Toxicological Sciences最新文献

{"title":"Lipid nanoparticle-formulated synthetic messenger RNA induces reversible hematopoietic bias via type I interferon responses under upper-bound inflammatory conditions in preclinical animal models.","authors":"Jae-Hun Ahn, Na-Young Lee, Hee-Jin Bae, Jooil Kim, Jina Kwak, Gahyun Roh, Seo-Hyeon Bae, Jisun Lee, Jae-Hwan Nam, Ji-Eun Kim, Byeong-Cheol Kang","doi":"10.1093/toxsci/kfag134","DOIUrl":"10.1093/toxsci/kfag134","url":null,"abstract":"<p><p>Synthetic messenger RNA (mRNA) formulated in lipid nanoparticles (LNPs) is increasingly used for vaccines and therapeutics, yet the consequences of high-dose systemic exposure for bone marrow hematopoiesis remain poorly defined. We previously reported that intramuscular mRNA/LNP administration transiently alters circulating reticulocytes and bone marrow erythroid cellularity in mice; here, we investigated the mechanistic basis and cross-species generalizability of this hematopoietic bias in murine and non-human primate models. Animals received intramuscular LNP-formulated mRNA encoding SARS-CoV-2 spike protein or firefly luciferase at deliberately supra-clinical, upper-bound doses, and type I interferon signaling was interrogated by interferon-α/β receptor blockade. Bone marrow was assessed by histopathology, bulk and single-cell RNA sequencing, and trajectory analysis. LNP-formulated mRNA induced reversible erythroid-lineage suppression with concomitant granulocytic expansion, irrespective of the encoded antigen. These effects were absent after naked mRNA and only modestly induced by LNP alone, indicating that formulation of synthetic mRNA within the LNP was required to elicit the full phenotype. Single-cell analysis showed biased hematopoietic stem and progenitor cell differentiation toward granulopoiesis with broad induction of interferon-stimulated genes, and the bias resolved within 2 wk. Interferon-α/β receptor blockade mitigated both changes, demonstrating type I interferon dependence. High-dose LNP-formulated synthetic mRNA can therefore drive reversible, type I interferon-dependent hematopoietic lineage bias in preclinical animal models. This study identifies type I interferon signaling as the driver of a reversible, dose-dependent shift in bone marrow hematopoiesis under upper-bound exposure to LNP-formulated synthetic mRNA, informing preclinical safety evaluation of the rapidly expanding class of nucleic acid-based therapeutics.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-gestational binge ethanol exposure induces persistent motor dysfunction associated with cerebellar redox and cytokine dysregulation in rat offspring.","authors":"Paulo Fernando Santos Mendes, Daiane Claydes Baia-da-Silva, Vinicius Ruan Neves Dos Santos, Leonardo de Oliveira Bittencout, Lucas Villar Pedrosa da Silva Pantoja, Luanna de Melo Pereira Fernandes, Rommel Mario Rodríguez Burbano, Cristiane do Socorro Ferraz Maia, Rafael Rodrigues Lima","doi":"10.1093/toxsci/kfag123","DOIUrl":"10.1093/toxsci/kfag123","url":null,"abstract":"<p><p>Ethanol (EtOH) exposure frequently occurs before pregnancy recognition, making early embryonic development particularly vulnerable to inadvertent alcohol exposure. This study evaluated the effects of binge-like EtOH exposure during early gestation on neurobehavioral, oxidative, and inflammatory outcomes in male and female rat offspring. Pregnant rats received EtOH (3 g/kg/day, intragastric gavage) on gestational days 6 to 8, whereas control animals received distilled water. Offspring were evaluated at postnatal day 23 (PN23) and postnatal day 42 (PN42) using the pole, open field, and rotarod tests. The cerebellum was collected for analysis of oxidative stress markers and cytokines. Data were analyzed by two-way ANOVA followed by Tukey's post hoc test (P < 0.05). EtOH exposure induced locomotor alterations at both PN23 and PN42, mainly characterized by reduced total distance traveled, accompanied by impaired balance and forced locomotion. In the cerebellum, both ages exhibited reduced glutathione levels and total antioxidant capacity, together with increased lipid peroxidation. Cytokine alterations displayed a temporal pattern, with reduced IL-1β and TNF-α levels at PN23 and increased levels at PN42, whereas IL-6 and IL-10 remained elevated at both time points. Females exhibited more pronounced impairments in spontaneous locomotion, particularly at PN42. These findings demonstrate that brief binge-like EtOH exposure during early gestation is sufficient to induce persistent motor dysfunction accompanied by cerebellar redox imbalance and cytokine dysregulation, with evidence of sex-dependent behavioral susceptibility.