single kidney compartment and another including a multi-compartmental kidney that includes organic cation transporter 2 (OCT2)-mediated active renal secretion. Observed single dose of 50 mg/m lead to nephrotoxicity in 30 % of patients. Using only in vitro and in silico-derived pharmacokinetic parameters, human benchmark dose levels (BMDL) values were calculated for all QIVIVE obtained dose-response curves using the maximum concentration in kidney blood or proximal tubule and the area under the concentration-time curve (AUC) in the proximal tubule. Based on the AUC in proximal tubule, the complex form of the model predicts nephrotoxicity in 30 % of patients best, between 23.1 and 65 mg/m. This study provides a case study for next generation risk assessment using PBK models that incorporate active renal secretion to better predict plasma concentration-time profiles are well as in vivo nephrotoxic dose levels.
Interaction-profile cheminformatic read-across identifies the UV filter benzophenone-4 as a PPARγ agonist and potential obesogen.
Gong J, Park IG, Hwang S … +6 more , Cho J, Lee MJ, Kim M, Kang J, An S, Noh M
Toxicology · 2026 Feb · PMID 41325878 · Publisher ↗
Obesogens are chemicals, often encountered as environmental contaminants, that disrupt metabolic regulation and promote obesity. Here, we present a cheminformatics framework that integrates interaction-profile docking si...
Obesogens are chemicals, often encountered as environmental contaminants, that disrupt metabolic regulation and promote obesity. Here, we present a cheminformatics framework that integrates interaction-profile docking simulations with cluster-level enrichment analysis to enhance read-across and prioritize candidate environmental metabolic disruptors. Protein-ligand contact features from docking to obesity-related nuclear receptors were summarized at the pose level and combined into a 327-dimensional interaction-profile descriptor. Dimensionality-reduced descriptors from 6022 Tox21 compounds were clustered, and enrichment analysis against Tox21 assay results identified clusters associated with specific nuclear receptor activities. One cluster was selectively enriched for peroxisome proliferator-activated receptor γ (PPARγ) agonists. Although benzophenone-4 (BP-4, sulisobenzone), a sunscreen UV filter in this cluster, is labeled as inactive in Tox21, experimental validation confirmed selective PPARγ binding and recruitment of SRC-2 and PGC-1α coactivators. In human bone marrow-derived mesenchymal stem cells, BP-4 promoted adipogenic differentiation, lipid accumulation, and adiponectin production, establishing its potential as an environmental obesogen. This study demonstrates the power of combining interaction-profile read-across with functional assays to predict environmental metabolic disruptors and provides a mechanistic template for systematic chemical safety evaluation.
2,4,6-triiodophenol induces glomerular mesangial cell damage through inflammatory imbalance, oxidative stress overactivation, and aberrant apoptosis.
Miao T, Zou S, Xu B … +3 more , Deng Z, Di M, Ying H
Toxicology · 2026 Feb · PMID 41319746 · Publisher ↗
OBJECTIVE: 2,4,6-Triiodophenol (TIP) is a highly toxic iodinated disinfection byproduct that is generated during water disinfection, and TIP is widely detected in drinking water. This study aimed to investigate the nephr...
