Pub Date : 2025-11-01Epub Date: 2025-09-29DOI: 10.1016/j.toxlet.2025.111730
Xianhao Wang , Xinyue Wang , Ruxu Yan , Tianqi Ma , Xiangyun Wang , Fengxue Shi , Zhongxu Zhao , Lingyue Kong , Jingen Zhou , Dong Li , Yangyang Yuan
Environmental pollutants are increasingly recognized as important modulators of immune function, yet the influence of volatile organic compound (VOC) exposure on immunoglobulin E (IgE) levels remains poorly characterized. Using data from the National Health and Nutrition Examination Survey (NHANES) 2005–2006, we systematically evaluated the association between VOC metabolites and total IgE levels through five statistical approaches combined with machine learning algorithms. Mediation analyses were conducted to examine the role of inflammatory markers in these associations. Finally, functional enrichment analyses were employed to identify potential pathways and key molecular targets. Our analyses consistently demonstrated significant positive associations between VOC exposure and elevated total IgE levels. 2-aminothiazoline-4-carboxylic acid (ATCA), N-Acetyl-S-(2-cyanoethyl)-L-cysteine (CYMA), and N-Acetyl-S- (3-hydroxypropyl)-L-cysteine (HPMA) emerged as robust risk factors. Mediation analysis revealed that eosinophil (EOS) counts accounted for 15.89–29.03 % of the observed associations between VOC metabolites and total IgE levels. TNF and IL-17 signaling pathways were significantly enriched. Integrated analyses confirmed VOC exposure as a significant environmental risk factor for elevated total IgE levels, primarily driven by ATCA, CYMA, and HPMA, with inflammatory responses as a plausible mechanism.
环境污染物被越来越多地认为是免疫功能的重要调节剂，但挥发性有机化合物（VOC）暴露对免疫球蛋白E （IgE）水平的影响尚不清楚。利用2005-2006年国家健康与营养检查调查（NHANES）的数据，我们通过五种统计方法结合机器学习算法，系统地评估了VOC代谢物与总IgE水平之间的关系。进行中介分析以检查炎症标志物在这些关联中的作用。最后，利用功能富集分析来确定潜在的途径和关键的分子靶点。我们的分析一致表明，VOC暴露与总IgE水平升高之间存在显著的正相关。2-氨基噻唑-4-羧酸（ATCA）、n -乙酰基- s -（2-氰乙基）- l-半胱氨酸（CYMA）和n -乙酰基- s -（3-羟丙基）- l-半胱氨酸（HPMA）被认为是强有力的危险因素。调解分析显示，在观察到的VOC代谢物与总IgE水平之间的相关性中，嗜酸性粒细胞（EOS）计数占15.89% ~ 29.03%。TNF、IL-17信号通路显著富集（Padjust < 0.05）。综合分析证实，VOC暴露是总IgE水平升高的重要环境风险因素，主要由ATCA、CYMA和HPMA驱动，炎症反应是一种可能的机制。
{"title":"Association between volatile organic compound exposure and elevated total immunoglobulin E: Risk factor screening in mixed exposure scenarios and potential biological mechanisms","authors":"Xianhao Wang , Xinyue Wang , Ruxu Yan , Tianqi Ma , Xiangyun Wang , Fengxue Shi , Zhongxu Zhao , Lingyue Kong , Jingen Zhou , Dong Li , Yangyang Yuan","doi":"10.1016/j.toxlet.2025.111730","DOIUrl":"10.1016/j.toxlet.2025.111730","url":null,"abstract":"<div><div>Environmental pollutants are increasingly recognized as important modulators of immune function, yet the influence of volatile organic compound (VOC) exposure on immunoglobulin E (IgE) levels remains poorly characterized. Using data from the National Health and Nutrition Examination Survey (NHANES) 2005–2006, we systematically evaluated the association between VOC metabolites and total IgE levels through five statistical approaches combined with machine learning algorithms. Mediation analyses were conducted to examine the role of inflammatory markers in these associations. Finally, functional enrichment analyses were employed to identify potential pathways and key molecular targets. Our analyses consistently demonstrated significant positive associations between VOC exposure and elevated total IgE levels. 2-aminothiazoline-4-carboxylic acid (ATCA), N-Acetyl-S-(2-cyanoethyl)-L-cysteine (CYMA), and N-Acetyl-S- (3-hydroxypropyl)-L-cysteine (HPMA) emerged as robust risk factors. Mediation analysis revealed that eosinophil (EOS) counts accounted for 15.89–29.03 % of the observed associations between VOC metabolites and total IgE levels. TNF and IL-17 signaling pathways were significantly enriched. Integrated analyses confirmed VOC exposure as a significant environmental risk factor for elevated total IgE levels, primarily driven by ATCA, CYMA, and HPMA, with inflammatory responses as a plausible mechanism.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111730"},"PeriodicalIF":2.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207645","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 : 2025-11-01Epub Date: 2025-10-13DOI: 10.1016/j.toxlet.2025.111743
W. Kyle Mandler , Walter McKinney , Chaolong Qi , Alycia Knepp , Eun Gyung Lee , Seungkoo Kang , Sarah Keeley , Yong Qian
Background
Workers fabricating solid-surface composite (SSC) materials like Corian® are exposed to airborne particulate matter (PM) containing aluminum trihydrate (ATH) and potentially abrasive particles from sanding tools, leading to concerns about respiratory health effects like pulmonary fibrosis. However, the relative toxicological contributions of the SSC material versus the sandpaper abrasives remain unclear.
