Frontiers in toxicology最新文献

{"title":"Combined predictive value of dose, MODS, and NLR for lethal risk of diquat poisoning: a retrospective cohort study.","authors":"Jifeng Dai, Meiyi He, Shi Chen, Yunchao Chen, Xin Li, Huaiman Ou, Yufan Deng, Caiying Zhong, Wenfeng Zeng, Yuquan Chen, Yanmei Ruan, Zhi Wang, Zejin Ou","doi":"10.3389/ftox.2026.1897012","DOIUrl":"https://doi.org/10.3389/ftox.2026.1897012","url":null,"abstract":"<p><strong>Objective: </strong>Accurate risk assessment for fatal diquat poisoning is critical to improving clinical outcomes. Therefore, this study aimed to evaluate the combined value of the multiple organ dysfunction syndrome (MODS) and neutrophil-to-lymphocyte ratio (NLR) in predicting in-hospital all-cause mortality from acute diquat poisoning.</p><p><strong>Methods: </strong>This work retrospectively enrolled diquat self-poisoning patients in Guangzhou 12th People's Hospital between 2017 and 2023. Demographic, exposure, and 24-h laboratory data were extracted. A time-dependent Cox model evaluated MODS as a time-varying predictor. LASSO and logistic regression identified independent predictors and established the prediction equation; restricted cubic splines assessed dose-response. Bootstrap internal validation evaluated discrimination and calibration; however, variable selection was not repeated within each resample, and therefore the optimism-corrected performance metrics should be interpreted with caution. SHAP quantified feature contributions.</p><p><strong>Results: </strong>NLR was significantly elevated in non-survivors compared to survivors (median 31.37 vs. 11.19, <i>P</i> < 0.001). In the time-dependent Cox analysis, MODS remained independently associated with mortality (hazard ratio [HR] = 35.24, 95% CI: 13.57-91.50, <i>P</i> < 0.001). In the exploratory logistic regression, MODS (adjusted odds ratio [aOR] = 34.63, 95% CI: 7.47-245.65, P < 0.001), diquat dose (aOR = 1.34 per 10 mL, 95% CI: 1.22-1.63, <i>P</i> < 0.001), and NLR (aOR = 1.07, 95% CI: 1.02-1.13, <i>P</i> = 0.01) were independently associated with in-hospital all-cause mortality. The combined model achieved an AUC of 0.976 (Bootstrap 95% CI: 0.951-0.998), with an optimism-corrected AUC of 0.970, an apparent calibration intercept of 0, an apparent calibration slope of 1, and a Brier score of 0.0553 (95% CI: 0.0140-0.0775). SHAP values ranked feature importance as diquat dose (0.179) > MODS (0.145) > NLR (0.069). Sensitivity analyses confirmed the robustness of these findings.</p><p><strong>Conclusion: </strong>MODS and NLR were independently associated with in-hospital all-cause mortality in acute diquat poisoning. When applied after the first 24-72 h of admission, the combined model shows promise as a potential exploratory tool for risk stratification; however, external validation in larger multicenter cohorts is required before any consideration of bedside application.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1897012"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149229506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polystyrene nanoplastics impair mitochondrial function, quality control, and ER-mitochondria crosstalk in HeLa cells.","authors":"Giuseppe Petito, Maria Teresa Gentile, Arianna Cuomo, Angelo Fusco, Sara Falvo, Maria Della Valle, Gianluca D'Abrosca, Carla Isernia, Roberto Fattorusso, Maria Emanuela Errico, Antonia Lanni, Gaetano Malgieri, Rosalba Senese","doi":"10.3389/ftox.2026.1907794","DOIUrl":"https://doi.org/10.3389/ftox.2026.1907794","url":null,"abstract":"<p><strong>Introduction: </strong>Polystyrene nanoplastics (PS-NPs) represent persistent environmental contaminants derived from the degradation of plastic debris and are increasingly detected in biological systems, raising concerns regarding their potential effects on human health. Emerging evidence suggests that, following cellular internalization, PS-NPs can induce intracellular stress responses and interfere with mitochondrial homeostasis, highlighting mitochondria as key targets of nanoplastic-induced cellular dysfunction. This study aimed to investigate the effects of PS-NPs on mitochondrial function in HeLa cells. Particular attention was devoted to Mitochondrial Quality Control (MQC) pathways, including the mitochondrial Unfolded Protein Response (UPR^mt), a stress-adaptive mechanism that remains poorly characterized in response to nanoplastic exposure in human cellular model. In addition, the study examined the functional crosstalk between the Endoplasmic Reticulum and mitochondria.