Archives of Toxicology最新文献

{"title":"Glutaminolysis impairment and immunometabolic dysregulation in U937 cells: Key mechanisms in occupational and environmental skin exposure to UV and benzo[a]pyrene","authors":"Christian Kersch,&nbsp;Viktor Masutin,&nbsp;Laura Kuhlmann,&nbsp;Rasha Alsaleh,&nbsp;Andrea Kaifie,&nbsp;Simone Schmitz-Spanke","doi":"10.1007/s00204-025-04155-4","DOIUrl":"10.1007/s00204-025-04155-4","url":null,"abstract":"<div><p>Dermal exposure to polycyclic aromatic hydrocarbons (PAHs) and UV irradiation in occupational and environmental settings poses a health risk by inducing skin toxicity, including immunomodulatory effects. This study investigated the effects of benzo[a]pyrene (B[a]P), a well-characterized PAH, at three concentrations (0.04 nM, 4 nM, and 4 µM) and UV irradiation on human monocytic U937 cells, employing both single and combined exposure scenarios. An integrated metabolomics and toxicological approach was utilized to assess cellular responses, with a focus on understanding the immunometabolic effects of these exposures. Our findings revealed that only the highest B[a]P concentration in combination with UV irradiation resulted in significant metabolic dysregulation and impaired cellular function. Notably, we observed a pronounced downregulation of glutaminolysis, a critical metabolic pathway for cellular energy production and biosynthesis. This was evidenced by decreased levels of glutamate and key intermediates within the tricarboxylic acid cycle (e.g., succinate, fumarate, malate, and citrate), as well as reduced levels of glycine, a precursor for glutathione synthesis. In parallel, toxicological assays revealed increased levels of oxidative stress markers, lipid peroxidation, and enhanced DNA damage. Furthermore, the combined exposure led to alterations in tryptophan metabolism and dysregulation of lipid species, particularly sphingolipids and phosphatidylinositols. These findings lead us to propose the hypothesis that metabolic disruption, specifically the impairment of glutaminolysis, initiated a cascade of events, including increased oxidative stress, lipid peroxidation, and ultimately, ferroptosis in our study. Our results indicate that the combined exposure to UV irradiation and B[a]P can induce immunometabolic reprogramming and significantly contribute to the pathogenesis of inflammatory skin diseases.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 11","pages":"4481 - 4492"},"PeriodicalIF":6.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-025-04155-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zebrafish exposed to a cocktail of pesticides during early development display long-lasting neurobehavioral alterations","authors":"Maria Abellán-Álvaro,&nbsp;Isabel Forner-Piquer,&nbsp;Ieremias Chousidis,&nbsp;Elliott Godden,&nbsp;Alba García-Deante,&nbsp;Nicola Marchi,&nbsp;Caroline H. Brennan,&nbsp;Jose V. Torres-Pérez","doi":"10.1007/s00204-025-04129-6","DOIUrl":"10.1007/s00204-025-04129-6","url":null,"abstract":"<div><p>The widespread use of pesticides is increasing the presence of environmental contaminants with potential impacts on biodiversity, ecosystems, and human health. Although long-term pesticide effects have been previously studied, the long-term impact of an acute pesticide exposure during critical early developmental periods remains poorly understood. Here, we used zebrafish to examine whether acute exposure to a pesticide mixture at 0.5 μg/L (the maximum allowed in drinking water) during the first 5 days post-fertilisation (dpf) of development has lasting effects at 28 dpf. Zebrafish were assessed behaviourally, morphologically, and molecularly both immediately after exposure at 5 dpf and later at 28 dpf. Our results show alterations in stress-response that start to emerge right after the developmental exposure and are associated with a less anxious-like phenotype at juvenile stages. Interestingly, despite the observed behavioural phenotype at 28 dpf, it did not lead to significant molecular changes in the hypothalamic-pituitary-interrenal (HPI) axis at this stage. On the contrary, a positive control group of juvenile fish subjected to a sustained pesticide exposure throughout the 28 dpf showed both reduced anxiety-like behaviour and HPI alterations. Our study suggests that even an acute exposure to a low-concentration of pesticides during critical developmental periods can result in enduring behavioural changes. </p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 10","pages":"4181 - 4195"},"PeriodicalIF":6.