OBJECTIVE: 2,4,6-Triiodophenol (TIP) is a highly toxic iodinated disinfection byproduct that is generated during water disinfection, and TIP is widely detected in drinking water. This study aimed to investigate the nephrotoxicity of TIP and its potential mechanisms. MATERIALS AND METHODS: An in vitro exposure model was constructed by using mouse glomerular mesangial cells (MES-13 cell line). The cytotoxicity of TIP was evaluated via the CCK-8 assay and microscopic morphological observation. The expression of inflammatory cytokines was detected by qRT-PCR and ELISA. Oxidative stress markers, including malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD), were detected using ELISA, and cell apoptosis was analyzed by flow cytometry. RESULTS: TIP exhibited obvious dose-dependent cytotoxicity in MES-13 cells. Low concentrations of exposure showed no significant cytotoxicity, whereas high concentrations of exposure markedly inhibited cell viability. Moreover, TIP can promote the gene and protein expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). However, while the gene expression of the anti-inflammatory cytokine IL-10 was increased, its protein expression level showed no significant change, suggesting a post-transcriptional regulation or a protein translation delay effect. Further studies revealed that TIP not only overactivates oxidative stress but also induces aberrant apoptotic regulation. This finding indicates that MES-13 cells may respond to TIP-induced damage by regulating oxidative stress and cell apoptosis. CONCLUSIONS: This study firstly demonstrated that TIP can induce glomerular mesangial cell damage through inflammatory imbalance, oxidative stress overactivation, and aberrant apoptosis. Our findings not only provide experimental evidence to elucidate the nephrotoxic mechanisms of TIP but also contribute to establishing relevant strategies for health risk prevention and control.
Dose-inverted neurotoxicity: La₂O₃ nanoparticles cause redox dysregulation at low concentrations but excitotoxic catastrophe at high doses.
Alyami NM, Alonaizan R, Alobaid H … +6 more , Maodaa S, Alothman NS, Alshiban NM, Alnakhli ZA, Alyami MM, Almeer R
Toxicology · 2026 Feb · PMID 41319745 · Publisher ↗
This study investigated the effects of lanthanum oxide nanoparticles (La₂O₃ NPs) on cognitive and motor functions in female mice. We used behavioral tests, biochemical analysis, and tissue examination. Our findings indic...
This study investigated the effects of lanthanum oxide nanoparticles (La₂O₃ NPs) on cognitive and motor functions in female mice. We used behavioral tests, biochemical analysis, and tissue examination. Our findings indicate that neurotoxicity is dose-dependent, with distinct mechanisms at play. Low doses (60 mg/kg) caused severe oxidative stress, increasing a key damage marker (MDA) by 40-80 times and depleting antioxidants (glutathione) in the blood. These doses also led to the accumulation of pro-oxidant metals (Fe, Mn, Cu, Ti) and a reduction in brain calcium levels, as determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). At moderate doses, mice exhibited hyperactive movement but normal muscle strength, indicating a brain-specific effect. In contrast, high doses (300 mg/kg) triggered a different pattern of damage. This included a harmful calcium-potassium imbalance, disruption of key brain health signals (BDNF pathway), and widespread neuronal death. These changes are associated with significant cognitive deficits in avoidance learning and a complete lack of response to warning stimuli. Histopathological analysis revealed that neurotoxicity primarily affected motor coordination pathways, with degeneration observed in the cerebellum and medulla. We propose that La₂O₃ NPs release La³ ⁺ ions, which disrupt cellular calcium balance and produce harmful reactive oxygen species (ROS). This leads to two toxicity phases: at low doses, metal ions drive ROS generation, while at high doses, nanoparticle aggregation causes a catastrophic failure of ion regulation in neurons. These findings have important implications for understanding nanomaterial-induced neurodegeneration and creating protective strategies against La₂O₃ exposure.
Acetyl tributyl citrate induces intestinal toxicity by regulating the IDH2/NF-κB pathway and lipid peroxidation.
Kang K, Huang Y
Toxicology · 2026 Feb · PMID 41317839 · Publisher ↗
In recent years, the increasing prevalence of environmental pollutants has raised concerns about their potential role in intestinal-related diseases. Previous studies have shown that various chemicals, including plastici...
