Pub Date : 2026-02-01Epub Date: 2026-01-07DOI: 10.1016/j.toxlet.2026.111826
Liya Fang , Chanlin Fang , Shanshan Di , Xinquan Wang , Yuanxiang Jin
This study examined the hepatic effects of parous exposure to the rubber-derived contaminant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its oxidation product, N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPDQ), in C57BL/6 mice during gestation and lactation. Both compounds exhibited dose-dependent bioaccumulation in the liver of the F0 generation and lactated F1 offspring, with 6PPDQ accumulating more due to its greater stability. Lactational transmission of both compounds was observed, and the accumulation declined with age, disappearing by 8 weeks. Notably, 6PPDQ exposure resulted in reduced body weight in mature F1 female mice, which was associated with altered cholesterol metabolism and disrupted expression of the estrogen receptor gene. In these mice, molecular analysis revealed dysregulation of key cholesterol-related genes, such as HMGCR and PCSK9. In contrast, male offspring showed less pronounced effects. These results indicate that the toxicity of 6PPD and 6PPDQ can be transmitted through placental and lactational pathways, with 6PPDQ presenting a greater risk, particularly to female mice, through its impact on cholesterol metabolism and endocrine signalling. These findings offer valuable insights for assessing the environmental and health risks associated with these compounds.
{"title":"Rubber-derived contaminants N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine and N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone alter intergenerational cholesterol metabolism in F1 offspring of exposed mice","authors":"Liya Fang , Chanlin Fang , Shanshan Di , Xinquan Wang , Yuanxiang Jin","doi":"10.1016/j.toxlet.2026.111826","DOIUrl":"10.1016/j.toxlet.2026.111826","url":null,"abstract":"<div><div>This study examined the hepatic effects of parous exposure to the rubber-derived contaminant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its oxidation product, N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPDQ), in C57BL/6 mice during gestation and lactation. Both compounds exhibited dose-dependent bioaccumulation in the liver of the F0 generation and lactated F1 offspring, with 6PPDQ accumulating more due to its greater stability. Lactational transmission of both compounds was observed, and the accumulation declined with age, disappearing by 8 weeks. Notably, 6PPDQ exposure resulted in reduced body weight in mature F1 female mice, which was associated with altered cholesterol metabolism and disrupted expression of the estrogen receptor gene. In these mice, molecular analysis revealed dysregulation of key cholesterol-related genes, such as HMGCR and PCSK9. In contrast, male offspring showed less pronounced effects. These results indicate that the toxicity of 6PPD and 6PPDQ can be transmitted through placental and lactational pathways, with 6PPDQ presenting a greater risk, particularly to female mice, through its impact on cholesterol metabolism and endocrine signalling. These findings offer valuable insights for assessing the environmental and health risks associated with these compounds.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111826"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145946081","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}
Pub Date : 2026-02-01Epub Date: 2025-12-31DOI: 10.1016/j.toxlet.2025.111812
Koushirou Sogawa , Masahiko Funada
Cannabidiol (CBD) is a non-psychoactive cannabinoid with increasing global use, yet safety data during pregnancy remain limited. Preclinical studies suggest possible developmental neurotoxicity. Here, we examined the effects of CBD (0.001–100 μM) on human induced pluripotent stem cells (hiPSCs) using cell counting, morphology, flow cytometry, and qRT-PCR. Acute exposure to CBD (≥10 μM) markedly reduced hiPSC viability, accompanied by morphological disruptions and upregulation of caspase-3 and −7 within 3–5 h. These effects were significantly attenuated by the pan-caspase inhibitor Z-VAD-FMK, indicating caspase-dependent apoptosis as a key mechanism. Chronic exposure to CBD (0.001–1 μM) for 7 days did not alter transcriptional profiles of Nanog, Pax6, or Map2 during neural ectodermal induction, and immunocytochemical analyses further confirmed that early neuroectodermal morphology was preserved, with comparable PAX6- and NESTIN-positive populations in CBD-treated and control cultures. However, higher CBD concentrations caused marked cytotoxicity and impaired colony formation. These findings define a narrow concentration window between safe and toxic levels, highlighting stage-specific vulnerability to CBD during early development. Use of CBD in pregnancy should therefore be approached cautiously, considering potential risks to fetal neural development.