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial proteotoxic stress drives inhaled benzene-induced vascular inflammation in mice.","authors":"Samantha A McFall, Marina V Malovichko, Nalinie S Wickramasinghe, Breandon S Taylor, Mohammad T Malik, Daniel J Conklin, Igor N Zelko, Sanjay Srivastava","doi":"10.1093/toxsci/kfag129","DOIUrl":"10.1093/toxsci/kfag129","url":null,"abstract":"<p><p>Benzene exposure is associated with increased cardiovascular disease (CVD) risk, yet the mechanisms linking benzene to vascular injury remain incompletely understood. Here, we investigated the effects of benzene and its reactive metabolite, trans, trans-muconaldehyde (MA), on endothelial activation and leukocyte recruitment, which are early events in atherogenesis. Wild-type and endothelial-specific heat shock protein A1B overexpressing mice were exposed to inhaled benzene (1 ppm), and leukocyte dynamics were assessed by intravital microscopy. Complementary studies in vitro examined MA-induced endothelial activation via leukocyte adhesion assays, RNA sequencing, pharmacological interventions, and small interfering RNA-mediated gene silencing. Benzene inhalation increased leukocyte rolling (16- to 21-fold) and adhesion (11- to 44-fold) in vivo with female mice exhibiting greater responses than males. In vitro, MA enhanced monocyte adhesion (1.7-fold) and transmigration (1.4-fold) and induced a conserved transcriptional program characterized by activation of oxidative stress, unfolded protein response, MAPK signaling, and heat shock pathways. MA stimulated phosphorylation of p38, JNK, and eIF2α, increased XBP1 splicing, elevated reactive oxygen species generation, and depleted glutathione. Alleviation of endoplasmic reticulum stress with 4-phenylbutyric acid attenuated MA-induced expression of HSPA1B, ATF3, and ICAM1. Conversely, HSPA1B silencing exacerbated endothelial activation and stress signaling, whereas endothelial-specific overexpression of HSPA1B significantly reduced benzene-induced leukocyte recruitment in vivo. Collectively, these findings identify proteotoxic stress as a central mechanism of benzene-induced vascular toxicity. Further, we demonstrate that activation of the heat shock pathway (HSF1-HSPA1B) serves as a protective response that limits endothelial inflammation. These results provide new mechanistic insight into how environmental benzene exposure may promote vascular injury and CVD in humans.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal gestational and lactational exposure to polystyrene nanoplastics triggers vascular injury and lipid deposition in mouse offspring.","authors":"Tan Ma, Yue Zhou, Chenghao Shen, Ruiping Hu, Haibo Jin, Hongliang Li, Jingyan Liang","doi":"10.1093/toxsci/kfag133","DOIUrl":"10.1093/toxsci/kfag133","url":null,"abstract":"<p><p>As pervasive environmental contaminants, nanoplastics (NPs) have garnered increasing concern due to their potential health hazards. However, the impact of gestational and lactational exposure to NPs on offspring vascular structural injury remains unexplored. In this study, we used BALB/c mice to model gestational and lactational exposure to 100 nm polystyrene nanoplastics (PS-NPs) at doses of 0.1, 1, and 10 mg/l. Our findings revealed that PS-NPs exposure significantly reduced offspring body weight in both sexes. Histopathological analysis demonstrated that exposure induced multiorgan damage in offspring at postnatal day 21 (PND 21), with partial recovery by PND 90. Critically, PS-NPs exposure induced cardiovascular toxicity in offspring, which included acute vascular injuries (disordered elastic fibers and evident calcium salt deposition) at PND 21 that were largely resolved by PND 90, alongside more persistent issues of abnormal lipid deposition in the aortic root and dyslipidemia observed at both time points. Integrated biomarker response indices, principal component analysis, and hierarchical clustering confirmed dose-dependent toxicity in PS-NPs-exposed offspring. In vitro studies further showed that PS-NPs induced lipid accumulation in 3 major cardiovascular cell types: endothelial cells, smooth muscle cells, and macrophages. Our study firstly reveals that maternal PS-NPs exposure throughout gestation and lactation induces vascular injury and lipid deposition in mouse offspring, indicating that PS-NP pollution represents a critical environmental risk factor for offspring cardiovascular adverse outcomes later in life.