</p><p><strong>Methods: </strong>HeLa cells were exposed to PS-NPs, and mitochondrial bioenergetics, oxidative stress, mitochondrial membrane potential, cellular ATP levels, extracellular lactate levels, and calcium homeostasis were assessed using functional assays. MQC-related pathways, including UPR^mt, mitochondrial biogenesis, dynamics, autophagy/mitophagy, and ER stress responses, were evaluated through biochemical, molecular, and imaging approaches.</p><p><strong>Results: </strong>Our results demonstrate that PS-NP exposure induces mitochondrial dysfunction, characterized by impaired mitochondrial coupling, mitochondrial membrane depolarization, increased H₂O₂ levels in cell lysates, and altered cellular redox homeostasis. Moreover, PS-NPs disrupt MQC processes, leading to an imbalance in the mechanisms that maintain mitochondrial homeostasis, including modulation of UPR^mt-associated proteins and dysregulation of ER-mitochondria communication via Mitochondria-Associated Membranes (MAMs).</p><p><strong>Conclusion: </strong>Collectively, these data advance our understanding of PS-NP toxicity by identifying alterations in MQC systems and ER-mitochondria crosstalk as key events in nanoplastic-induced cellular stress. These findings provide novel mechanistic insights into nanoplastic toxicity and highlight the potential impact of environmental PS-NP exposure on cellular homeostasis and human health.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1907794"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13677859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Xeno-free production of lentiviral particles: implementing hPL as FBS replacement in cell culture.","authors":"Mariana Soares Guedes, Marnie Cole, Daniela Yildiz","doi":"10.3389/ftox.2026.1903400","DOIUrl":"10.3389/ftox.2026.1903400","url":null,"abstract":"<p><p>Commonly used for delivering fluorescent or bioluminescent reporters to target genes, lentiviral vectors are an \"easy-to-clone\" vehicle to study up- and downregulation of gene expression induced by drug inhibitors, cytokine stimulants, chemicals, and environmental toxicants. To produce viral particles safely, several plasmid constructs are delivered to human embryonic kidney cells (HEK293-T), which use the cellular machinery to package and assemble non-replicative lentiviruses with high efficiency. However, the cell culture of HEK293-T cells still largely relies on the use of fetal bovine serum for cell survival and proliferation. At large scale, this cell culture practice consumes a great amount of animal-derived serum, driving the need for continuous farming of animals whose fetuses would be used to obtain serum, posing grave ethical and practical concerns for human-relevant research. In this study, we present a feasible and scalable method to adapt the culture medium formulation for HEK293-T cells and demonstrate how virus production responds to this cell culture adaptation. Using a commercially available platelet-based supplement derived from human blood byproducts, we maintain cell viability and proliferation rates, with up to 82% confluence, and can produce lentiviruses (approximately 10⁶ infectious units/mL with up to 20% infectivity), while sparing the killing of bovine fetuses for serum collection, in a cost-efficient and humanized manner. Envisioning adoption in the pharma industry and large-scale virus production facilities, this simple yet robust cell medium formulation presents itself as an ethical and practical avenue to advance scientific innovation and bring one more layer of human relevance to biomedical research.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1903400"},"PeriodicalIF":5.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping DEHP-induced metabolic dysregulation through multi-omics and systems biology: an adverse outcome pathway network approach.","authors":"Elisavet Renieri, Achilleas Karakoltzidis, Nafsika Papaioannou, Dayna R Schultz, Thanasis Papageorgiou, Catherine Gabriel, Ilias S Frydas, Kévin Bernal, Xavier Coumoul, Etienne B Blanc, Normand Podechard, Hélène Le Mentec, Charbel Touma, Sophie Langouët, Talía Boronat-Belda, Hilda Ferrero, Paloma Alonso-Magdalena, Karine Audouze, Spyros Karakitsios, Dimosthenis A Sarigiannis","doi":"10.3389/ftox.2026.1930835","DOIUrl":"https://doi.org/10.3389/ftox.2026.1930835","url":null,"abstract":"<p><p>Di(2-ethylhexyl) phthalate (DEHP) is a widespread endocrine-disrupting plasticizer associated with metabolic disorders. To elucidate their mechanistic basis, we developed an Adverse Outcome Pathway Network (AOPN) informed by DEHP-induced perturbations, by integrating multi-omics