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-025-04129-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative genotoxicity assessment of N-nitrosodimethylamine in mice by error-corrected next-generation sequencing and DNA methylation quantification for toxicity threshold determination","authors":"Xinyue You,&nbsp;Chen Sun,&nbsp;Yiyi Cao,&nbsp;Jing Xi,&nbsp;Weiying Liu,&nbsp;Jiaying Wu,&nbsp;Jiang Zheng,&nbsp;Yang Luan","doi":"10.1007/s00204-025-04166-1","DOIUrl":"10.1007/s00204-025-04166-1","url":null,"abstract":"<div><p>The contamination of <i>N</i>-nitrosamines (<i>N</i>-NAs) in pharmaceuticals has raised global concerns, due to potential carcinogenic risks. <i>N</i>-nitrosodimethylamine (NDMA) is a rodent carcinogen and the most prevalent <i>N</i>-NAs impurity in drug products. Current acceptable intake of NDMA (96 ng/day) is a simple linear extrapolation from rodent carcinogenicity data, which may not comprehensively characterize its genotoxic potential in humans. Most <i>N</i>-NAs react with DNA to form DNA adducts after metabolic activation, leading to mutations and carcinogenesis. Here, we combined high-accuracy LC–MS/MS with error-corrected next-generation sequencing (ecNGS) to assess NDMA-induced DNA adduction and somatic mutations in mice using the quantitative benchmark dose (BMD) approach. NDMA induced dose-dependent increases in both DNA adduction and somatic mutations in liver tissues, with significant increases in mutation frequencies observed at ≥ 1 mg/kg/day. NDMA induced mutations mainly with CG &gt; TA and TA &gt; CG transitions, exhibiting a signature resembling COSMIC signature 11, the mutational profile of alkylating agents. BMD₅₀ (90% CI) was estimated as 0.08–0.32 mg/kg for <i>N</i>7-methylguanine and 1.64–3.83 mg/kg for mutations. Permitted daily exposure (PDE) for NDMA was calculated from the lower confidence limit of BMD₅₀ (BMDL₅₀) of genotoxic endpoints using appropriate uncertainty factors, revealing a PDE value of 245 ng/day for NDMA-induced mutation. This PDE value was higher than the limit of 96 ng/day recommended by regulatory agencies. Based on the quantitative genotoxicity assessment, our findings may improve the risk assessment of NDMA-contaminated pharmaceuticals and demonstrate the potential implementation of ecNGS in regulatory decision-making.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 11","pages":"4665 - 4676"},"PeriodicalIF":6.9,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sirtuins as mediators and targets of arsenic toxicity: unraveling signaling pathway crosstalk","authors":"Sara R. El-Mahrouk,&nbsp;Ayman O. S. El-Kadi","doi":"10.1007/s00204-025-04158-1","DOIUrl":"10.1007/s00204-025-04158-1","url":null,"abstract":"<div><p>Arsenic, a widespread environmental contaminant, threatens millions globally through contaminated water, soil, and food. While arsenic compounds are used to treat acute promyelocytic leukemia, their toxic legacy includes cancers, cardiovascular disease, diabetes, and neurodegeneration, primarily driven by oxidative stress, mitochondrial dysfunction, and epigenetic instability. Sirtuins, a family of NAD⁺-dependent enzymes, are central to cellular defense, orchestrating metabolism, stress resistance, DNA repair, and longevity. Arsenic disrupts sirtuin function, particularly SIRT1, SIRT2, and SIRT3, via microRNA-mediated silencing and post-translational modifications, impairing antioxidant defenses, disturbing energy metabolism, and accelerating cellular injury across organ systems. However, activating sirtuins with agents like resveratrol, metformin, or berberine, as well as through lifestyle interventions, can counteract arsenic toxicity, restore cellular resilience, and provide new therapeutic strategies. This review synthesizes current knowledge on the interplay between arsenic exposure and sirtuin biology, examining how arsenic alters sirtuin expression and activity, the downstream consequences for cellular signaling and organ health, and emerging interventions targeting sirtuin pathways. By bridging molecular insights with translational potential, we highlight the promise of sirtuins as therapeutic targets in combating arsenic toxicity and guide future research directions.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 11","pages":"4319 - 4335"},"PeriodicalIF":6.