{"title":"Effects of cannabidiol on the viability and neuronal differentiation of human iPS cells","authors":"Koushirou Sogawa , Masahiko Funada","doi":"10.1016/j.toxlet.2025.111812","DOIUrl":"10.1016/j.toxlet.2025.111812","url":null,"abstract":"<div><div>Cannabidiol (CBD) is a non-psychoactive cannabinoid with increasing global use, yet safety data during pregnancy remain limited. Preclinical studies suggest possible developmental neurotoxicity. Here, we examined the effects of CBD (0.001–100 μM) on human induced pluripotent stem cells (hiPSCs) using cell counting, morphology, flow cytometry, and qRT-PCR. Acute exposure to CBD (≥10 μM) markedly reduced hiPSC viability, accompanied by morphological disruptions and upregulation of caspase-3 and −7 within 3–5 h. These effects were significantly attenuated by the pan-caspase inhibitor Z-VAD-FMK, indicating caspase-dependent apoptosis as a key mechanism. Chronic exposure to CBD (0.001–1 μM) for 7 days did not alter transcriptional profiles of <em>Nanog</em>, <em>Pax6</em>, or <em>Map2</em> during neural ectodermal induction, and immunocytochemical analyses further confirmed that early neuroectodermal morphology was preserved, with comparable PAX6- and NESTIN-positive populations in CBD-treated and control cultures. However, higher CBD concentrations caused marked cytotoxicity and impaired colony formation. These findings define a narrow concentration window between safe and toxic levels, highlighting stage-specific vulnerability to CBD during early development. Use of CBD in pregnancy should therefore be approached cautiously, considering potential risks to fetal neural development.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111812"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893162","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}
Drug-induced liver injury (DILI) is one of the most common adverse drug effects and a major cause of drug development failure. However, preclinically identifying drugs that cause liver injury remains difficult and represents a major challenge in drug development. MicroRNAs (miRNAs) have been proposed as biomarkers for the early detection of DILI owing to the dynamic changes in their expression in response to hepatotoxic insults. Therefore, identifying human-specific miRNAs that change early in response to diverse hepatotoxicants may enable a practical screening approach for drug development. Here, we evaluated whether hepatic miRNA responses can distinguish hepatotoxic from non-hepatotoxic drugs using a highly humanized liver chimeric mouse model (PXB-mouse). We administered eight hepatotoxic compounds (hTOX) and three non-hepatotoxic compounds (non-hTOX) to PXB-mice and performed a comprehensive analysis of the changes in hepatic RNA expression. PXB-mice exposed to hTOX exhibited an increased expression of liver mRNAs which were related to early activation of transcriptional pathways induced by liver damage. Among the miRNAs that exhibited expression changes exclusively in the hTOX-treated group but not in the non-hTOX group compared to the controls, we identified miR-4306 and miR-1237 as potential candidates of human-specific miRNAs whose expression was changed only after hTOX treatment. Although further validation studies are warranted, our findings suggest that detection of miR-4306 and miR-1237 in PXB-mice may help discriminate hepatotoxic from non-hepatotoxic drug exposure.
{"title":"MicroRNA-based discrimination of hepatotoxic and non-hepatotoxic drugs using a humanized liver mouse model","authors":"Naoto Okada , Hatsune Enomoto , Ryota Goto , Hidehisa Tachiki , Takashi Kitahara","doi":"10.1016/j.toxlet.2026.111832","DOIUrl":"10.1016/j.toxlet.2026.111832","url":null,"abstract":"<div><div>Drug-induced liver injury (DILI) is one of the most common adverse drug effects and a major cause of drug development failure. However, preclinically identifying drugs that cause liver injury remains difficult and represents a major challenge in drug development. MicroRNAs (miRNAs) have been proposed as biomarkers for the early detection of DILI owing to the dynamic changes in their expression in response to hepatotoxic insults. Therefore, identifying human-specific miRNAs that change early in response