Frontiers in toxicology最新文献

{"title":"Quantitative adverse outcome pathway modeling for cigarette smoke-inducible airway mucus hypersecretion. Part 2: Bayesian network modeling for probabilistic risk estimation.","authors":"Shigeaki Ito, Sakuya Ichikawa, Risa Matsumoto, Shugo Muratani, Keigo Sano, Akina Mori, Kazuo Erami","doi":"10.3389/ftox.2025.1564864","DOIUrl":"https://doi.org/10.3389/ftox.2025.1564864","url":null,"abstract":"<p><p>The development of <i>in vitro</i> tests that reproduce real-world situations is crucial for toxicity- and disease-risk assessment without animal testing. Because signs and symptoms of health concerns can be complex, it is helpful to create a simplified representation of such manifestations using a conceptual framework such as an adverse outcome pathway (AOP). Combining an AOP with computational models could be a potential tool for the extrapolation of <i>in vitro</i> results to real-world scenarios. Here, we applied Bayesian network-based probabilistic quantitative models for disease-related risk estimation using an <i>in vitro</i> dataset on the AOP of mucus hypersecretion-a known representative symptom of chronic airway disease-obtained by repeated exposure of human bronchial epithelial cells to whole cigarette smoke. We also used a computational aerosol dosimetry model to account for differences between <i>in vitro</i> exposure concentrations and human exposure scenarios. The results revealed dose- and exposure repetition-dependent increases in adverse outcome probability, suggesting that the model reflects the risk continuum of cigarette smoking. Furthermore, under certain assumptions, dosimetry modeling indicated that our <i>in vitro</i> exposure concentrations were similar to actual smoking scenarios. As an exercise, we also calculated <i>in vitro</i> odds ratios for chronic bronchitis that were comparable to the range of real-world odds ratios for chronic bronchitis due to cigarette smoking. Our combinatory risk-assessment approach could be a valuable tool for estimating the chronic inhalation effects of inhalable products and chemicals.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1564864"},"PeriodicalIF":3.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144182198","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":"Quantitative adverse outcome pathway modeling for cigarette-smoke-induced airway mucus hypersecretion. Part 1: adverse-outcome-pathway-based <i>in vitro</i> assessment with repeated exposure to whole cigarette smoke.","authors":"Sakuya Ichikawa, Shugo Muratani, Keigo Sano, Kazuo Erami, Akina Mori, Risa Matsumoto, Shigeaki Ito","doi":"10.3389/ftox.2025.1564857","DOIUrl":"https://doi.org/10.3389/ftox.2025.1564857","url":null,"abstract":"<p><p>Adverse outcome pathway (AOP)-based chemical risk assessment is a promising tool for regulatory decision-making and is typically used in toxicological assessments. However, it also holds potential for pharmacological and disease-related evaluations. The present study focuses on an AOP for decreased lung function. Lung function is normally robustly maintained by homeostatic capacity, but repeated and chronic stimulation can disrupt this capacity, leading to impaired lung function and mucus hypersecretion. We developed an AOP-based <i>in vitro</i> method to test the disease-related states that can be reproduced by exposing three-dimensionally cultured human bronchial epithelial cells (3D-HBECs) to whole cigarette smoke (WCS). Over a duration of 2 weeks, we repeatedly exposed 3D-HBECs from six different donors to WCS six times to observe both acute phase responses (oxidative stress, epidermal growth factor receptor activation, and SP1 activation) and chronic phase responses (intracellular mucus production, goblet cell metaplasia/hyperplasia, and mucus hypersecretion) along the AOP. Our results demonstrate that although the repeated exposure to WCS induced biological responses along the AOP in all donors, there were interdonor differences, particularly in the timing and amplitudes of the chronic phase responses. All smokers do not exhibit phenotypic changes with the same smoking duration, so this variability likely reflects individual differences. We anticipate that our AOP-based assessment method combined with computational quantitative AOP modeling (discussed in Part 2) will become a valuable tool for assessing the disease risk of airborne materials and inhalable products.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1564857"},"PeriodicalIF":3.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180619","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":"Editorial: Legacy & emerging contaminants in the aquatic environment-bridging knowledge, policy, and future.","authors":"Abdul Qadeer, Mengyang Liu, Sanjeeb Mohapatra, Racliffe Weng Seng Lai","doi":"10.3389/ftox.2025.1611852","DOIUrl":"https://doi.org/10.3389/ftox.2025.1611852","url":null,"abstract":"","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1611852"},"PeriodicalIF":3.