Objective
This study aimed to compare the in vitro cellular responses induced by respirable dust generated from sanding SSC with different commercial sandpapers (aluminum oxide [Al2O3], ceramic, silicon carbide [SiC]) to the responses elicited by ATH and corresponding abrasive analogue particles.
Methods
Respirable dust (PM with an aerodynamic diameter less than 5 µm) was generated from sanding Corian® using the three sandpaper types via a fluidized bed generator coupled with a cyclone separator. Human monocytic THP-1 cells, differentiated into macrophage-like cells, were exposed for 48 h to suspensions of these SSC dusts, ATH, or Al2O3, ceramic, and SiC abrasive analogue particles (10 µg/well). Cytotoxicity (LDH release), apoptosis (Caspase 3/7 activity), necrosis (propidium iodide uptake), cell cycle distribution, and nuclear morphology (including mono-, bi-, multi-, and micronucleation) and the Nuclear Division Index were assessed.
Results
Exposure to SSC dusts generated with any sandpaper type, as well as ATH, resulted in significant increases in apoptosis compared to controls. However, these exposures did not cause significant LDH release or alterations in cell cycle progression or mitotic indices. Conversely, the Al2O3, ceramic, and SiC abrasive analogue particles induced significant disruptions in cell cycle (S phase population reduction) and mitosis (increased multinucleation, micronucleation, and NDI), alongside apoptosis (Al2O3, SiC) or necrosis (ceramic, SiC), but also caused minimal LDH release.
Conclusion
Under these in vitro conditions, the apoptotic response to respirable SSC sanding dust appears primarily driven by components inherent to the SSC material itself, consistent with the effects of ATH. This response profile was distinct from the cell cycle arrest and mitotic disruption prominently caused by the abrasive analogue particles. These findings suggest the intrinsic properties of SSC material components are key drivers of initial macrophage responses in vitro, differing significantly from the effects of the abrasive materials alone.
{"title":"Differentiating the in vitro toxicity of solid-surface composite dust: A comparison of material components and abrasive particles","authors":"W. Kyle Mandler , Walter McKinney , Chaolong Qi , Alycia Knepp , Eun Gyung Lee , Seungkoo Kang , Sarah Keeley , Yong Qian","doi":"10.1016/j.toxlet.2025.111743","DOIUrl":"10.1016/j.toxlet.2025.111743","url":null,"abstract":"<div><h3>Background</h3><div>Workers fabricating solid-surface composite (SSC) materials like Corian® are exposed to airborne particulate matter (PM) containing aluminum trihydrate (ATH) and potentially abrasive particles from sanding tools, leading to concerns about respiratory health effects like pulmonary fibrosis. However, the relative toxicological contributions of the SSC material versus the sandpaper abrasives remain unclear.</div></div><div><h3>Objective</h3><div>This study aimed to compare the <em>in vitro</em> cellular responses induced by respirable dust generated from sanding SSC with different commercial sandpapers (aluminum oxide [Al2O3], ceramic, silicon carbide [SiC]) to the responses elicited by ATH and corresponding abrasive analogue particles.</div></div><div><h3>Methods</h3><div>Respirable dust (PM with an aerodynamic diameter less than 5 µm) was generated from sanding Corian® using the three sandpaper types via a fluidized bed generator coupled with a cyclone separator. Human monocytic THP-1 cells, differentiated into macrophage-like cells, were exposed for 48 h to suspensions of these SSC dusts, ATH, or Al2O3, ceramic, and SiC abrasive analogue particles (10 µg/well). Cytotoxicity (LDH release), apoptosis (Caspase 3/7 activity), necrosis (propidium iodide uptake), cell cycle distribution, and nuclear morphology (including mono-, bi-, multi-, and micronucleation) and the Nuclear Division Index were assessed.</div></div><div><h3>Results</h3><div>Exposure to SSC dusts generated with any sandpaper type, as well as ATH, resulted in significant increases in apoptosis compared to controls. However, these exposures did not cause significant LDH release or alterations in cell cycle progression or mitotic indices. Conversely, the Al2O3, ceramic, and SiC abrasive analogue particles induced significant disruptions in cell cycle (S phase population reduction) and mitosis (increased multinucleation, micronucleation, and NDI), alongside apoptosis (Al2O3, SiC) or necrosis (ceramic, SiC), but also caused minimal LDH release.