to diverse hepatotoxicants may enable a practical screening approach for drug development. Here, we evaluated whether hepatic miRNA responses can distinguish hepatotoxic from non-hepatotoxic drugs using a highly humanized liver chimeric mouse model (PXB-mouse). We administered eight hepatotoxic compounds (hTOX) and three non-hepatotoxic compounds (non-hTOX) to PXB-mice and performed a comprehensive analysis of the changes in hepatic RNA expression. PXB-mice exposed to hTOX exhibited an increased expression of liver mRNAs which were related to early activation of transcriptional pathways induced by liver damage. Among the miRNAs that exhibited expression changes exclusively in the hTOX-treated group but not in the non-hTOX group compared to the controls, we identified miR-4306 and miR-1237 as potential candidates of human-specific miRNAs whose expression was changed only after hTOX treatment. Although further validation studies are warranted, our findings suggest that detection of miR-4306 and miR-1237 in PXB-mice may help discriminate hepatotoxic from non-hepatotoxic drug exposure.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111832"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023571","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}
Pub Date : 2026-02-01Epub Date: 2026-01-21DOI: 10.1016/j.toxlet.2026.111831
Bing Zhu , Guanchao Mao , Qinghe Meng , Ang Li , Chaoying Jin , Yuchong Wang , Xinwei Wang , Wenjun Xue , Fangzhen Hou , Junjie Yang , Qingqiang Xu , Chunyu Xue , Minliang Wu
{"title":"Corrigendum to “Mechanisms, pathological features, and intervention strategies for nitrogen mustard-induced skin toxicity” [Toxicol. Lett. 416 (2026) 111815]","authors":"Bing Zhu , Guanchao Mao , Qinghe Meng , Ang Li , Chaoying Jin , Yuchong Wang , Xinwei Wang , Wenjun Xue , Fangzhen Hou , Junjie Yang , Qingqiang Xu , Chunyu Xue , Minliang Wu","doi":"10.1016/j.toxlet.2026.111831","DOIUrl":"10.1016/j.toxlet.2026.111831","url":null,"abstract":"","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111831"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030821","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}
Pub Date : 2026-02-01Epub Date: 2025-12-30DOI: 10.1016/j.toxlet.2025.111814
Shanshan Chen , Wenqi Chen , Hong Geng , Zhiping Li , Jianwei Yue , Ruijin Li
Introduction
While fine particulate matter (PM2.5) is an established risk factor for cardiovascular disease (CVD), the relative contribution of its specific chemical components to cardiotoxicity remains unclear. This study aimed to systematically compare the cytotoxicity driven by the oxidative potential (OP) of different PM2.5 components and elucidate the underlying mechanisms.
Methods
We conducted a comparative assessment of the water-soluble particle (WSP), non-water-soluble particle (NWSP), and organic matter (OM) of PM2.5 collected in winter in Taiyuan, China, in H9c2 cardiomyocytes, focusing on OP, cytotoxicity, and mitochondrial biogenesis. OP was measured by the dithiothreitol (DTT) assay, a non-cellular method. The mitochondrial biogenesis-related gene expressions (AMPKα, PGC-1α, Nrf1, Nrf2, TFAM) were quantified by RT-qPCR and western blot. The mitochondrial DNA (mtDNA) copy number was detected. The correlation between the PM2.5 composition (water-soluble ions, metals, and PAHs, etc.) and OP was analyzed.
Results
Among the three components, OM exhibited the highest OP values. Cellular experiments consistently demonstrated that the OM was the most potent inducer of ROS, LDH release, and ATP depletion, and displayed the lowest LD50. Mechanistically, it most severely suppressed mtDNA copy number and the expression of key regulators of mitochondrial biogenesis, including AMPKα, PGC-1α, and its downstream targets Nrf1, Nrf2, and TFAM. Critically, correlation analysis revealed that the OP was strongly associated with the content of PM2.5-bound PAHs.
Conclusion
The OM fraction, particularly the PAHs, is the primary driver of PM2.5-induced cardiomyocyte toxicity. This effect is mediated through a mechanism involving high oxidative potential, which triggers severe oxidative stress and disrupts mitochondrial biogenesis. This study provides crucial experimental evidence for the increased CVD risk associated with PM2.5.