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing genotoxicity assessment with transcriptomic biomarkers: from 2D to 3D HepaRG spheroid models.","authors":"Mariam Saleh, Kevin Hogeveen, Anouck Thienpont, Emmanuel Demuynck, Valérie Fessard, Birgit Mertens, Ludovic Le Hégarat","doi":"10.1093/toxsci/kfag095","DOIUrl":"10.1093/toxsci/kfag095","url":null,"abstract":"<p><p>The development of New Approach Methodologies (NAMs) for genotoxicity testing is needed to support the transition toward animal-free human-relevant chemical genotoxicity assessment. In this context, we investigated the predictive power of two transcriptomic biomarkers developed in 2D cell systems (GENOMARK and TGx-DDI) in metabolically active 3D HepaRG spheroids to classify chemicals as genotoxic (GTx) or non-genotoxic (NGTx). Human-hepatic HepaRG spheroids were treated for 72 h with three different groups of chemicals: (i) five genotoxic chemicals: Lasiocarpine, cyclophosphamide, ethyl methanesulfonate, aflatoxin B1, benzo[a]pyrene; (ii) five non-genotoxic non-carcinogens: Aflatoxin B2, 2-deoxy-D-glucose, D-mannitol, caffeine, ampicillin trihydrate; and (iii) five non-genotoxic carcinogens: Perfluorooctanoic acid, diethanolamine, thioacetamide, phorbol-12-myristate-13-acetate, di(2-ethylhexyl) phthalate. Gene expression data from the treated HepaRG spheroids were collected using the high-throughput TempO-Seq technology and analyzed with the transcriptomic biomarkers GENOMARK and TGx-DDI. Results with both biomarkers generally aligned with existing knowledge for all three groups of tested chemicals, effectively distinguishing genotoxic from non-genotoxic chemicals. The results of this study indicate that combining the 3D HepaRG spheroid model with transcriptomic biomarkers offers a promising, human-relevant approach to complement traditional in vitro genotoxicity tests.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Friend and foe?: metals as facilitators and disruptors of steroid nuclear receptor signaling.","authors":"Kyle R Siegel, Christopher D Kassotis","doi":"10.1093/toxsci/kfag106","DOIUrl":"10.1093/toxsci/kfag106","url":null,"abstract":"<p><p>Steroid hormone signaling, transduced by nuclear receptors (NRs), is essential for mammalian physiology. Like other transcription factors, NRs are structurally and functionally influenced by essential and nonessential metal ions. Here, we provide a scoping review of the role metal ions play in NR signal transduction, focusing on class I steroid hormone receptors (androgen, estrogen, glucocorticoid, mineralocorticoid, and progesterone). Biochemical assessments, prior to and concomitant with the advent of NR cloning, suggest metal-mediated modification of NR ligand-binding domains, cytosolic chaperone complexes, and zinc-finger DNA-binding domains as crucial mechanisms of metal-by-NR interactions. Subsequent molecular studies indicate that metals differentially affect NRs, largely driven by a metals' valence state (divalent, trivalent, etc). Some toxic metals can directly activate NRs. Despite six decades of work, crucial gaps in our knowledge of metal-by-NR effects remain, including in vitro to in vivo extrapolations, incorporation of mixture effects, and further delineation of direct and indirect receptor activation. This review concatenates how trace elements affect steroid hormone NR activity and identifies future areas of research that could mitigate metal-induced endocrine disruption.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world river water organic pollutant mixture induces ovarian hyperandrogenism via aryl hydrocarbon receptor activation.","authors":"Samantha L Cheron, Kunlin Ou, Tingjie Zhan, Jiyang Zhang, Congcong Zhang, Hilly Yang, Shichao Liu, Qiang Zhang, Daniel R Millemann, Josephine A Bonventre, Brian Buckley, Shuo Xiao","doi":"10.1093/toxsci/kfag135","DOIUrl":"10.1093/toxsci/kfag135","url":null,"abstract":"<p><p>Humans are exposed to complex mixtures of endocrine-disrupting chemicals (EDCs) in the real world. Most prior studies, however, focus on individual EDCs. Here, we investigated the ovarian impact of organic pollutant mixtures extracted from the Raritan River, a heavily industrialized watershed in central New Jersey, using a three-dimensional (3D) in vitro ovarian follicle culture system. Ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) identified organic pollutant mixtures dominated by alkylphenols, pharmaceuticals, per- and polyfluoroalkyl substances (PFAS), and phthalates, together with previous reports demonstrating that the Raritan River also contains hydrophobic persistent organic pollutants (POPs), including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and dioxins. In vitro exposure to the Raritan River-derived EDC mixture did not affect follicle growth and ovulation but dose-dependently increased preovulatory testosterone (T) secretion while suppressing postovulatory progesterone (P4) production. Transcriptomic analysis, gene set enrichment analysis (GSEA), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and in situ RNA hybridization revealed widespread reprogramming of follicular somatic cell gene expression, including altered steroidogenic pathways and activation of aryl hydrocarbon receptor (AhR) signaling. An established AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), reproduced the phenotype of EDC mixture-induced hyperandrogenism, which was reversed by a selective AhR inhibitor. Together, this study demonstrates that real-world EDC mixtures, particularly AhR-activating chemicals, disrupt ovarian steroidogenesis and induce hyperandrogenism, highlighting EDC mixtures as an underrecognized mechanism potentially linking aquatic pollution to impaired women's reproductive health.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nonclinical safety assessment of SBT777101, a CAR-engineered regulatory T cell therapy for autoimmune diseases.","authors":"Herve Lebrec, Jonathan M Clingan, Anne-Renee van der Vuurst de Vries, Lauren Mihalcik, Yuchi Honaker, Sara Charmsaz, Seonhwa Dura, Kathryn A Hooper, Yuanyuan Xiao, Michelle Blake, Max Fiebiger, Radha Dhayal, Christine Saechao, Alexandre Iannello, Fred Ramsdell, Jeffrey A Bluestone, Josh Beilke","doi":"10.1093/toxsci/kfag125","DOIUrl":"10.1093/toxsci/kfag125","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-regulatory T cell (Treg) therapies represent a promising approach for autoimmune diseases, but their nonclinical safety assessment remains challenging due to antigen-, disease-, and species-specific pharmacology that limits the relevance of conventional animal models. SBT777101, a CAR-Treg therapy targeting citrullinated proteins associated with rheumatoid arthritis and hidradenitis suppurativa, was evaluated using a nonclinical strategy centered on in vitro and ex vivo New Approach Methodologies (NAMs) and in vivo studies benchmarked against untransduced polyclonal Tregs, which are manufactured identically but lack the CAR and have an established clinical safety record, complemented by immunodeficient mouse studies. We hypothesized that CAR engineering would not destabilize the Treg phenotype or introduce new toxicological liabilities relative to polyclonal Tregs. SBT777101 maintained phenotypic stability under repeated stimulation and proinflammatory conditions, produced minimal proinflammatory cytokines following activation, and demonstrated immunomodulatory activity comparable to untransduced Tregs. Tissue cross-reactivity and primary cell studies identified limited membrane-associated binding, no evidence of CAR-mediated cytotoxicity or activation in normal human tissues, and no off-target binding by broad protein array screening. Immunosuppressive activity toward natural killer and CD8+ T cell responses was limited and comparable to polyclonal Tregs. Lentiviral integration site analyses demonstrated polyclonal integration profiles without evidence of transformation or abnormal growth in a cytokine- and activation-independent growth assay. This study establishes a combined in vivo and NAM-based nonclinical safety framework for CAR-Treg therapies and demonstrates that CAR engineering of SBT777101 does not introduce new safety liabilities relative to unmodified polyclonal Tregs. These findings supported progression of SBT777101 into Phase 1 clinical trials and offer a generalizable approach for evaluating the safety of future CAR-Treg therapeutics.