Archives of Toxicology最新文献

{"title":"Mitochondrial oxidative stress and ion-channel suppression reveal a distinct neurotoxic profile of fentanyl analogues in a human neuronal model.","authors":"Daniela Ratto, Sabrine Bilel, Francesca Dalle Sasse, Marta Bassi, Matteo Marti, Carlo Alessandro Locatelli, Elisa Roda, Paola Rossi, Federico Brandalise","doi":"10.1007/s00204-026-04538-1","DOIUrl":"https://doi.org/10.1007/s00204-026-04538-1","url":null,"abstract":"<p><p>Fentanyl analogues, including butyrylfentanyl (BUF) and 4-fluorobutyrylfentanyl (4F-BUF), are increasingly implicated in severe toxicity and fatal overdoses. While their pharmacological activity at µ-opioid receptors is well established, the cellular mechanisms underlying their neurotoxic effects remain incompletely understood, particularly with respect to mitochondrial dysfunction and its relationship with neuronal functional impairment. In this study, differentiated SH-SY5Y cells were used as a human neuronal model to evaluate the toxicodynamic effects of morphine, fentanyl, BUF, and 4F-BUF. Cell viability assays were performed to define sub-toxic concentrations, while oxidative stress was assessed by measuring cytoplasmic reactive oxygen species (ROS) and mitochondrial superoxide at early (25 min) and prolonged (24 h) time points. Functional alterations were examined using whole-cell patch-clamp recordings of voltage-gated inward and outward membrane currents. All compounds induced concentration-dependent cytotoxicity, with BUF and 4F-BUF exhibiting the lowest IC₂₅ values (8.39 ± 0.55 and 8.36 ± 0.67 µM, respectively), compared with fentanyl (37.87 ± 4.23 µM) and morphine (59.09 ± 4.72 µM). Cytoplasmic ROS levels increased similarly across all treatments, whereas mitochondrial superoxide generation displayed a time-dependent divergence, with 4F-BUF producing the highest mitochondrial superoxide levels after prolonged exposure (334.7 ± 26.1% of control), significantly exceeding fentanyl (281.6 ± 21.6% of control). Electrophysiological analysis revealed that fentanyl preferentially reduced inward currents, whereas BUF and 4F-BUF induced a broader suppression of both inward and outward membrane conductance. Importantly, mitochondrial ROS scavenging with mitoTEMPO markedly attenuated 4F-BUF-induced mitochondrial superoxide accumulation (278.6 ± 24.8% vs. 152.5 ± 7.8% of control) and prevented the associated suppression of voltage-gated membrane currents. These findings indicate that fentanyl analogues exert distinct cellular effects characterized by enhanced mitochondrial oxidative stress and associated alterations in membrane conductance. Notably, mitochondrial superoxide emerges as an indicator of fentanyl analogue toxicity, revealing differences not captured by cytoplasmic ROS measurements and highlighting mitochondrial dysfunction as a relevant target for toxicological evaluation.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910656","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":"Genotoxicity threshold for methyl methacrylate in Chinese workers: a novel multi-endpoint genotoxicity assessment incorporating biological aging.","authors":"Xinyue You, Wenqian Xu, Yun Sun, Mengqiu Cao, Jing Xi, Tongshuai Wang, XinYu Zhang, Yang Luan, Changhui Zhou, Yiyi Cao","doi":"10.1007/s00204-026-04539-0","DOIUrl":"https://doi.org/10.1007/s00204-026-04539-0","url":null,"abstract":"<p><p>Methyl methacrylate (MMA) is a widely used foundational monomer in industrial and medical manufacturing. Current occupational exposure limits (OELs) for MMA are established based on its irritant and sensitizing effects, which may not fully prevent its genotoxicity. Here, we conducted an occupational biomonitoring study, including 45 MMA-exposed workers, 26 MMA-toluene/xylene-exposed (MMA-TX) workers, and 31 concurrent controls from a machinery manufacturing plant. Genetic damage in peripheral blood was assessed using the novel PIG-A mutation assay and cytokinesis-block micronucleus test. MMA-exposed workers showed significantly higher PIG-A mutant frequencies (10.49 ± 7.84 vs. 5.00 ± 2.70 × 10^-6), and frequencies of micronuclei (6.28 ± 2.97 vs. 3.40 ± 1.67‰), nucleoplasmic bridges (0.80 ± 0.67 vs. 0.32 ± 0.49‰), and nuclear buds (1.68 ± 1.02 vs. 0.48 ± 0.58‰) than the controls. MMA-TX-exposed workers had significantly higher PIG-A mutant frequencies (15.15 ± 11.37 × 10^-6) than MMA-exposed workers, and exhibited a slightly higher but non-significant biological age acceleration, as estimated using the Klemera-Doubal method from clinical biomarkers. Quantitative benchmark dose analysis yielded a point of departure of 0.03 mg/m³-year for MMA-induced genetic damage, indicating a lower exposure threshold than the current OELs. In MMA-treated TK6 cells, a slight increase in C > T mutations was observed using high-accuracy error-corrected sequencing, resembling the mutational signature of formaldehyde, a metabolite of MMA. The findings demonstrate that MMA below the current OELs may induce cumulative genetic damage in MMA-exposed workers, providing a quantitative basis for revising OELs to better protect worker health.