{"title":"Organic matter of PM2.5 induces cardiomyocyte toxicity by driving oxidative potential and impairing AMPK/PGC-1α-dependent mitochondrial biogenesis","authors":"Shanshan Chen , Wenqi Chen , Hong Geng , Zhiping Li , Jianwei Yue , Ruijin Li","doi":"10.1016/j.toxlet.2025.111814","DOIUrl":"10.1016/j.toxlet.2025.111814","url":null,"abstract":"<div><h3>Introduction</h3><div>While fine particulate matter (PM<sub>2.5</sub>) is an established risk factor for cardiovascular disease (CVD), the relative contribution of its specific chemical components to cardiotoxicity remains unclear. This study aimed to systematically compare the cytotoxicity driven by the oxidative potential (OP) of different PM<sub>2.5</sub> components and elucidate the underlying mechanisms.</div></div><div><h3>Methods</h3><div>We conducted a comparative assessment of the water-soluble particle (WSP), non-water-soluble particle (NWSP), and organic matter (OM) of PM<sub>2.5</sub> collected in winter in Taiyuan, China, in H9c2 cardiomyocytes, focusing on OP, cytotoxicity, and mitochondrial biogenesis. OP was measured by the dithiothreitol (DTT) assay, a non-cellular method. The mitochondrial biogenesis-related gene expressions (AMPKα, PGC-1α, Nrf1, Nrf2, TFAM) were quantified by RT-qPCR and western blot. The mitochondrial DNA (mtDNA) copy number was detected. The correlation between the PM<sub>2.5</sub> composition (water-soluble ions, metals, and PAHs, etc.) and OP was analyzed.</div></div><div><h3>Results</h3><div>Among the three components, OM exhibited the highest OP values. Cellular experiments consistently demonstrated that the OM was the most potent inducer of ROS, LDH release, and ATP depletion, and displayed the lowest LD<sub>50</sub>. Mechanistically, it most severely suppressed mtDNA copy number and the expression of key regulators of mitochondrial biogenesis, including AMPKα, PGC-1α, and its downstream targets Nrf1, Nrf2, and TFAM. Critically, correlation analysis revealed that the OP was strongly associated with the content of PM<sub>2.5</sub>-bound PAHs.</div></div><div><h3>Conclusion</h3><div>The OM fraction, particularly the PAHs, is the primary driver of PM<sub>2.5</sub>-induced cardiomyocyte toxicity. This effect is mediated through a mechanism involving high oxidative potential, which triggers severe oxidative stress and disrupts mitochondrial biogenesis. This study provides crucial experimental evidence for the increased CVD risk associated with PM<sub>2.5</sub>.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111814"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145886411","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}
Pub Date : 2026-02-01Epub Date: 2026-01-01DOI: 10.1016/j.toxlet.2025.111813
Christian Novello , Matteo Riccardo Di Nicola , Jean Lou CM Dorne , Erika Colombo , Edoardo Luca Viganò , Manuel E. Ortiz-Santaliestra , Nynke Kramer , Edoardo Carnesecchi , Anna Melina Steinbach , Ivano Eberini , Antony Williams , Emilio Benfenati , Alessandra Roncaglioni
<div><div>Global decline of amphibian populations has been correlated with a range of endogenous and exogenous variables including their unique physiology and ecology, exposure to chemicals, habitat reduction, climate change, as well as biological hazards such as emerging infectious diseases. The African clawed frog (<em>Xenopus laevis</em>) is an OECD test species used in toxicity testing as a specific proxy for humans and environmentally relevant species, for which acute toxicity data for a range of chemicals have been generated historically by industry, a number of public health agencies and academia. Of particular relevance are mechanistic effects of endocrine-active substances on metamorphosis and the thyroid axis, resulting in developmental toxicity. From such toxicity data, no open-source quantitative structure-activity relationships (QSARs) have been developed as in silico tools to predict such toxicity for data-poor chemicals in <em>X</em>. <em>laevis.</em> Such QSAR models can provide a quantitative starting point for the hazard assessment of chemicals in other anuran amphibians. This manuscript provides a description of the data collection and curation from the largest historical databases including the US EPA ECOTOX knowledgebase and the Ortiz-Santaliestra databases available for <em>Xenopus</em> embryos as acute median lethal concentrations (LC<sub>50</sub>-12 h) for a total of 349 unique structures and 1978 individual entries. After data curation, the database contained 359 individual entries for a total of 175 compounds, and were computed using the negative logarithm of molar concentrations expressed as 12 h log 1/LC50 mmol/L. Subsequently, the database was then split into training set, test set and prediction set with 120, 40 and 13 compounds, respectively. These datasets were then used for the development and validation of two different QSAR models: 1. A k-Nearest Neighbours (k-NN) models using istKNN (in silico tools – KNN). 2. A multiple linear regression model (MLR) using the QSARINS (QSAR-INSUBRIA) software version 2.2.4. Overall, the QSAR models performed well for predicting acute toxicity of chemicals in <em>Xenopus</em> embryos and the MLR model performed slightly better than the k-NN model with correlation coefficients of 0.76 and 0.75 and root mean square errors of 0.63 and 0.67, respectively. However, underestimation of predictions for highly toxic compounds were observed and these limitations are discussed for both the k-NN and multiple linear regression model in the light of mechanistic interpretation and expert knowledge. Variability in the experimental datasets as well as under-representation of the most toxic compounds in the database are highlighted as major drivers influencing such underpredictions. Future directions from the present work include the modelling of other endpoints and developmental stages as well as other amphibian species using the available, although limited, data. Overall, it can be foreseen in