In recent years, the increasing prevalence of environmental pollutants has raised concerns about their potential role in intestinal-related diseases. Previous studies have shown that various chemicals, including plasticizers like acetyl tributyl citrate (ATBC), may adversely affect intestinal health, but the specific mechanisms remain unclear. Herein, we aimed to elucidate the potential molecular mechanisms underlying ATBC-induced intestinal toxicity. We systematically screened professional databases, including ChEMBL, STITCH, and GSE16879, and identified 29 potential targets associated with ATBC-related intestinal toxicity. Through rigorous filtering using the STRING platform and Cytoscape software, 15 hub genes were ultimately selected, and four core targets-ATM, FYN, IDH2, and TOP1-were identified using two machine-learning methods. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that these core targets were primarily enriched in NF-κb pathways. Molecular docking simulations using the AutoDock software further confirmed strong binding interactions between ATBC and the core targets, and IDH2 was selected for the following analyses. In vitro experiments demonstrated that ATBC treatment decreases IDH2 expression in NCM460 and HCT116 cells and activates the NF-κB pathway. Given the pivotal role of the IDH2 gene in cellular energy metabolism, we systematically evaluated reactive oxygen species (ROS) levels and performed JC-1 staining assays. Our findings demonstrate that ATBC significantly promotes intracellular ROS accumulation, induces mitochondrial membrane-potential depolarization, and concurrently triggers cellular lipid peroxidation damage. Overall, our findings confirm that ATBC induces intestinal damage by regulating the IDH2/NF-κB pathway and lipid peroxidation, and lay the foundation for the development of preventive and therapeutic strategies against intestinal damage caused by exposure to ATBC-containing plastics.
Advances in antituberculosis drug-induced liver injury: Molecular mechanisms, genetic insights, and emerging animal-free prediction models.
Yang R, Jin Z, Jin X … +3 more , Li Y, Wang D, Chao J
Toxicology · 2026 Feb · PMID 41314589 · Publisher ↗
Approximately 10 million tuberculosis patients worldwide require drug therapies annually. However, prolonged use of tuberculocidal drugs in combination regimens may induce hepatotoxicity, ranging from asymptomatic serum...
Approximately 10 million tuberculosis patients worldwide require drug therapies annually. However, prolonged use of tuberculocidal drugs in combination regimens may induce hepatotoxicity, ranging from asymptomatic serum transaminase elevation to acute liver failure, which often necessitates treatment discontinuation. Antituberculosis drug-induced liver injury (AT-DILI) represents a predominant cause of clinical DILI in humans globally. The multifactorial and incompletely uncovered mechanisms underlying AT-DILI necessitate human-relevant models to predict liver injury progression and guide timely interventions. This review synthesizes current knowledge of mechanisms implicated in AT-DILI, focusing on metabolic activation of first-line drugs, immune-mediated hepatocyte damage, and cholestasis via transporter inhibition. Genetic polymorphisms in N-acetyltransferase 2, Cytochrome P450 2E1 and glutathione S-transferase genes are highlighted as critical determinants of interindividual susceptibility. Meanwhile, we critically evaluate the evolution of animal-free prediction models, spanning in vitro systems (2D hepatocytes and 3D culture system including hepatic spheroid, organoids, microfluidic systerms, and 3D bioprinting) to computational approaches such as quantitative structure-activity relationship modeling and machine learning. These models address ethical concerns, interspecies variabilities, and translatability limitations inherent to traditional animal studies while enabling high-throughput toxicity profiling. Despite advancements, challenges persist in standardizing experimental architectures, reducing operational costs, establishing physiological fidelity, and validating computational predictions. Robust characterization of emerging animal-free platforms including spanning the physiological fidelity, multi-omics integration capacity, and clinical translatability is therefore indispensable for advancing regulatory-ready frameworks toward safer tuberculosis therapy.
Notch1-dependent hippocampal apoptosis is associated with monocrotaline-induced anxiety-like behavior.
Baochang L, Fan L, Fei W … +13 more , Xianchun Y, Zichen W, Mengzhuan H, Yiman Z, Mengyang K, Bing L, Ying W, Qiang M, Pu J, Xiaohui Z, Hao H, Hongyan T, Qian Y
Toxicology · 2026 Feb · PMID 41314588 · Publisher ↗
Monocrotaline (MCT), an alkaloid from the genus Crotalaria, is widely used to establish an animal model of pulmonary hypertension. The toxicity of MCT extends not only to peripheral organs but also to the nervous system....