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baseline Environmental Contamination Data and Model-based Screening of Children's Exposure-Risk Estimates from Metal(loid)-laden Vegetables and Soils.","authors":"Brian Turyahabwe, Godswill J Udom, Modinat A Adefisayo, Muyiwa M Orosun, Emmanuel O Ademilusi, Rashid Iqbal, Kamola Zaynalova, Nafisakhon Mamatova, Ibrahim Mahariq, Aseel Smerat","doi":"10.1093/toxsci/kfag132","DOIUrl":"https://doi.org/10.1093/toxsci/kfag132","url":null,"abstract":"<p><p>Potentially toxic metal(loid) contamination of agricultural environments may pose serious public health concerns, particularly for children. This study assessed contamination of agricultural soils, irrigation water, and commonly consumed vegetables in Kasese District, Uganda, an area influenced by mining and industrial activities. Agricultural soils (n = 9 composite samples), point-source irrigation water (n = 1), and vegetables (onion, cabbage, and amaranth; n = 36 composite samples) were analysed for 14 potentially toxic elements (PTEs) using Inductively Coupled Plasma Optical Emission Spectroscopy. Age-specific health risks for children were evaluated using the Agency for Toxic Substances and Disease Registry's Public Health Assessment Site Tool and complemented with Monte Carlo simulation (10,000 iterations) to account for exposure variability and uncertainty. Mean concentrations of arsenic (1.780-3.569 mg/kg), lead (2.017-9.670 mg/kg), mercury (0.025-0.700 mg/kg), nickel (0.523-3.655 mg/kg), and chromium (0.043-2.043 mg/kg) frequently exceeded recommended limits. Hazard index values were greater than one, indicating significant non-carcinogenic health risks. Deterministic cancer risk (6.4 × 10⁻⁴-2.1 × 10⁻³) and probabilistic estimates (5.79 × 10⁻⁴-3.86 × 10⁻³) exceeded acceptable priority screening thresholds (10⁻⁶-10⁻⁴), with arsenic and nickel as dominant contributors to probabilistic cancer-risk variability. However, the study is based on a single sampling campaign, and the exposure model relies partly on default parameters; therefore, the risk estimates should be interpreted as screening-level estimates rather than population-level incidence predictions. The findings support expanded spatial and seasonal monitoring, improved characterisation of dietary exposure and contaminant speciation, and targeted food-safety and agricultural risk-management interventions in the Mubuku irrigation scheme.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of Vacuole Membrane Protein 1 protects against acetaminophen-induced liver injury by modulating inflammation and hepatocyte proliferation.","authors":"Khue Nguyen, Mengwei Niu, Hong-Min Ni","doi":"10.1093/toxsci/kfag112","DOIUrl":"10.1093/toxsci/kfag112","url":null,"abstract":"<p><p>Acetaminophen (APAP) overdose is a leading cause of severe liver injury and acute liver failure (ALF). Increased hepatic macrophages promote inflammation and clear necrotic cell debris, thereby promoting a regenerative state for liver repair during APAP-induced liver injury. Vacuole membrane protein 1 (VMP1) is an ER transmembrane protein essential for autophagy. Deletion of VMP1 in the liver impairs autophagy. The role of VMP1 in APAP-induced liver injury is unknown. In this study, the human APAP ALF RNA sequencing database was analyzed. Liver-specific Vmp1 knockout (Vmp1LKO) and matched wild-type (Vmp1LWT) mice were administered 500 mg/kg APAP. Liver injury, necrosis, and other biochemical analyses were assessed. Increased mRNA levels of VMP1 and autophagy-related genes were found in human APAP ALF livers. Serum ALT and hepatic necrosis were increased in WT mice following APAP treatment. LC3B-II and p62 were increased, but VMP1 protein decreased in WT mouse livers following APAP treatment. Liver injury was markedly decreased in Vmp1LKO mice compared with their WT littermates. Basal hepatic CYP2E1 and glutathione (GSH) levels were similar between genotypes, but increased lipid-laden macrophages (foam cells) were present in Vmp1LKO livers. Interestingly, APAP protein adduct formation decreased in Vmp1LKO mouse livers, but mitochondrial damage was similar in both phenotypes. Peroxynitrite formation was observed in APAP-treated Vmp1LWT hepatocytes but was limited in foam cells of Vmp1LKO mouse livers. Furthermore, GSH replenishment and liver regeneration were enhanced in Vmp1LKO mouse livers. In conclusion, loss of hepatic VMP1 protects against APAP-induced liver injury by replenishing GSH, modulating inflammation, and enhancing liver regeneration.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13614422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148913399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}