{"title":"Predicting acute developmental toxicity of chemicals in embryos of the African clawed frog (Xenopus laevis): Calibration and validation of regression-based quantitative structure activity relationship models for hazard assessment of chemicals in anuran amphibians","authors":"Christian Novello , Matteo Riccardo Di Nicola , Jean Lou CM Dorne , Erika Colombo , Edoardo Luca Viganò , Manuel E. Ortiz-Santaliestra , Nynke Kramer , Edoardo Carnesecchi , Anna Melina Steinbach , Ivano Eberini , Antony Williams , Emilio Benfenati , Alessandra Roncaglioni","doi":"10.1016/j.toxlet.2025.111813","DOIUrl":"10.1016/j.toxlet.2025.111813","url":null,"abstract":"<div><div>Global decline of amphibian populations has been correlated with a range of endogenous and exogenous variables including their unique physiology and ecology, exposure to chemicals, habitat reduction, climate change, as well as biological hazards such as emerging infectious diseases. The African clawed frog (<em>Xenopus laevis</em>) is an OECD test species used in toxicity testing as a specific proxy for humans and environmentally relevant species, for which acute toxicity data for a range of chemicals have been generated historically by industry, a number of public health agencies and academia. Of particular relevance are mechanistic effects of endocrine-active substances on metamorphosis and the thyroid axis, resulting in developmental toxicity. From such toxicity data, no open-source quantitative structure-activity relationships (QSARs) have been developed as in silico tools to predict such toxicity for data-poor chemicals in <em>X</em>. <em>laevis.</em> Such QSAR models can provide a quantitative starting point for the hazard assessment of chemicals in other anuran amphibians. This manuscript provides a description of the data collection and curation from the largest historical databases including the US EPA ECOTOX knowledgebase and the Ortiz-Santaliestra databases available for <em>Xenopus</em> embryos as acute median lethal concentrations (LC<sub>50</sub>-12 h) for a total of 349 unique structures and 1978 individual entries. After data curation, the database contained 359 individual entries for a total of 175 compounds, and were computed using the negative logarithm of molar concentrations expressed as 12 h log 1/LC50 mmol/L. Subsequently, the database was then split into training set, test set and prediction set with 120, 40 and 13 compounds, respectively. These datasets were then used for the development and validation of two different QSAR models: 1. A k-Nearest Neighbours (k-NN) models using istKNN (in silico tools – KNN). 2. A multiple linear regression model (MLR) using the QSARINS (QSAR-INSUBRIA) software version 2.2.4. Overall, the QSAR models performed well for predicting acute toxicity of chemicals in <em>Xenopus</em> embryos and the MLR model performed slightly better than the k-NN model with correlation coefficients of 0.76 and 0.75 and root mean square errors of 0.63 and 0.67, respectively. However, underestimation of predictions for highly toxic compounds were observed and these limitations are discussed for both the k-NN and multiple linear regression model in the light of mechanistic interpretation and expert knowledge. Variability in the experimental datasets as well as under-representation of the most toxic compounds in the database are highlighted as major drivers influencing such underpredictions. Future directions from the present work include the modelling of other endpoints and developmental stages as well as other amphibian species using the available, although limited, data. Overall, it can be foreseen in ","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111813"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896940","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}
Per- and polyfluoroalkyl substances (PFAS) are widely used chemicals known for their persistence, bioaccumulation, and adverse health effects, particularly on the immune system. Epidemiological studies link PFAS exposure to immunosuppression, with increased infection susceptibility and reduced vaccine efficacy. In this paper, we describe the workflow we used to establish an integrated testing strategy (ITS) combining in vitro and in silico methods to model PFAS inhibition of antibody production and to define a tolerable daily intake. This strategy was based on data generated within an EFSA-sponsored project. Using human peripheral blood mononuclear cells, the effects of PFAS on antibody production were assessed. Mathematical models were then applied to determine PFAS free concentrations in vitro, while Physiologically Based Kinetics (PBK) modeling enabled quantitative in vitro to in vivo extrapolation (QIVIVE) to translate in vitro effects into external doses. In addition, the Universal Immune System Simulator was used to predict immune-related outcomes and threshold doses for sensitive populations. Following this strategy, we were able to demonstrate that the oral equivalent effect doses derived through QIVIVE were similar to, or lower than, the tolerable weekly intake established by EFSA for PFAS, indicating that our approach is conservative. We demonstrate the possibility of using alternative methods for studying PFAS toxicity, offering insights into their dynamics and kinetics without animal testing. The strategy provides a promising framework for assessing other chemicals, advancing toxicology toward more human-relevant and ethical practices.