data, systems biology modeling, and targeted literature evidence. Multi-omics data were generated in 3D human hepatic cells, pancreatic β-cells, and zebrafish larvae exposed to DEHP across biologically relevant concentration ranges. Transcriptomic and metabolomic analyses revealed perturbations in lipid metabolism, mitochondrial function and oxidative stress pathways, including altered sphingolipid signaling and dysregulation of sphingosine-1-phosphate (S1P). Systems biology modeling contextualized these perturbations within metabolic pathways and generated dose-dependent predictions for key intermediates, highlighting potential reinforcing feedback mechanisms such as ATP-ROS interactions that may further destabilize metabolic homeostasis. Integrating experimental and literature evidence identified key event relationships proposed to link early molecular perturbations to downstream adverse metabolic outcomes, including hepatic steatosis, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and obesity. Central mechanistic features of the network converge on lipid remodeling, mitochondrial dysfunction, oxidative stress, serine/S1P pathway disruption, and impaired insulin signaling. Because the individual omics contrasts are based on three replicates per condition, statistical support in this work is evaluated at pathway rather than single-feature level: under Benjamini-Hochberg control almost no individual transcript is significant, whereas the pathways carrying the mitochondrial and lipid-handling key events remain significant in competitive gene-set tests. Cross-system comparison showed that suppression of oxidative-energy metabolism is the only module conserved across all three systems, whereas PPAR signalling and fatty-acid handling are liver-specific and non-monotonic. Together, these data support a coherent, evidence-integrating mechanistic hypothesis linking early molecular events to adverse metabolic outcomes across multiple levels of biological organization, rather than a quantitatively validated causal pathway. To our knowledge, this study provides a novel integrative AOPN framework combining multi-omics data across liver and pancreatic models and reveals previously underappreciated metabolic cross-talk, including involvement of serine and S1P pathways. The proposed framework is explicitly hypothesis-generating and evidence-integrating: it provides a transparent, FDR-audited basis for future quantitative AOP development and supports mechanistically informed chemical risk assessment by identifying early key events, potential biomarkers, and intervention points relevant to human metabolic health.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1930835"},"PeriodicalIF":5.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic evidence and multi-omics characterization of DEHP-relevant detoxification and metabolic heterogeneity in hepatocellular carcinoma.","authors":"Zeyang Fan, Guoqing Zhang, Letian Ren, Wence Zhou","doi":"10.3389/ftox.2026.1925431","DOIUrl":"https://doi.org/10.3389/ftox.2026.1925431","url":null,"abstract":"<p><strong>Background: </strong>Human evidence linking di(2-ethylhexyl) phthalate (DEHP) exposure to hepatocellular carcinoma (HCC) is limited, and it remains unclear whether DEHP-relevant detoxification biology captures clinically meaningful HCC heterogeneity.</p><p><strong>Methods: </strong>We integrated two-sample Mendelian randomization, proteomic and phosphoproteomic subtyping, bulk, single-cell and spatial transcriptomics, computational candidate prioritization, molecular docking, and cell-based assays. Genetically proxied MECPP and MEHHP were evaluated for associations with HCC and liver-related outcomes. DPTS-related molecular, cellular, spatial, and experimental patterns were then characterized.</p><p><strong>Results: </strong>MR did not support a causal association of genetically proxied MECPP or MEHHP with HCC. In 165 CPTAC tumors, consensus clustering identified two detoxification-phosphorylation tumor subtypes. Compared with DPTS1, DPTS2 showed coordinated suppression of xenobiotic metabolism, bile acid metabolism, fatty-acid oxidation, phase II conjugation, and transport programs. A transcriptomically projected DPTS2-like state was associated with poorer overall survival in TCGA-LIHC, but this association was not replicated in ICGC-LIRI-JP. Single-cell and spatial analyses localized these programs mainly to hepatocyte-like compartments and showed modest spatial coordination with nine prioritized genes, including ALDH2, EHHADH, and PCK2. LINCS-based screening and molecular docking prioritized PD-0325901, trametinib, and regorafenib, but these predictions did not demonstrate binding or efficacy, and the compounds were not tested experimentally. Basal qPCR and DEHP-treatment experiments showed cell-line-specific expression and phenotypic responses.