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910619","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":"The missing microbial link in triclosan toxicity: comment on mechanism of liver fibrosis induced by life-long triclosan exposure in offspring rats.","authors":"Yajun He, Ruifang Wang, Fang Wang","doi":"10.1007/s00204-026-04492-y","DOIUrl":"https://doi.org/10.1007/s00204-026-04492-y","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910606","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":"Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.","authors":"Sandra Ramos, Francesco Marchetti","doi":"10.1007/s00204-026-04540-7","DOIUrl":"https://doi.org/10.1007/s00204-026-04540-7","url":null,"abstract":"<p><p>Advanced maternal age is a well-established risk factor for adverse reproductive outcomes due to increased rates of aneuploidy. However, emerging evidence indicates that the genetic consequences of maternal aging extend well beyond chromosome mis-segregation. Aging oocytes acquire a broad spectrum of genetic abnormalities, including maternally derived nuclear de novo mutations (DNMs) and mitochondrial DNA mutations, together with epigenetic dysregulation of DNA methylation and post-translational modification levels. These changes reflect the unique biology of the female germline in which oocytes remain arrested in meiotic prophase I for decades. Age-related deterioration of key processes, such as erosion of cohesion complexes, altered meiotic recombination, and weakened spindle assembly checkpoint surveillance collectively destabilize meiotic chromosome architecture, directly driving chromosome mis-segregation. At the same time, accumulation of endogenous DNA damage and declining DNA damage and repair processes increase the chances of transmitting lesions that can be converted into sequence-level mutations during the earliest embryonic divisions, when genome maintenance relies exclusively on maternal factors. High-resolution sequencing studies further demonstrate that maternal aging is associated with increased DNMs burden in both nuclear and mitochondrial DNA. Together, these findings support a model in which maternal aging is a driver of genome-wide instability that links aneuploidy and mutagenesis through shared defects in meiotic surveillance, declining DNA repair efficiency, and mitochondrial function. This framework positions delayed childbearing as a multifaceted genetic risk factor that extend beyond aneuploidy to include mutations and other genomic alterations that can impact intergenerational genetic risk.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910681","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":"Hepatic cytochrome P450 induction following Kashin-Beck disease-related selenium deficiency and T-2 toxin exposure in mice.","authors":"Tong Zhao, Yichen Zhao, Tingting Mao, Weixuan Da, Lina Qin, Li Liu, Huan Liu, Bolun Cheng, Yan Wen, Feng Zhang, Yumeng Jia","doi":"10.1007/s00204-026-04532-7","DOIUrl":"https://doi.org/10.1007/s00204-026-04532-7","url":null,"abstract":"<p><p>Kashin-Beck disease (KBD) is a multifactorial endemic osteoarthropathy that has been associated with nutritional and environmental factors, including selenium deficiency and T-2 toxin exposure. However, whether combined selenium deficiency and T-2 toxin exposure affects hepatic xenobiotic metabolism has not been systematically investigated. Male C57BL/6 mice were fed a selenium-adequate or selenium-deficient diet for 4 weeks, followed by another 4 weeks with or without daily oral T-2 toxin (0.2 mg/kg). Plasma selenium and glutathione peroxidase (GPx) activity were measured. Hepatic histology, activities of major mouse cytochrome P450 (Cyp450) isoforms, and corresponding mRNA and protein expression were assessed. RNA sequencing was performed using liver samples from four biological replicates per group to identify differentially expressed genes (DEGs) and enriched pathways. Selenium deficiency was confirmed by significantly reduced plasma selenium levels and GPx activity. Histological examination revealed marked hepatic steatosis. Transmission electron microscopy further showed prominent ultrastructural alterations including endoplasmic reticulum dilation. The activities of five hepatic Cyp450 isoforms, Cyp1a2, Cyp2b10, Cyp2c29, Cyp2c50, and Cyp3a11, were significantly increased to 1.64-2.51 times the control levels, consistent with increased mRNA and protein expression. Combined selenium deficiency and T-2 toxin exposure was associated with increased hepatic Cyp450 enzyme activity and expression, identifying the liver as a responsive target of KBD-related exposures. These findings suggest the need to further evaluate hepatic xenobiotic metabolism in populations from KBD-endemic areas.