{"title":"An integrated in vitro and in silico testing strategy applied to PFAS inhibition of antibody production to define a tolerable daily intake","authors":"Martina Iulini , Aafke W.F. Janssen , Karsten Beekmann , Giulia Russo , Francesco Pappalardo , Styliani Fragki , Alicia Paini , Emanuela Corsini","doi":"10.1016/j.toxlet.2025.111817","DOIUrl":"10.1016/j.toxlet.2025.111817","url":null,"abstract":"<div><div>Per- and polyfluoroalkyl substances (PFAS) are widely used chemicals known for their persistence, bioaccumulation, and adverse health effects, particularly on the immune system. Epidemiological studies link PFAS exposure to immunosuppression, with increased infection susceptibility and reduced vaccine efficacy. In this paper, we describe the workflow we used to establish an integrated testing strategy (ITS) combining <em>in vitro</em> and <em>in silico</em> methods to model PFAS inhibition of antibody production and to define a tolerable daily intake. This strategy was based on data generated within an EFSA-sponsored project. Using human peripheral blood mononuclear cells, the effects of PFAS on antibody production were assessed. Mathematical models were then applied to determine PFAS free concentrations <em>in vitro</em>, while Physiologically Based Kinetics (PBK) modeling enabled quantitative <em>in vitro</em> to <em>in vivo</em> extrapolation (QIVIVE) to translate <em>in vitro</em> effects into external doses. In addition, the Universal Immune System Simulator was used to predict immune-related outcomes and threshold doses for sensitive populations. Following this strategy, we were able to demonstrate that the oral equivalent effect doses derived through QIVIVE were similar to, or lower than, the tolerable weekly intake established by EFSA for PFAS, indicating that our approach is conservative. We demonstrate the possibility of using alternative methods for studying PFAS toxicity, offering insights into their dynamics and kinetics without animal testing. The strategy provides a promising framework for assessing other chemicals, advancing toxicology toward more human-relevant and ethical practices.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111817"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906689","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}
Pub Date : 2026-02-01Epub Date: 2026-01-11DOI: 10.1016/j.toxlet.2026.111827
Hefnawy Ahmad A. , Siam Mohamed , Mofarih Y. Alkhaldi , Hassan A. Asiri , Atheer M. Ali , Faisal A. Shaher , Mubarak Sultan Al-Shahrani , Mohammed Ahmed Al-Qarni , Hossam M. El-Hawary
Background
Dioxins, are highly potent environmental carcinogens. Their toxic effects are mediated primarily by the Aryl Hydrocarbon Receptor (AhR). A comprehensive understanding of how AhR-induced genetic and epigenetic alterations drive carcinogenesis, especially through effects on cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) and transgenerational inheritance, remains imperative.
Objectives
This study investigated the interplay between AhR signaling and some molecular modifications in dioxin-induced carcinogenicity. We aimed to characterize resultant gene expression signatures, cell-specific responses, identify novel AhR targets and susceptible organs, and develop a molecular profile for biomarker and therapeutic development.
Methods
We searched databases for peer-reviewed experimental and epidemiological studies on AhR activation by dioxins and its effects on genetic/epigenetic mechanisms, cancer pathways, EMT/CSCs, or transgenerational impacts. Two reviewers performed selection, data extraction, and bias assessment.
Results
From 7510 records, 39 studies were incorporated in the qualitative synthesis including 19 in the meta-analyses. Dioxin/AhR significantly increased the expression of certain DNA methylating enzymes. AhR upregulates Gadd45b and LAT1/SLC7A5, induces IL-6, promotes cell cycle progression and interacts with key cancer pathways. AhR signaling alters DNA methylation at promoters, modulates histone modifications, dysregulates ncRNAs, facilitates EMT, influences CSCs, and elicits cell-specific liver responses. Evidence for transgenerational epigenetic inheritance of disease susceptibility was identified.
Conclusion
Dioxin-induced carcinogenicity involves intricate AhR-mediated genetic damage and profound epigenetic reprogramming. These alterations, which are often cell-type and species-specific, disrupt critical cellular processes, including EMT and CSC biology, and are susceptible to transgenerational inheritance. The identified molecular signatures offer a foundation for improved biomarkers and targeted therapeutic interventions.