</p><p><strong>Conclusion: </strong>DPTS defines a DEHP-relevant, detoxification-suppressed HCC molecular phenotype rather than an exposure-defined or DEHP-induced subtype. These findings provide a bounded framework for future mechanistic validation of metabolic vulnerability in HCC.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1925431"},"PeriodicalIF":5.1,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytocannabinoid-drug interactions: pharmacokinetic and pharmacodynamic mechanisms, clinical relevance and toxicological considerations.","authors":"Diogo Alexandre Gomes, Wellyngton Vieira Eufrázio, Marcella Silva Ribeiro, Linério Ribeiro de Novais Júnior, Flávia Rigo, Patrícia de Aguiar Amaral, Antonella Campanale, Antônio Inserra, Rafael Mariano de Bitencourt","doi":"10.3389/ftox.2026.1952599","DOIUrl":"https://doi.org/10.3389/ftox.2026.1952599","url":null,"abstract":"<p><p>The therapeutic use of phytocannabinoids has expanded considerably over the past decade because of their potential application across a wide range of clinical conditions. However, their concomitant use with conventional medications raises important concerns regarding drug interactions and patient safety. This narrative review provides a critical overview of current evidence on the pharmacokinetic (PK), pharmacodynamic, and toxicological interactions of major phytocannabinoids, with particular emphasis on cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), while also discussing emerging evidence related to minor phytocannabinoids and the potential contribution of terpenes. Phytocannabinoids modulate the activity of drug-metabolizing enzymes, particularly cytochrome P450 isoenzymes, and may affect selected drug transporters, thereby altering the systemic exposure and clinical effects of co-administered medications. Conversely, conventional medications that inhibit or induce cannabinoid-metabolizing enzymes may modify phytocannabinoid exposure, efficacy, and tolerability. Documented or potentially clinically relevant interactions have been reported for antiseizure medications, anticoagulants, antidepressants, opioids, alcohol, and other central nervous system depressants. However, the strength of the supporting evidence varies considerably, ranging from <i>in vitro</i> predictions and case reports to controlled PK and clinical studies. The magnitude and clinical relevance of these interactions are influenced by multiple factors, including cannabinoids formulation, dose, route of administration, treatment duration, pharmacogenetic variability, patient-specific characteristics, and polypharmacy. Particular attention should be given to vulnerable populations, such as pregnant women, children, older adults, and patients with hepatic impairment, in whom altered PK and increased susceptibility to adverse effects may further complicate treatment. Although substantial progress has been made in understanding cannabinoid pharmacology, important knowledge gaps remain regarding the clinical significance of many predicted interactions, the interaction profiles of minor phytocannabinoids, full-spectrum preparations, and terpenes and the long-term safety of cannabinoid-based therapies. Careful differentiation between mechanistically plausible and clinically demonstrated interactions, together with consideration of cannabinoid composition, dose, route of administration, patient vulnerability, and concomitant medications, can support safer and more individualized clinical management while guiding future research priorities.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1952599"},"PeriodicalIF":5.1,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pragmatic workflow for integrating large language models into toxicological risk assessment.","authors":"Arianna Bassan, Alexander Amberg, Maria Letizia Barreca, Paul M Bradley, Frank Bringezu, Joyce De Paula Souza, Corinne Guicheney, Elena Lo Piparo, Simona Kovarich, Andrey Massarsky, Georgia Maundrill, Lance Molnar, Cristina Parenti, Patricia Parris, Manuela Pavan, John F Reichard, Ron Steigerwalt, Olga Tcheremenskaia, Kenneth Unice, Christopher J Waine, Geraldine Whelan, Angela White, Glenn J Myatt","doi":"10.3389/ftox.2026.1877128","DOIUrl":"https://doi.org/10.3389/ftox.2026.1877128","url":null,"abstract":"<p><p>Artificial intelligence (AI), particularly in