</div></div><div><h3>Conclusion</h3><div>Under these <em>in vitro</em> conditions, the apoptotic response to respirable SSC sanding dust appears primarily driven by components inherent to the SSC material itself, consistent with the effects of ATH. This response profile was distinct from the cell cycle arrest and mitotic disruption prominently caused by the abrasive analogue particles. These findings suggest the intrinsic properties of SSC material components are key drivers of initial macrophage responses <em>in vitro</em>, differing significantly from the effects of the abrasive materials alone.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111743"},"PeriodicalIF":2.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145303577","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}
The constitutive androstane receptor (CAR, NR1I3) has been recognised as a nuclear receptor for various xenobiotics, such as barbiturates and dietary polyphenols. In this study, the CAR responded to internal metabolites produced by intestinal bacteria from the dietary amino acid tryptophan. We screened 15 indole-containing compounds in HepG2 cells using a luciferase reporter assay and found that three of them, tryptamine, indole-3-pyruvic acid, and indole-3-ethanol, significantly increased transcriptional activity of both mouse and human CAR. The estimated EC50 values of these compounds at the micromolar concentration order, which were close to those found in the host sera and tissues. Importantly, 3-methyl indole (skatole) inhibited mouse CAR activity to a lesser extent than androstanol, an inverse agonist of mouse CAR. Considering this, we investigated the transactivation mechanisms of these compounds in terms of their nuclear translocation. Indole-3-pyruvic acid and diindolylmethane slightly but not significantly increased the nuclear translocation of mouse CAR, whereas skatole significantly increased nuclear translocation. This is in contrast to the observation that androstanol does not induce nuclear translocation. Tryptamine is produced by Ruminococcus gnavus and skatole by Lactobacillus spp. Our findings suggest that the CAR can be positively or negatively regulated by indole-containing metabolites, depending on the composition of the gut microbiota.
{"title":"Distinct responses of the constitutive androstane receptor NR1I3 to indole-containing metabolites of bacterial origin","authors":"Ryuya Narita , Misaki Kaito , Takashi Kondo , Keiko Abe , Akihito Yasuoka","doi":"10.1016/j.toxlet.2025.111724","DOIUrl":"10.1016/j.toxlet.2025.111724","url":null,"abstract":"<div><div>The constitutive androstane receptor (CAR, NR1I3) has been recognised as a nuclear receptor for various xenobiotics, such as barbiturates and dietary polyphenols. In this study, the CAR responded to internal metabolites produced by intestinal bacteria from the dietary amino acid tryptophan. We screened 15 indole-containing compounds in HepG2 cells using a luciferase reporter assay and found that three of them, tryptamine, indole-3-pyruvic acid, and indole-3-ethanol, significantly increased transcriptional activity of both mouse and human CAR. The estimated EC<sub>50</sub> values of these compounds at the micromolar concentration order, which were close to those found in the host sera and tissues. Importantly, 3-methyl indole (skatole) inhibited mouse CAR activity to a lesser extent than androstanol, an inverse agonist of mouse CAR. Considering this, we investigated the transactivation mechanisms of these compounds in terms of their nuclear translocation. Indole-3-pyruvic acid and diindolylmethane slightly but not significantly increased the nuclear translocation of mouse CAR, whereas skatole significantly increased nuclear translocation. This is in contrast to the observation that androstanol does not induce nuclear translocation. Tryptamine is produced by <em>Ruminococcus gnavus</em> and skatole by <em>Lactobacillus spp</em>. Our findings suggest that the CAR can be positively or negatively regulated by indole-containing metabolites, depending on the composition of the gut microbiota.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111724"},"PeriodicalIF":2.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065540","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 : 2025-11-01Epub Date: 2025-10-07DOI: 10.1016/j.toxlet.2025.111741
Chenglong Zhang , Ruiqin Yang , Shuai Liu , Peng Li , Fei Guo