{"title":"Piecing together the puzzles: Aryl hydrocarbon receptor-mediated genetic and epigenetic signatures in dioxin-induced carcinogenicity- A systematic review and meta-analysis","authors":"Hefnawy Ahmad A. , Siam Mohamed , Mofarih Y. Alkhaldi , Hassan A. Asiri , Atheer M. Ali , Faisal A. Shaher , Mubarak Sultan Al-Shahrani , Mohammed Ahmed Al-Qarni , Hossam M. El-Hawary","doi":"10.1016/j.toxlet.2026.111827","DOIUrl":"10.1016/j.toxlet.2026.111827","url":null,"abstract":"<div><h3>Background</h3><div>Dioxins, are highly potent environmental carcinogens. Their toxic effects are mediated primarily by the Aryl Hydrocarbon Receptor (AhR). A comprehensive understanding of how AhR-induced genetic and epigenetic alterations drive carcinogenesis, especially through effects on cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) and transgenerational inheritance, remains imperative.</div></div><div><h3>Objectives</h3><div>This study investigated the interplay between AhR signaling and some molecular modifications in dioxin-induced carcinogenicity. We aimed to characterize resultant gene expression signatures, cell-specific responses, identify novel AhR targets and susceptible organs, and develop a molecular profile for biomarker and therapeutic development.</div></div><div><h3>Methods</h3><div>We searched databases for peer-reviewed experimental and epidemiological studies on AhR activation by dioxins and its effects on genetic/epigenetic mechanisms, cancer pathways, EMT/CSCs, or transgenerational impacts. Two reviewers performed selection, data extraction, and bias assessment.</div></div><div><h3>Results</h3><div>From 7510 records, 39 studies were incorporated in the qualitative synthesis including 19 in the meta-analyses. Dioxin/AhR significantly increased the expression of certain DNA methylating enzymes. AhR upregulates Gadd45b and LAT1/SLC7A5, induces IL-6, promotes cell cycle progression and interacts with key cancer pathways. AhR signaling alters DNA methylation at promoters, modulates histone modifications, dysregulates ncRNAs, facilitates EMT, influences CSCs, and elicits cell-specific liver responses. Evidence for transgenerational epigenetic inheritance of disease susceptibility was identified.</div></div><div><h3>Conclusion</h3><div>Dioxin-induced carcinogenicity involves intricate AhR-mediated genetic damage and profound epigenetic reprogramming. These alterations, which are often cell-type and species-specific, disrupt critical cellular processes, including EMT and CSC biology, and are susceptible to transgenerational inheritance. The identified molecular signatures offer a foundation for improved biomarkers and targeted therapeutic interventions.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111827"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960459","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}
Pub Date : 2026-02-01Epub Date: 2025-12-30DOI: 10.1016/j.toxlet.2025.111811
Gerui Zhu , Fan Wang , Siyuan Wang , Kai Huang , Gaofeng Chen , Chenghai Liu , Yuan Peng , Yanyan Tao
Aristolochic acids, such as Aristolochic acid I (AAI), are widely recognized for their nephrotoxicity and potential to cause hepatocellular carcinoma. Although previous studies have demonstrated the ability of AAI to induce hepatorenal toxicity, the precise underlying mechanism remains unclear. The objective of this research is to investigate the mechanisms by which AAI induces hepatorenal toxicity. Both in vivo and in vitro studies were conducted, involving the administration of AAI to C57BL/6 mice and the exposure of human hepatocytes (HL-7702/L-02) and proximal kidney tubular epithelial cell (HK-2) to AAI. RNA sequencing analysis of liver and kidney was conducted to ascertain hepatorenal toxicity mechanism, with follow-up experiments for validation. Upon identifying the common target, STAT3, for AAI induced hepatorenal toxicity, we further employed STAT3 inhibitor, Stattic for in vitro validation. The results revealed that elevated expressions of STAT3 caused hepatorenal toxicity, leading to impaired liver and kidney functions, as well as tissue damage. Western Blot demonstrated that AAI increased STAT3 phosphorylation. Furthermore, the application of the STAT3 inhibitor reduced damage to hepatocytes and kidney tubular epithelial cell, confirming the effectiveness of Stattic against AAI-induced harm. These findings provide evidence of the significant hepatorenal toxicity of AAI and indicate that STAT3 may serve as a potential common target.