the form of large language models (LLMs), offers promising support for toxicological risk assessment (TRA), which integrates multiple lines of evidence to support health-based conclusions, including those used in regulatory decision-making. Effective use of LLMs in TRA requires a clear understanding of their strengths and limitations, especially in the context of regulatory expectations for transparency, reproducibility, and accountability. This work explores the emerging role of LLMs in TRA through three integrated components: an overview of LLMs in the context of TRA, an exemplar case study examining LLM-assisted derivation (mainly using ChatGPT) of the Permitted Daily Exposure (PDE) for acetyl tributyl citrate under the draft ICH Q3E guideline, and a workflow hypothesis for the integration of LLMs into TRA. Observations from the case study suggest that LLMs may support pattern recognition, targeted information retrieval, and rapid summarization of large bodies of text, facilitating literature triage, extraction of study details, and evidence summaries. At the same time, the case study highlights important limitations for LLMs. Observed variability in LLM outputs reflects inherent model stochastic behavior, model limitations, and the intrinsic complexity of TRA, where different experts may reasonably reach distinct, yet scientifically defensible conclusions based on the available evidence. The observations from the case study, interpreted in the context of the available literature, are used to inform a hypothesis that LLMs may be most effectively integrated into TRA through structured, modular, human-supervised workflows. This hypothesis reflects the view that the suitability of LLM-assisted TRA depends not only on LLM capabilities, but also on how LLMs are integrated into the assessment process to address both LLM variability and the interpretive nature of TRA. The proposed pragmatic workflow separates data search, information extraction, and integrated summarization while maintaining human-in-the-loop control over interpretation, expert judgment, and final conclusions.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1877128"},"PeriodicalIF":5.1,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alcohol consumption: from biochemistry to behavior, health, and beyond.","authors":"Evgeny Pechkovsky, Boris Kershengoltz, Valentin V Vlassov, Vasiliy Vlassov, Andrey Turchinovich","doi":"10.3389/ftox.2026.1876876","DOIUrl":"https://doi.org/10.3389/ftox.2026.1876876","url":null,"abstract":"<p><p>Alcohol metabolism is a multi-step biochemical process driven primarily by hepatic oxidation of ethanol to acetaldehyde and then to acetate. Although this pathway protects the body from prolonged ethanol exposure, transient acetaldehyde accumulation generates substantial toxicity, and chronic alcohol intake activates auxiliary pathways that amplify oxidative stress, inflammation, and tissue injury. Both metabolic capacity and physiological response to alcohol vary widely between individuals, reflecting genetic and epigenetic variation in the alcohol- and aldehyde-dehydrogenase enzymes, the cytochrome P450 system, and modulating factors such as sex, age, body composition, nutrition, and overall health. In this review we consolidate 3 decades of biochemical, clinical, and epidemiological evidence into an integrated picture of alcohol's effects on the liver, brain, and other organ systems, with attention to oxidative stress, neurochemistry, glycoconjugate biology, and the convergence of alcohol- and metabolic-driven liver disease. We also examine recent advances in the treatment of alcohol use disorder (AUD) - including incretin-based pharmacotherapies, ketamine-assisted therapy, focused ultrasound neuromodulation, exercise interventions, and combination drug regimens - and we critically evaluate ongoing controversies surrounding moderate drinking, resveratrol, and the use of heterogeneous non-drinker comparison groups in observational studies. Finally, we discuss the changing social context of drinking, the role of endogenous ethanol/acetaldehyde systems in stress resilience across species, and the implications of these insights for personalized prevention and risk-reduction strategies. We conclude by proposing an exposure-susceptibility-context model that integrates the principal determinants of alcohol-related harm.