Exposure to methanethiol (MT) presents a significant challenge in public healthcare and could be a concern in the context of terrorist attacks. Therefore, reliable verification procedures for MT intoxication are essential for forensic, toxicological, and clinical purposes. We developed and validated a bioanalytical method for the simultaneous detection and identification of biomarkers indicative of MT exposure. Neat human serum albumin (HSA) and human plasma were incubated with MT to form adducts, which served as references. Subsequently, HSA and human plasma were subjected to proteolysis using two proteases, resulting in the formation of disulfide adducts detected as adducts of the single amino acid cysteine (MT-Cys), the dipeptide cysteine-proline (MT-Cys34Pro), and the tripeptides aspartic acid-isoleucine-cysteine (AspIleCys514-MT) and cysteine-proline-phenylalanine (MT-Cys34ProPhe). The adducts were analyzed using a sensitive ultra-performance liquid chromatography-quadrupole exactive orbitrap-high resolution mass spectrometry (UPLC-Q Exactive Orbitrap-HRMS) method operating in full scan mass spectrometry (Full MS) and parallel reaction monitoring (PRM) mode. Time- and concentration-dependent adduct formation during exposure was investigated. The limits of detection (LODs) for the adducts ranged from 20 ng/mL to 2 μg/mL, corresponding to the MT concentrations in plasma. Adducts at Cys34 exhibited the lowest LOD (20 ng/mL MT in plasma), the fastest adduct formation (20 min), and superior stability in plasma at 37 °C. The applicability of the method was demonstrated by the successful detection of adducts in sample from MT-poisoned patient, establishing the method as a reliable bioanalytical procedure for forensic and toxicological analysis.
{"title":"Human serum albumin-adduct biomarkers to prove human poisoning with methanethiol","authors":"Chenglong Zhang , Ruiqin Yang , Shuai Liu , Peng Li , Fei Guo","doi":"10.1016/j.toxlet.2025.111741","DOIUrl":"10.1016/j.toxlet.2025.111741","url":null,"abstract":"<div><div>Exposure to methanethiol (MT) presents a significant challenge in public healthcare and could be a concern in the context of terrorist attacks. Therefore, reliable verification procedures for MT intoxication are essential for forensic, toxicological, and clinical purposes. We developed and validated a bioanalytical method for the simultaneous detection and identification of biomarkers indicative of MT exposure. Neat human serum albumin (HSA) and human plasma were incubated with MT to form adducts, which served as references. Subsequently, HSA and human plasma were subjected to proteolysis using two proteases, resulting in the formation of disulfide adducts detected as adducts of the single amino acid cysteine (MT-Cys), the dipeptide cysteine-proline (MT-Cys<sup>34</sup>Pro), and the tripeptides aspartic acid-isoleucine-cysteine (<em>Asp</em>IleCys<sup>514</sup>-MT) and cysteine-proline-phenylalanine (MT-Cys<sup>34</sup>ProPhe). The adducts were analyzed using a sensitive ultra-performance liquid chromatography-quadrupole exactive orbitrap-high resolution mass spectrometry (UPLC-Q Exactive Orbitrap-HRMS) method operating in full scan mass spectrometry (Full MS) and parallel reaction monitoring (PRM) mode. Time- and concentration-dependent adduct formation during exposure was investigated. The limits of detection (LODs) for the adducts ranged from 20 ng/mL to 2 μg/mL, corresponding to the MT concentrations in plasma. Adducts at Cys<sup>34</sup> exhibited the lowest LOD (20 ng/mL MT in plasma), the fastest adduct formation (20 min), and superior stability in plasma at 37 °C. The applicability of the method was demonstrated by the successful detection of adducts in sample from MT-poisoned patient, establishing the method as a reliable bioanalytical procedure for forensic and toxicological analysis.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111741"},"PeriodicalIF":2.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252766","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 : 2025-11-01Epub Date: 2025-09-08DOI: 10.1016/j.toxlet.2025.111722
Jeong Weon Choi , Seungho Lee , Jangwoo Lee , Mi-Yeon Shin , Sungkyoon Kim
Environmental phenols are widely used in consumer products and are of increasing concern due to their potential endocrine-disrupting effects. Physiologically based toxicokinetic (PBTK) models offer a powerful tool for estimating human exposure by translating biomonitoring data into external intake values. However, conventional PBTK models are typically chemical-specific and resource-intensive. In this study, we developed a core human PBTK model capable of describing the absorption, distribution, metabolism, and excretion (ADME) of four groups of environmental phenols—parabens (MeP, EtP, PrP), bisphenols (BPA, BPS), triclosan (TCS), and benzophenone-3 (BP-3)—based on shared toxicokinetic characteristics.