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183446","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":"Optimizing Wnt activation in fetal calf serum (FCS)-free organoid expansion media.","authors":"Esther J M Liefting, Jeffrey J Bajramovic","doi":"10.3389/ftox.2025.1504469","DOIUrl":"https://doi.org/10.3389/ftox.2025.1504469","url":null,"abstract":"<p><p>Organoid technology can revolutionize biomedical research by increasing the translational value of experimental results while at the same time reducing the need for experimental animal use. However, in most cases the organoid culture workflow relies on expansion media that contain fetal calf serum (FCS). The production of FCS causes animal suffering, and the use of it is hampered by factors that negatively impact the reproducibility (such as the large inter-batch variation and the undefined composition of FCS), relevance (such as the induction of a non-physiological cellular phenotype), as well as the clinical translatability (such as the potential to cause xeno-immunization or to contain xenogeneic pathogens). There is thus a strong impetus to find animal-free alternatives to the use of FCS. Most contemporary expansion media for organoid culture are not FCS-free. This is mainly contributable to the use of FCS for the recombinant production of the growth factor Wnt3A. Wnt3A-conditioned medium is added to expansion media to induce Wnt signaling, which is necessary for organoid proliferation. In turn, FCS is pivotal to stabilize and solubilize the Wnt3A protein, and not perse for the survival, adhesion or proliferation of cells. This mini-review explores alternative methods to induce Wnt signaling in organoid expansion media, encompassing the use of soluble Wnt mimetics, the use of carriers, and the use of small molecule inhibitors. Ultimately, alternative Wnt activation approaches for different experimental goals are reviewed and discussed.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1504469"},"PeriodicalIF":3.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12116640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176005","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":"Case report: Treatment of severe phorate poisoning.","authors":"Wang Kunlun, Yuan Jun, Xu Shiming, Shen Jie, Gao Mingqiang, Zhang Yuxia, Mo Weichun","doi":"10.3389/ftox.2025.1581362","DOIUrl":"10.3389/ftox.2025.1581362","url":null,"abstract":"<p><strong>Background: </strong>Phorate is a highly toxic organophosphorus pesticide. Owing to its low cost and insecticidal potency, it is still widely used in parts of China, resulting in cases of occupational and life poisoning. This article presents the treatment process for phorate poisoning and monitoring the toxic metabolites terminology in the body.</p><p><strong>Case report: </strong>A 23-year-old male patient ingested about 300 mL (180 g) of 60% phorate emulsion 4 h before admission at our hospital. The patient had ingested over 300 times the lethal dose. During hospitalization, the patient's levels of cholinesterase, phorate and its metabolites, atropine and pralidoxime chloride (PAM), were monitored. Phorate was quickly absorbed into the blood, producing five metabolites. Before hemoperfusion (HP), the concentration of phorate in the blood could not be detected. After the first HP we found five metabolites of phorate in the blood (phoratoxon sulfoxide,phoratoxon sulfone, phorate sulfone, phorate sulfoxide, and phoratoxon). In the follow-up treatment, the concentration of five metabolites gradually decreased. The concentration of the phorate sulfoxide and phorate sulfone rebounded with the suspension of HP, but that of the other metabolites did not rebound. It took 20 days for cholinesterase to recover. Treatment included multiple rounds of HP, atropinization, and reactivator of cholinesterase by PAM. The patient recovered after 34 days and was discharged from hospital.</p><p><strong>Conclusion: </strong>Phorate is oxidized and catalyzed into five metabolites, which cause the toxic effects. Phoratoxon sulfoxide has the highest concentration of these metabolites, followed by phoratoxon sulfone, phorate sulfone, phorate sulfoxide, and phoratoxon, respectively. HP treatment significantly lowered the serum levels of the toxic metabolites terminology. If HP treatment is interrupted, the serum levels of phorate sulfoxide and phorate sulfone tend to rise again. It takes a long time for cholinesterase to recover from severe phorate poisoning.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1581362"},"PeriodicalIF":3.