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1876876"},"PeriodicalIF":5.1,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential toxicity of water- and DMSO-extractable PM2.5 fractions in human alveolar organoids.","authors":"Shasha Yu, Shangyao Liu, Jiajie Pan, Xinyang Guo, Shuyang Dai, Shaopeng Chen, Jie Ma","doi":"10.3389/ftox.2026.1943932","DOIUrl":"10.3389/ftox.2026.1943932","url":null,"abstract":"<p><p>PM2.5 is a major air pollutant associated with the onset and exacerbation of various diseases. However, due to the lack of suitable experimental models, the damage caused by PM2.5 to the organism and its relationship with diseases remain poorly understood. This study aims to establish a toxicity exposure model for PM2.5 using human alveolar organoids (hALOs) and investigate the differences in alveolar damage caused by water-extractable fraction and DMSO-extractable fraction of PM2.5. The results revealed that PM2.5 induced morphological damage in hALOs in a dose- and time-dependent manner, with the DMSO-extractable fraction eliciting more severe damage than the water-extractable fraction. PM2.5-induced increases in ROS levels and cell death were associated with the observed morphological damage. During the damage process, we also observed a sustained decline in the number of AT2 cells within the organoids, accompanied by a slight increase in the number of AT1 cells, suggesting that AT2-to-AT1 transdifferentiation may be occurring. This study helps advance the application of <i>in vitro</i> 3D organoid models in toxicological research and facilitate a deeper integration of PM2.5 toxicology and pathology.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1943932"},"PeriodicalIF":5.1,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149139577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging the developmental neurotoxicity <i>in vitro</i> battery: lessons learned interpreting assay outputs and integrating human exposure.","authors":"Agnes L Karmaus, Stefan Masjosthusmann, Lisa Bertomeu, Colin Ehnes, Claire Koenig, Hilary S McCarren, Desirée Mineo, Paige Santos, Maaike E Schutte, Bibek Sharma, Abigail C Toltin, Kathrin Bothe","doi":"10.3389/ftox.2026.1919390","DOIUrl":"10.3389/ftox.2026.1919390","url":null,"abstract":"<p><p>The developing brain is highly sensitive to chemical insults due to the complexity and precise timing of neurodevelopmental processes. <i>In vitro</i> assays targeting key neurodevelopmental events offer insights into developmental neurotoxicity (DNT) pathways and represent an important advance in alternative testing strategies. The Organisation for Economic Co-operation and Development (OECD) published initial recommendations on the design and evaluation of a DNT <i>in vitro</i> battery (DNT IVB) for screening chemical effects on neurodevelopment. Thus far, there has been no characterization of the regulatory application of this new testing battery due to uncertainties in assay performance, interpretation, and contextualization of bioactivity. To gain experience with evaluating assay performance and interpretation of the DNT IVB, a subset of representative, commercially available assays were used to evaluate eight natural compounds, each with established dietary background exposure and no assumed DNT risk under \"normal\" dietary intake: EGCG, folic acid, vanillin, limonene, vitamin E, curcumin, genistein, and caffeine. Of the compounds tested, four were found to have \"specific hits\" including EGCG, genistein, caffeine, and curcumin. Concentrations at which <i>in vitro</i> specific hits occurred were compared with published human plasma levels, revealing that <i>in vitro</i> bioactive concentrations for EGCG were within relevant human exposure levels. Conversely, for curcumin, genistein, and caffeine, any identified specific hits in the evaluated DNT IVB assays occurred at concentrations higher than reported human plasma levels indicating limited relevance for human risk assessment. Moreover, our study highlights the need for well-defined performance criteria, reproducible reference controls, a standardized approach for hit calling, benchmark response determination, and interpretation across the battery to ensure reliability and reproducibility for bolstering readiness for regulatory acceptance. Overall, while the DNT IVB provides valuable insights and opportunities for screening applications to refine chemical safety evaluation, its effective use requires strengthened guidance on assay performance, data interpretation, and integration with exposure assessment to support robust application in human health risk assessment.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1919390"},"PeriodicalIF":5.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149139594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}