Monocrotaline (MCT), an alkaloid from the genus Crotalaria, is widely used to establish an animal model of pulmonary hypertension. The toxicity of MCT extends not only to peripheral organs but also to the nervous system. However, the molecular mechanism responsible for the development of anxiety disorders after MCT poisoning remains unclear. MCT (60 mg/kg) administration for 4 weeks was used to induce a rat model of anxiety-like behavior with pulmonary hypertension. Open field and elevated plus maze tests showed MCT increased anxiety-like behavior in rats with pulmonary hypertension. Hematoxylin and eosin staining of the hippocampus and annexin V-FITC/PI staining of the mouse hippocampal cell line HT22 with MCT infusion showed that MCT promoted apoptosis in hippocampal neurons. The western blot showed MCT increased the apoptosis effector caspase-3 expression and activation in vivo and in vitro. Simultaneously, Notch1 and its downstream gene expression were also increased in vivo and in vitro. Furthermore, Notch1 deletion with siRNA can eliminate MCT-induced apoptosis and caspase-3 expression and activation. The Notch1 inhibitor DAPT has the same effect in vitro. In addition, DAPT alleviated MCT-induced anxiety-related behavior and attenuated hippocampal apoptosis in vivo. The present study reveals that the mechanism of MCT-induced neurotoxic effects in hippocampal neurons is mediated by the Notch1/caspase-3 pathway.
Corrigendum to "Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress" [Toxicology 361-362 (2016) 39-48].
Gomez-Quiroz LE, Seo D, Lee YH … +9 more , Kitade M, Gaiser T, Gillen M, Lee SB, Gutierrez-Ruiz MC, Conner EA, Factor VM, Thorgeirsson SS, Marquardt JU
Toxicology · 2026 Feb · PMID 41298195 · Publisher ↗
Abstract loading — click title to view on PubMed.
A meta-analysis-based adverse outcome pathway for the reproductive toxicity induced by per- and poly-fluoroalkyl substances in animals.
Zhu Y, Zhao C, Guo H … +5 more , Shi Q, Dong R, Wang Q, Wu Y, Zhang H
Toxicology · 2026 Feb · PMID 41290085 · Publisher ↗
Per- and poly-fluoroalkyl substances (PFAS) were highly toxic to reproductive systems due to the widespread environmental distribution and persistence. However, the underlying mechanisms were not well understood. This st...
Per- and poly-fluoroalkyl substances (PFAS) were highly toxic to reproductive systems due to the widespread environmental distribution and persistence. However, the underlying mechanisms were not well understood. This study systematically evaluated the association between existing adverse outcome pathways (AOPs) and PFAS-induced reproductive toxicity using the AOP conceptual framework. A meta-analysis of 28 studies quantified the effect sizes, providing a comprehensive assessment of PFAS-induced reproductive toxicity in animals. Within the AOP framework, the molecular initiating event (MIE) was increased reactive oxygen species (ROS), which triggered several key events (KEs) at different levels. At the cellular level, the KEs included oxidative stress, mitochondrial dysfunction, DNA damage, endoplasmic reticulum stress, reduced steroidogenic protein expression, decreased thyroid hormone synthesis, epigenetic modification process, lipid metabolism disorders, decreased androgen and estrogen receptors. These KEs led to decreased testosterone and elevated estrogen levels, alongside disruptions in spermatogenesis, oocyte maturation, and ovulation. Consequently, this resulted in lower sperm count, impaired sperm quality, and decline in oocyte quantity. Meta-analysis results showed that PFAS exposure significantly decreased juvenile survival rates (Standardized Mean Difference (SMD): -3.10, 95 % Confidence Interval (CI): -4.01, -2.18), reduced male testosterone (SMD: -4.17, 95 % CI: -6.00, -2.33) and female estradiol levels (SMD: -1.98, 95 % CI: -3.15, -0.81) in animals. Our findings systematically summarized the reproductive toxicity mechanisms of PFAS and alternatives, providing scientific basis for assessing the environmental impact.