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging dimensions: a comparative analysis of 2D and 3D in vitro models for hepatocellular carcinoma research","authors":"Leticia C. Valente,&nbsp;Luana Riechelman-Casarin,&nbsp;Laura L. P. Esteves,&nbsp;Gabriel P. Bacil,&nbsp;Tereza Cristina da Silva,&nbsp;Mathieu Vinken,&nbsp;Bruno Cogliati,&nbsp;Scott L. Friedman,&nbsp;Amedeo Columbano,&nbsp;Luís Fernando Barbisan,&nbsp;Guilherme R. Romualdo","doi":"10.1007/s00204-025-04167-0","DOIUrl":"10.1007/s00204-025-04167-0","url":null,"abstract":"<div><p>The tumor microenvironment (TME) influences hepatocellular carcinoma (HCC) behavior and disease progression. Cell–cell dynamics of non-parenchymal components, such as hepatic stellate cells (HSC), are key factors in understanding HCC onset and progression. This study established mono- and co-culture in vitro HCC models in both 2D and 3D configurations to investigate HCC cell behavior at both functional and transcriptional levels. Human HCC C3A cells were co-cultured with human HSC LX2 cells or alone in ultra-low attachment plates to form spheroids (3D) or in a transwell system (2D). In the 2D model, the paracrine signaling of HSC-HCC cells promoted colony formation and HCC cells motility compared to the C3A monolayer, showing a pro-inflammatory transcriptomic signature through a positive regulation of canonical NF-κB pathway. In the 3D model, co-culture spheroids exhibited higher cell viability, enhanced angiogenesis, migration, and extracellular matrix (ECM)-related transcriptomic hallmarks compared to C3A monoculture. Regardless of the configuration, co-culture models shared 74 genes, including angiogenesis, proteolysis and response to wounding functional annotations, indicating a LX2-induced pro-tumoral signature in C3A cells. The 2D <i>vs</i>. 3D comparison revealed that the 3D model enriched proliferation-related genes in monocultured C3A spheroids compared to C3A monolayers, whilst co-culture spheroids showed cholesterol, angiogenesis, migration and ECM annotations compared to co-culture transwell model. These findings reinforce the importance of HSC as key microenvironmental cellular components in HCC and highlight how cellular dynamics modify HCC cell behavior in vitro.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 11","pages":"4531 - 4542"},"PeriodicalIF":6.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic profile of TiO₂ particle overload in rat alveolar macrophages: examining responses between P25 and two pigment grade particles in vitro.","authors":"Laeticia Perez, Jérôme Ambroise, Bertrand Bearzatto, Yousof Yakoub, Mihaly Palmai-Pallag, Caroline Bouzin, Laurence Ryelandt, Cristina Pavan, François Huaux, Dominique Lison","doi":"10.1007/s00204-025-04152-7","DOIUrl":"https://doi.org/10.1007/s00204-025-04152-7","url":null,"abstract":"<p><p>The industrial uses of titanium dioxide (TiO₂) are extensive, with pigment grades (particle size > 100 nm) being the most common forms produced. Nanoforms (particle size < 100 nm) of TiO₂ (e.g., P25) are also produced for specialist applications such as photocatalysts. P25 induced inflammatory and carcinogenic lung responses in rats at high exposure doses inducing lung overload. We previously identified an in vitro transcriptomic signature (18 genes) associated with overload of P25, in rat alveolar macrophages. The objective of the present study was to determine whether this signature also applies to other, more commonly used pigment grades of TiO₂. Using high-throughput sequencing, we examined the transcriptomic responses of three TiO₂ grades (the photocatalyst P25 and two pigment grades, G3-1 and Bayertitan T) in primary rat alveolar macrophages exposed in vitro at non-overload (4 µg/mL for P25; 2 µg/mL for G3-1 and Bayertitan T) or overload (40 µg/mL for P25; 20 µg/mL for G3-1 and Bayertitan T) doses. At an equivalent internalized volume of particles, the response to P25 overload was significantly higher than those to pigment particles. However, a consistent modulation of the 18-gene signature was observed across all three TiO₂ grades, albeit with a markedly lower magnitude of response for the pigment particles. Although the gene signature of particle overload in rat alveolar macrophages seems to apply across different TiO₂ particle grades, our results suggest that unrealistic and extreme exposure concentrations to the pigment TiO₂ particles would be required to induce in vivo toxicity similar to that observed with P25 particles.