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890924","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":"Micro- and nanoplastics-induced neurotoxicity: a CNS-centered, evidence-graded adverse outcome pathway framework based on systematic weight-of-evidence assessment.","authors":"Kexin Zheng, Jun Xie, Yong Hu, Zhen Zhou, Changjian Quan, Hongwei Xie, Hua Zou, Lifang Zhou, Xiangjing Gao","doi":"10.1007/s00204-026-04528-3","DOIUrl":"https://doi.org/10.1007/s00204-026-04528-3","url":null,"abstract":"<p><p>Micro- and nanoplastics (MPs/NPs) are ubiquitous anthropogenic particulate pollutants posing emerging threats to human neurological health. Severe heterogeneity in particle physicochemical properties, environmental aging status, exposure paradigms and experimental platforms has created persistent mechanistic uncertainties in MP/NP neurotoxicology, hindering reliable hazard characterization and risk translation. Here, we systematically consolidate empirical toxicological evidence and construct a dedicated central nervous system (CNS)-targeted adverse outcome pathway (AOP) network integrated with rigorous weight-of-evidence (WoE) grading to elucidate the hierarchical, particle-specific toxic cascades underlying MP/NP-induced neural injury. Our synthesis overturns the conventional linear toxicity paradigm, demonstrating that MPs/NPs trigger neurotoxicity via a complex multi-input mechanistic network. We definitively establish oxidative stress as a robust early convergent key event-rather than a universal molecular initiating event-orchestrating ROS overproduction, lipid peroxidation, mitochondrial dysfunction, and neuroinflammation to propagate neuronal damage. This core module is driven by five distinct particulate upstream triggers: particle-biomolecule interfacial perturbation, corona-facilitated cellular internalization, plastic-associated chemical leaching, aging-derived free radical reactivity, and gut-borne systemic neurotoxic signaling. Downstream pathogenic outcomes encompass glial overactivation, neurotransmitter dyshomeostasis, autophagy-lysosome dysfunction, metabolic reprogramming, regulated neuronal cell death, and behavioral impairments. Tiered WoE analysis confirms strong validation for early oxidative/inflammatory cascades, moderate support for gut-brain axis crosstalk and intracellular trafficking disruption, and nascent evidence for synaptic dysfunction and neurodegeneration-linked proteostatic defects. Extrapolation to human health risk remains constrained by the frequent use of high-dose exposure paradigms, limited validated data on internal dosimetry in the human brain, discrepancies between effective concentrations in experimental models and environmentally relevant human tissue burdens, and insufficient causal validation of distal adverse outcomes. We highlight key research priorities including aged mixed-particle exposure systems, leachate-controlled assays, quantitative internal dose evaluation, and mechanistic intervention verification. This evidence-stratified AOP framework resolves longstanding mechanistic ambiguities in particulate neurotoxicity, providing a standardized, causality-based foundation for future mechanistic exploration and health risk assessment of global plastic pollution.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863400","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":"Diet modulates metabolic and hepatic responses to chronic pesticide mixture exposure in mice.","authors":"C Rives, N Poirier-Jaouen, Y Malaisé, C M P Martin, M Huillet, S Ellero-Simatos, P Perrier, A Polizzi, F Lasserre, V Alquier-Bacquié, C Guyon, Y Lippi, C Naylies, C Comera, H Budzinski, K Le Menach, E L Jamin, N K Dieng, R Vuillaume, C Orlandi, J Gomez, S Costes, A Arrar, A Lucas, S Fried, E Boutet-Robinet, J Guillermet-Guibert, E Kesse-Guyot, H Guillou, N Loiseau, A Fougerat, L Gamet-Payrastre","doi":"10.1007/s00204-026-04533-6","DOIUrl":"https://doi.org/10.1007/s00204-026-04533-6","url":null,"abstract":"<p><p>Chronic exposure to pesticide mixtures through diet is common, yet their combined metabolic effects and interactions with dietary factors remain unclear. We identified four pesticides prevalent in human exposure (imazalil, thiabendazole, boscalid, lambda-cyhalothrin) and assessed their combined impacts on hepatic metabolism and metabolic homeostasis using human liver cells and male mice fed standard chow or western diets. We found that the pesticide mixture induced metabolic perturbations in human hepatocytes. In addition, the pesticide mixture altered hepatic gene expression in chow-fed mice and exacerbated western diet-induced glucose intolerance, fasting hyperglycemia, and insulin resistance without affecting body weight or liver steatosis. These findings reveal that dietary context influences the metabolic consequences of pesticide mixtures, highlighting the need to consider nutritional status when evaluating environmental contaminant risks. Our results suggest that pesticide mixtures at reference doses may contribute to metabolic dysregulation, particularly under obesogenic dietary conditions.