Long-term low-dose exposure to polystyrene nanoplastics induces morphological and transcriptional reprogramming to enhance metastatic potential of colorectal cancer cells.
Kim Y, Park SY, Jo A … +9 more , Ahn S, Kwon J, Jung EM, Kim HS, Jeong S, Lee KE, Oh CK, Kim YH, Oh JM
Toxicology · 2026 Feb · PMID 41290084 · Publisher ↗
Despite global efforts to reduce plastic consumption, its usage continues to rise, leading to increased environmental contamination and heightened concerns regarding the potential health impacts of nanoplastics. Owing to...
Despite global efforts to reduce plastic consumption, its usage continues to rise, leading to increased environmental contamination and heightened concerns regarding the potential health impacts of nanoplastics. Owing to their prolonged residence time in the intestine, nanoplastics contribute to prolonged exposure and absorption by intestinal epithelial cells. In this study, we examined the effects of polystyrene micro- and nanoplastics of varying sizes (20 nm-1000 nm) on colorectal cancer cells (HCT116) through a series of in vitro experiments, including cell viability assays, morphological assessments, and transcriptomic profiling. Notably, long-term exposure of HCT116 cells to small-sized (20 nm) nanoplastics at a low-dose, one that does not cause acute toxicity, led to significant morphological changes and gene expression alterations. These modifications included the upregulation of markers associated with migration, cancer stem cell (CSC) properties, and epithelial-mesenchymal transition (EMT). The enhanced expression of migration markers correlated with increased cell motility. Consistent with these in vitro findings, zebrafish models demonstrated accelerated metastasis of colorectal cancer cells following nanoplastic exposure. Collectively, these results suggest that nanoplastics may contribute to colorectal cancer progression, providing new insights into the molecular mechanisms underlying this process.
Palmitic acid induced the onset of lipotoxicity in a HepaSH-on-chip model with raised of HO and IL-6, and altered p38/MAPK & JAK/STAT pathways.
Wang H, Poulain S, Cao W … +6 more , Arakawa H, Kim SH, Kato Y, Nishikawa M, Sakai Y, Leclerc E
Toxicology · 2026 Feb · PMID 41285220 · Publisher ↗
Hepatic inflammation induced by lipotoxicity is a key event in the progression of liver steatosis to non-alcoholic steatohepatitis (NASH). To characterize this process, we investigated the response of HepaSH cells-a nove...
Hepatic inflammation induced by lipotoxicity is a key event in the progression of liver steatosis to non-alcoholic steatohepatitis (NASH). To characterize this process, we investigated the response of HepaSH cells-a novel mature human hepatocyte derived from chimeric mice-to a weak but chronic palmitic acid (PA) exposure, a prevalent dietary fatty acid. To mimic the hepatic microphysiological environment, cells were cultured using organ-on-chip technology and exposed to PA for two weeks. Functional assays revealed no changes in glucose or lactate metabolism. Likewise, PA exposure did not alter albumin secretion, TGF-β1 or TNF-α production, bile acid synthesis, or CYP450 biotransformation activity. Furthermore, there was no lipid accumulation or change in triglyceride production. However, PA-treated cells cleared the palmitic acid and increased the levels of reactive oxygen species (H₂O₂) and interleukin-6 (IL-6) compared to controls. mRNA analysis concurrently revealed perturbations in transcriptional regulators and genes associated with lipid metabolism, NF-B, inflammation, and mitochondrial functions. Addtional RT-qPCR confirmed the activation of the JNK1/MAPK8 gene in p38/MAPK and JAK2 in the JAK/STAT/IL-6 pathways in response to PA. We believed that our findings using an advanced mature human hepatic on-chip model would help to provide insight of the early stages of PA-induced lipotoxicity in hepatocytes.
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