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2,2',4,4'-tetrabromodiphenyl ether (BDE-47) induces early hearing loss in guinea pigs via activating AhR to trigger mitochondrial and endoplasmic reticulum stress-regulated autophagy","authors":"Jie Tang,&nbsp;Li Zhang,&nbsp;Yujia Yang,&nbsp;Chunji Wang,&nbsp;Fang Zhang,&nbsp;Muxin Yu,&nbsp;Nenghua Zhang,&nbsp;Guangtao Xu,&nbsp;Bo Hu,&nbsp;Meiling Shi,&nbsp;Long Xu","doi":"10.1007/s00204-025-04154-5","DOIUrl":"10.1007/s00204-025-04154-5","url":null,"abstract":"<div><p>2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is a ubiquitous environmental pollutant linked to early neurotoxicity, but its effects on hearing loss during early development remain unclear. We exposed weanling guinea pigs to BDE-47 (1, 10, 50 mg/kg/day) via gavage for 28 days, finding increased hearing thresholds at 0.5 and 4 kHz, hair cell damage, and elevated AhR, LC3B, and P-SQSTM1 levels. In vitro, BDE-47 reduced HEI-OC1 cell viability dose dependently, increasing AhR, oxidative stress (MitoTracker, MitoSOX, ROS), and activating the Keap1-Nrf2 antioxidant pathway. Elevated autophagosomes, P-SQSTM1 and LC3B-II, were observed, indicating autophagic flux inhibition. The AhR inhibitor CH223191 mitigated these effects, while Mdivi-1 (mitochondrial division inhibitor) reduced ROS and autophagy, suggesting AhR promotes mitochondrial oxidative stress, impairing autophagy. BDE-47 also increased ER-Tracker fluorescence, reduced lysosomes, and altered UPR markers (Calnexin, PDI, IRE1-α, Bip, Erol-α, PERK, and Chop), most of which were attenuated by CH223191. The ER stress inhibitor TUDCA further alleviated ROS, Keap1-Nrf2 dysregulation, and autophagy disruption. Our findings demonstrate that early BDE-47 exposure induces hearing impairment via AhR-mediated mitochondrial oxidative stress and ER stress, suppressing autophagy. These findings enhance our understanding of environmental chemical-induced ototoxicity and provide valuable insights for both auditory disorder risk assessment and therapeutic strategies for hearing preservation.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 11","pages":"4611 - 4629"},"PeriodicalIF":6.9,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicity assessment of VX in zebrafish: multi-organ toxicity evaluation and tissue distribution visualization using DESI-MSI","authors":"Manzhu Cao,&nbsp;Yi Zhang,&nbsp;Mengxuan Dong,&nbsp;Dongxin Liu,&nbsp;Yuxin Lin,&nbsp;Qian Jin,&nbsp;Liqin Li,&nbsp;Xingxing Zong,&nbsp;Chen Wang","doi":"10.1007/s00204-025-04148-3","DOIUrl":"10.1007/s00204-025-04148-3","url":null,"abstract":"<div><p>As a chemical warfare agent posing a persistent threat, VX’s potential hazards in military and terrorist scenarios underscore the urgency of investigating its multi-organ toxicity and bioaccumulative properties. In this study, first of all, zebrafish larvae were first used as a model to evaluate the toxic effects of VX, and the median lethal concentration (LC₅₀) and maximum non-lethal concentration (MNLC) of acute exposure was determined to be 409.98 μg/L, and the MNLC was 77.43 μg/L. Subsequent multi-organ toxicity evaluations at MNLC-based exposure concentrations revealed distinct pathological phenotypes in VX-exposed zebrafish larvae, including microphthalmia, pericardial edema, hepatic degeneration, renal edema, and delayed yolk sac resorption, concomitant with significant dose-dependent impairment of burst-swimming capacity and spontaneous movement frequency. Histological examinations revealed that VX induced multi-organ damage in adult zebrafish, involving the spinal cord, brain, gills, kidneys, and liver. Finally, a DESI-MSI-driven analytical framework was established to achieve micrometer-resolution mapping of VX and its metabolites, delineating spatiotemporal accumulation of VX in multiple organ systems. DESI-MSI spatial mapping revealed VX and EMPA biodistribution across nine anatomically defined zebrafish organs (eye, brain, gill, heart, liver, kidney, spinal cord, gonad, muscle), while LC–MS/MS validation confirmed the semi-quantitative reliability of DESI-MSI data. The bioaccumulation factor (BCF) analysis revealed gender-specific accumulation of VX in zebrafish (females: 30.86 ± 2.35; males: 4.28 ± 0.47, after VX exposure for 4 days), demonstrating pronounced bioaccumulation potential with a 7.2-fold sex disparity. This study pioneers the evaluation of VX-induced multi-organ toxicity and delineates its spatiotemporal biodistribution in zebrafish, providing critical evidence for mechanistic investigations of organ-specific damage and establishing a methodological foundation for comparative toxicological research and risk mitigation strategies related to chemical warfare agents.