{"title":"Comparative transcriptomic analysis reveals STAT3 as a candidate gene involved in aristolochic acid I-induced hepatorenal toxicity","authors":"Gerui Zhu , Fan Wang , Siyuan Wang , Kai Huang , Gaofeng Chen , Chenghai Liu , Yuan Peng , Yanyan Tao","doi":"10.1016/j.toxlet.2025.111811","DOIUrl":"10.1016/j.toxlet.2025.111811","url":null,"abstract":"<div><div>Aristolochic acids, such as Aristolochic acid I (AAI), are widely recognized for their nephrotoxicity and potential to cause hepatocellular carcinoma. Although previous studies have demonstrated the ability of AAI to induce hepatorenal toxicity, the precise underlying mechanism remains unclear. The objective of this research is to investigate the mechanisms by which AAI induces hepatorenal toxicity. Both in vivo and in vitro studies were conducted, involving the administration of AAI to C57BL/6 mice and the exposure of human hepatocytes (HL-7702/L-02) and proximal kidney tubular epithelial cell (HK-2) to AAI. RNA sequencing analysis of liver and kidney was conducted to ascertain hepatorenal toxicity mechanism, with follow-up experiments for validation. Upon identifying the common target, STAT3, for AAI induced hepatorenal toxicity, we further employed STAT3 inhibitor, Stattic for in vitro validation. The results revealed that elevated expressions of STAT3 caused hepatorenal toxicity, leading to impaired liver and kidney functions, as well as tissue damage. Western Blot demonstrated that AAI increased STAT3 phosphorylation. Furthermore, the application of the STAT3 inhibitor reduced damage to hepatocytes and kidney tubular epithelial cell, confirming the effectiveness of Stattic against AAI-induced harm. These findings provide evidence of the significant hepatorenal toxicity of AAI and indicate that STAT3 may serve as a potential common target.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111811"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889390","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}
Pub Date : 2026-02-01Epub Date: 2026-01-10DOI: 10.1016/j.toxlet.2026.111829
Koki Kanameda , Masayo Hirao-Suzuki , Shuso Takeda
Fulvestrant (FUL), an estrogen receptor α (ERα)-degradative anti-estrogen, is used alone or in combination with cyclin-dependent kinase 4/6 inhibitors for the treatment of advanced ERα-positive breast cancer (BC) in postmenopausal women. Cadmium (Cd), an environmental pollutant and metalloestrogen, binds to ERα as a ligand. Patients with BC may experience disease progression despite FUL treatment, suggesting potential interactions between FUL and Cd in long-term estrogen-deprived (LTED) cells. Therefore, the effect of FUL and Cd interaction in LTED cells, a model of postmenopausal BC, was investigated. LTED cells were treated with FUL and Cd at therapeutically or physiologically relevant concentrations, both simultaneously and sequentially (either with FUL treatment followed by Cd or Cd pre-treatment followed by FUL). FUL treatment alone decreased LTED cell viability; however, Cd pre/post-treatment attenuated the antiproliferative effect of FUL. Western blotting showed that Cd pre/post-treatment did not affect FUL-induced ERα degradation. Hence, Cd could suppress the antiproliferative effect of FUL in LTED cells.
{"title":"Cadmium interferes with the antiproliferative effect of fulvestrant in endocrine therapy-resistant estrogen receptor α-positive breast cancer cells","authors":"Koki Kanameda , Masayo Hirao-Suzuki , Shuso Takeda","doi":"10.1016/j.toxlet.2026.111829","DOIUrl":"10.1016/j.toxlet.2026.111829","url":null,"abstract":"<div><div>Fulvestrant (FUL), an estrogen receptor α (ERα)-degradative anti-estrogen, is used alone or in combination with cyclin-dependent kinase 4/6 inhibitors for the treatment of advanced ERα-positive breast cancer (BC) in postmenopausal women. Cadmium (Cd), an environmental pollutant and metalloestrogen, binds to ERα as a ligand. Patients with BC may experience disease progression despite FUL treatment, suggesting potential interactions between FUL and Cd in long-term estrogen-deprived (LTED) cells. Therefore, the effect of FUL and Cd interaction in LTED cells, a model of postmenopausal BC, was investigated. LTED cells were treated with FUL and Cd at therapeutically or physiologically relevant concentrations, both simultaneously and sequentially (either with FUL treatment followed by Cd or Cd pre-treatment followed by FUL). FUL treatment alone decreased LTED cell viability; however, Cd pre/post-treatment attenuated the antiproliferative effect of FUL. Western blotting showed that Cd pre/post-treatment did not affect FUL-induced ERα degradation. Hence, Cd could suppress the antiproliferative effect of FUL in LTED cells.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111829"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960442","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}
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