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144777","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":"Rat embryonic stem cell-based <i>in vitro</i> testing platform for mammalian embryo toxicology at pre- and post-implantation stages.","authors":"Corinne Quadalti, Marzia Moretti, Fabio Ferrazzi, Laura Calzà, Luciana Giardino, Vito Antonio Baldassarro","doi":"10.3389/ftox.2025.1561386","DOIUrl":"10.3389/ftox.2025.1561386","url":null,"abstract":"<p><strong>Introduction: </strong>The international guidelines outlining the mandatory developmental toxicology studies of new molecules on pre-implantation, post-implantation and organogenesis phases, require a minimum of 60 pregnant female rats for each molecule to be tested. To date, available in vitro methods still have many limitations, resulting in poor translational power.</p><p><strong>Methods: </strong>In the present study, an innovative in vitro platform is proposed, based on rat embryonic stem cells (RESCs), which is easy to use and suitable for wide-scale screening, mimicking two different developmental stages: i) pre-implant model (undifferentiated pluripotent cells), ii) post-implant model (neuroectodermal lineage differentiation).</p><p><strong>Results: </strong>The in vitro platform was validated by testing the toxicity on the pre-implant model of RA itself, as a known teratogen, a member of the environmental pollutant family per- and polyfluoroalkyl substances (PFAS), the perfluorooctanic acid (PFOA), and the endocrine disruptor chemical 2,2',6,6'-tetrabromobisphenol A (TBBPA) as test compound, targeting the thyroid hormone (TH) signal. The post-implant model showed inactivation of the pluripotent markers and activation of the neuroectodermal markers. The preimplant model resulted high responsive and sensitive to the embryotoxic effect of the tested compounds. The TBBPA was selected to test the potential effects of on viability and neuroectodermal differentiation, assessed through colorimetric and cell-based high-content screening methods establishing sub-toxic (20 μM) and toxic (40 μM) doses. A high-throughput gene expression array-based analysis showed a prompt response of the in vitro testing platform to TBBPA treatment. A rescue experiment exploiting a pan-thyroid receptor (pan-TR) inhibitor (1-850) showed that the effects of TBBPA on RESCs was blocked, demonstrating its activity through TRs.</p><p><strong>Discussion: </strong>The RESCs-based platform allowed reproducible, robust and highly predictable results, thanks to the coupling of RESCs with high-throughput technologies. These results support the possible use of RESCs-based models as a screening platform for developmental toxicity testing to reduce the number of animals currently used for this aim.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1561386"},"PeriodicalIF":3.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12095294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129693","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":"Raising awareness of riverine populations in the Brazilian Amazon about MeHg intoxication in <i>APOE</i>4 carriers: cardiovascular risk and potential benefit of native selenium diets.","authors":"Camila G M Carvalho, Patrícia Marçal Da Costa, Luana M Rocha Souza, Vitória K Félix Monteiro, Jacqueline I Alvarez-Leite, Maria Elena Crespo-Lopez, Reinaldo B Oriá","doi":"10.3389/ftox.2025.1571658","DOIUrl":"10.3389/ftox.2025.1571658","url":null,"abstract":"","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1571658"},"PeriodicalIF":3.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12095312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129691","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":"Editorial: Women in nanotoxicology 2023-2024.","authors":"Iseult Lynch, Ilika Ghosh","doi":"10.3389/ftox.2025.1599767","DOIUrl":"10.3389/ftox.2025.1599767","url":null,"abstract":"","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1599767"},"PeriodicalIF":3.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12089971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112993","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":"Nutrients and phytochemicals characterisations, acute and sub-acute oral toxicity studies of BobyGuard C, a polyherbal nutraceutical with anti-breast cancer properties.","authors":"Borelle Mafogang, Roger Ponka, Joseph Ngakou Mukam, Elie Fokou","doi":"10.3389/ftox.2025.1598185","DOIUrl":"https://doi.org/10.3389/ftox.2025.1598185","url":null,"abstract":"<p><strong>Background: </strong>In 2022, approximately 2.3 million new cases of female breast cancer and 670,000 related deaths worldwide despite significant advancements in conventional treatments. BobyGuard C (BGC) is a novel polyherbal nutraceutical formulated from five plants, selected for their antioxidant, anticancer, anti-inflammatory and nutritional properties to be used for breast cancer management. This study aimed to characterize its physicochemical, nutritional, and phytochemical properties as well as assess its safety through acute and sub-acute oral toxicity studies in Wistar rats.