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 11","pages":"4555 - 4573"},"PeriodicalIF":6.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay of cGAS-STING and ferroptosis: crosstalk, molecular mechanisms, and therapeutic prospects.","authors":"Yumin Wang, Shuang Wu, Yitong Wang, Clara Xi Wang, Weihua Zheng, Xia Yun, Zhiji Wang, Junjing Zhang, Lida Du, Hongquan Wang","doi":"10.1007/s00204-025-04150-9","DOIUrl":"10.1007/s00204-025-04150-9","url":null,"abstract":"<p><p>The cGAS-STING pathway, a crucial cytosolic DNA sensor, initiates innate immune responses by detecting microbial and aberrant self-DNA. This evolutionarily conserved axis plays pivotal roles in autoimmune disorders, sterile inflammation, and cellular senescence. While transient activation confers protective immunity, dysregulated cGAS-STING signaling drives pathogenesis in inflammatory and autoimmune diseases. Emerging evidence reveals its functional convergence with diverse cell death modalities-notably ferroptosis, an iron-dependent regulated cell death driven by lipid peroxidation. Their dynamic interplay emerges as a key pathogenic mechanism across diseases, offering novel therapeutic opportunities. This review first outlines the core molecular architecture of cGAS-STING signaling and its disease roles. We then analyze the mechanisms and pathophysiological consequences of cGAS-STING-ferroptosis crosstalk in various disorders, followed by advances in therapeutic strategies targeting this interface. Finally, we discuss translational challenges and propose innovative solutions. By highlighting the therapeutic potential of pharmacologically modulating this nexus, we identify a promising treatment for diseases with inflammatory conditions.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental exposure to methyl ester sulfonate induces autism-like behavioral deficits in mice by dysregulation of the Notch/Hes signaling pathway disrupting neuronal differentiation","authors":"Liehai Hu,&nbsp;Ke Ren,&nbsp;Yichang Li,&nbsp;Yunhui Xia,&nbsp;Guijuan Chen,&nbsp;Xiaojian Wang,&nbsp;Chunyu Luo,&nbsp;Yun Sun,&nbsp;Dongmei Li","doi":"10.1007/s00204-025-04157-2","DOIUrl":"10.1007/s00204-025-04157-2","url":null,"abstract":"<div><p>Developmental exposure to environmental pollutants is increasingly recognized as a significant risk factor for autism spectrum disorder (ASD), yet the specific mechanisms by which individual toxicants contribute to this neurodevelopmental disorder remain largely unknown. Methyl ester sulfonate (MES), a widely used anionic surfactant with widespread environmental detection, lacks comprehensive evaluation for developmental neurotoxicity. Here, we exposed pregnant mice to environmentally relevant MES doses (0.06–6 mg/L) from gestational day 8.5 (GD8.5) to postnatal day 21.5 (PND21.5) and assessed their offspring for neurodevelopmental changes. Results showed dose-dependent ASD-like behavioral deficits, including impaired social interactions, heightened anxiety-like behaviors, and increased repetitive/stereotypic patterns. These behavioral anomalies were accompanied by neuropathological alterations, including blood–brain barrier disruption, neuronal loss, and reduced dendritic spine density, indicative of impaired synaptogenesis. Integrative transcriptomic analysis of hippocampal tissue revealed significant dysregulation of key pathways involved in neurodevelopment, prominently featuring the Notch/Hes signaling pathway. Molecular docking simulations suggested that MES could directly interact with Notch receptors, potentially disrupting ligand–receptor interactions. Further in vitro experimental validation demonstrated that MES exposure suppressed neural stem cell differentiation. Collectively, these findings provided evidence that early-life MES exposure acts as a neurodevelopmental toxicant by disrupting Notch/Hes signaling, thereby impairing neuronal differentiation and synaptogenesis, which underlined the observed ASD-like behavioral deficits in mice. This study offers novel mechanistic insights into how environmental factors contribute to ASD pathogenesis and highlights the need for toxicological assessment of widely distributed surfactants.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 11","pages":"4631 - 4647"},"PeriodicalIF":6.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}