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863393","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":"Current status of human biomonitoring of beauvericin and enniatins.","authors":"Gsela H Degen, Anamarija Romac","doi":"10.1007/s00204-026-04527-4","DOIUrl":"https://doi.org/10.1007/s00204-026-04527-4","url":null,"abstract":"<p><p>Beauvericin (BEA) and enniatins (ENNs) are Fusarium mycotoxins found in cereals and cereal-based foods as reported in several studies. But information on human internal exposure remains scattered. Human biomonitoring (HBM) enables the investigation of exposure to these nonregulated contaminants. This review summarizes data from studies published since 2014 on occurrence of BEA and ENNs in human urine, blood, breast milk, tissues and hair. Most studies from Europe, Africa, Asia and North America applied state-of-art methodologies for biomarker analysis. ENN B was the most frequently detected compound and was found in a high proportion of blood samples across different populations. Although BEA was reported less frequently, measurable levels were found in plasma, breast milk, tissues and, more recently, in urine. Both BEA and ENNs were found in human milk, indicating transfer from mother to infant, but generally at low concentrations. Data for human tissues suggest differences in distribution, with BEA occurring mainly in adipose tissue and ENN B reaching the highest concentrations in liver. Some studies reported phase-I metabolites of ENNs in urine, demonstrating that biotransformation contributes to their elimination in humans. Available HBM data indicate widespread dietary exposure to BEA and ENNs in several human populations. Concentrations measured in blood and tissues are much lower than those associated with their cytotoxic effects in vitro. Uncertainties remain regarding human toxicokinetics and the toxicological relevance of their metabolites. Further studies addressing these gaps will improve interpretation of biomonitoring data and support the human health risk assessment of these emerging mycotoxins.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863427","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":"Between evidence and allegation: factual accuracy in discussions on fluoride toxicity and research integrity","authors":"Andrea Buettner,&nbsp;Patrick Diel,&nbsp;Gerhard Eisenbrand,&nbsp;Bernd Epe,&nbsp;Petra Först,&nbsp;Tilman Grune,&nbsp;Sabine Guth,&nbsp;Dirk Haller,&nbsp;Volker Heinz,&nbsp;Michael Hellwig,&nbsp;Hans-Ulrich Humpf,&nbsp;Henry Jäger,&nbsp;Sabine E. Kulling,&nbsp;Alfonso Lampen,&nbsp;Marcel Leist,&nbsp;Angela Mally,&nbsp;Doris Marko,&nbsp;Ute Nöthlings,&nbsp;Elke Röhrdanz,&nbsp;Angelika Roth,&nbsp;Joachim Spranger,&nbsp;Stefan Vieths,&nbsp;Wim Wätjen,&nbsp;Jan G. Hengstler","doi":"10.1007/s00204-026-04531-8","DOIUrl":"10.1007/s00204-026-04531-8","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"100 10","pages":"4801 - 4803"},"PeriodicalIF":10.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-026-04531-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863359","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":"Pregnane X receptor-mediated liver growth: a controlled clinical trial in healthy volunteers and identification of the role of AKT-MTOR pathway in mouse.","authors":"Piia Lassila, Mikko Karpale, Outi Kummu, Aaron Stahl, Aki Käräjämäki, Eija Pääkkö, Helen Sophie Hammer, Albert Braeuning, Oliver Pötz, Markus Templin, Janne Hukkanen, Jukka Hakkola","doi":"10.1007/s00204-026-04526-5","DOIUrl":"https://doi.org/10.1007/s00204-026-04526-5","url":null,"abstract":"<p><p>Pregnane X receptor (PXR) is a nuclear receptor acting as a master xenobiotic receptor for many exogenous chemicals. Activation of PXR has been linked to liver growth in mice, usually via interaction with Yes-associated protein (YAP), but this adaptive response has not been observed in humans. We investigated the effect of human PXR agonist, rifampicin, on liver size in a controlled clinical trial in healthy volunteers. Moreover, we developed a novel protocol to reveal mechanisms of PXR-mediated liver growth in mice. One-week rifampicin treatment caused a 2.7% mean increase in liver volume-to-body weight ratio without affecting liver fat content in human volunteers (n=16). Pxr^-/- mice were transduced with adenovirus carrying either murine PXR or green fluorescent protein and both groups were treated with pregnenolone-16α-carbonitrile (PCN) for 0 to 4 days. In this setup, activation of PXR with PCN significantly increased liver size in male mice already after 1-day PCN treatment and the liver growth was further enhanced after 4 days. No significant liver enlargement was observed in female mice. 4-day PCN treatment also improved glucose tolerance in the male mice. RNA-sequencing revealed upregulation of genes and pathways involved in proliferation. DigiWest protein profiling and immunoblotting revealed increased activity of AKT-mammalian target of rapamycin (MTOR) pathway in the male mice. In contrast, we did not observe YAP activation. Our results indicate that PXR activation induces liver growth and activates proliferative AKT-MTOR pathway in male mice and may also induce liver growth in humans.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824387","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}