</p><p><strong>Methods: </strong>Thecomposition of BGC was analyzed for macronutrients, minerals, and phytochemicals using standard methods. Antioxidant activity was assessed through DPPH, TAC and FRAP assays, while antiproliferative activity was evaluated using the MTT assay on MDA-MB 231 and MCF-7 breast cancer cell lines. Acute (single 5,000 mg/kg dose with 14 days observation) and sub-acute oral (daily administration of 784, 1,568, and 3,136 mg/kg for 28 days) toxicity studies in female Wistar rats followed OECD guidelines.</p><p><strong>Results: </strong>BGC was found to be rich in proteins (38.36 g/100 g), carbohydrates (59.70 g/100 g), and essential minerals such as magnesium (60,066.67 µg/100 g), and it was free from toxic heavy metals. Several bioactive compounds, including diosgenin, diosbulbin H, β-carotene, Bafoudiosbulbin G and catechin were identified in BGC. Phytochemical analysis revealed high levels of phenols (9,783.48 mg GAE/100 g), flavonoids (47.72 mg QuE/100 g), and alkaloids (106.14 mg berberine eq/100 g), contributing to its strong antioxidant activity (DPPH inhibition: 90.39%). BGC exhibited significant antiproliferative effects on MDA-MB 231 cells, highlighting its potential anticancer activity. Acute toxicity tests showed no mortality at 5,000 mg/kg, with an LD₅₀ exceeding this dose. In the sub-acute 28-day repeated-dose oral study, doses up to 3,136 mg/kg/day resulted in some dose dependent hematological and biochemical changes but no histopathological abnormalities were observed indicating its safety at lower doses.</p><p><strong>Conclusion: </strong>BGC is a nutritionally rich formulation with potent antioxidant and anticancer potential, demonstrating a favorable safety profile at lower dose (784 mg/kg).</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1598185"},"PeriodicalIF":3.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082537","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":"Associations of environmental pollution with pro-oxidant, antioxidant and inflammatory markers in pregnant mothers and newborns.","authors":"Antonin Ambroz, Jiri Klema, Andrea Rossnerova, Alena Milcova, Anna Pastorkova, Jana Pulkrabova, Ondrej Parizek, Veronika Gomersall, Tomas Gramblicka, Jaroslav Zelenka, Tomas Ruml, Nikola Vrzackova, Milos Veleminsky, Newroz Hasan, Jan Topinka, Radim J Sram, Pavel Rossner","doi":"10.3389/ftox.2025.1572486","DOIUrl":"10.3389/ftox.2025.1572486","url":null,"abstract":"<p><p>The aim of the study was to analyze the variables that modify the levels of oxidative DNA damage and lipid peroxidation in non-smoking mothers and their newborns from environmentally distinct localities of the Czech Republic: Ceske Budejovice (CB, an agricultural region) and Karvina (an industrial region). Personal, socio-economic and medical data, concentrations of particulate matter of aerodynamic diameter < 2.5 µm (PM2.5) and benzo[a]pyrene (B[a]P) in the ambient air, the activities of antioxidant mechanisms (superoxide dismutase, catalase, glutathione peroxidase) and antioxidant capacity), the levels of pro-inflammatory cytokines, the concentrations of persistent organic pollutants (POPs) in blood plasma/cord blood plasma and urinary levels of polycyclic aromatic hydrocarbons metabolites (OH-PAHs) were investigated as parameters potentially affecting the markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-oxodG) and lipid peroxidation (15-F₂t-isoprostane, 15-F₂t-IsoP). Significantly higher levels of POPs were detected in the plasma of mothers/newborns from CB (p < 0.001), while increased external levels of B[a]P and PM2.5, confirmed by analyzing urinary OH-PAHs, were found in Karvina subjects (p < 0.001). In mothers, multivariate analysis showed no significant difference in oxidative stress markers (15-F₂t-IsoP, 8-oxodG) between the two localities. The analysis further revealed that neither in CB nor, unexpectedly, in Karvina, did PAH exposure affect maternal lipid peroxidation. Significant associations between OH-PAHs and 15-F₂t-IsoP or 8-oxodG were observed only in newborns. In addition, multivariate analyses revealed a borderline significant association between locality and 8-oxodG in the urine of all newborns (p = 0.05). In conclusion, not only the maternal exposure of PAHs but also some POPs can negatively affect oxidative stress status in the early-life of newborns.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1572486"},"PeriodicalIF":3.6,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12069330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057867","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}