The model was calibrated and validated using human volunteer data and applied to urinary biomonitoring data from 3787 Korean adults in the Korean National Environmental Health Survey (KoNEHS 2015–2017). Estimated daily intakes (EDIs) for MeP, EtP, PrP, and BPA were estimated via reverse dosimetry and compared with values derived from the conventional fractional urinary excretion (Fue) method. Median EDIs derived from the PBTK model were 3.7, 4.8, 0.4, and 0.02 μg/kg-bw/day for MeP, EtP, PrP, and BPA, respectively, and showed good agreement with Fue based estimates.
The core model successfully captured blood and urinary concentration profiles across multiple phenols, demonstrating its potential as a practical and scalable framework for exposure assessment. Furthermore, the model was used in a reverse dosimetry framework to estimate human exposure levels from urinary biomonitoring data. This approach can be particularly valuable when chemical-specific models are unavailable, offering an efficient alternative for interpreting biomonitoring data in environmental health risk assessment.
{"title":"A core physiologically based toxicokinetic (PBTK) model for exposure assessment of multiple environmental phenols","authors":"Jeong Weon Choi , Seungho Lee , Jangwoo Lee , Mi-Yeon Shin , Sungkyoon Kim","doi":"10.1016/j.toxlet.2025.111722","DOIUrl":"10.1016/j.toxlet.2025.111722","url":null,"abstract":"<div><div>Environmental phenols are widely used in consumer products and are of increasing concern due to their potential endocrine-disrupting effects. Physiologically based toxicokinetic (PBTK) models offer a powerful tool for estimating human exposure by translating biomonitoring data into external intake values. However, conventional PBTK models are typically chemical-specific and resource-intensive. In this study, we developed a core human PBTK model capable of describing the absorption, distribution, metabolism, and excretion (ADME) of four groups of environmental phenols—parabens (MeP, EtP, PrP), bisphenols (BPA, BPS), triclosan (TCS), and benzophenone-3 (BP-3)—based on shared toxicokinetic characteristics.</div><div>The model was calibrated and validated using human volunteer data and applied to urinary biomonitoring data from 3787 Korean adults in the Korean National Environmental Health Survey (KoNEHS 2015–2017). Estimated daily intakes (EDIs) for MeP, EtP, PrP, and BPA were estimated via reverse dosimetry and compared with values derived from the conventional fractional urinary excretion (<em>F</em><sub><em>ue</em></sub>) method. Median EDIs derived from the PBTK model were 3.7, 4.8, 0.4, and 0.02 μg/kg-bw/day for MeP, EtP, PrP, and BPA, respectively, and showed good agreement with <em>F</em><sub><em>ue</em></sub> based estimates.</div><div>The core model successfully captured blood and urinary concentration profiles across multiple phenols, demonstrating its potential as a practical and scalable framework for exposure assessment. Furthermore, the model was used in a reverse dosimetry framework to estimate human exposure levels from urinary biomonitoring data. This approach can be particularly valuable when chemical-specific models are unavailable, offering an efficient alternative for interpreting biomonitoring data in environmental health risk assessment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111722"},"PeriodicalIF":2.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034286","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 : 2025-11-01Epub Date: 2025-09-18DOI: 10.1016/j.toxlet.2025.111728
Fengting Liang , Shuaishuai Zhang , Wenhong Zhou , Guofang Bi , Xiao Yang , Peng Wang , Shicheng Fan , Shuang Hu , Chenghua Wu , Xiaowen Jiang , Dan Li , Hui Ouyang , Jian-Hong Fang , Huichang Bi
Constitutive Androstane Receptor (CAR) is a member of the nuclear receptor superfamily that significantly contributes to the metabolism of endogenous and exogenous substances and the homeostatic regulation of the body. Yes-associated protein (YAP) is a core component of the Hippo signaling pathway. We have previously demonstrated that CAR activation interacts with YAP and induces the nuclear translocation of YAP, although the specific binding site and regulatory mechanism remain unclear. In this study, we identified the ligand-binding domain (LBD) of CAR as essential for its interaction with YAP, while the WW domain (Tryptophan- Tryptophan domain) of YAP was found to be crucial for CAR binding. We further explored the impact of CAR activation on YAP post-translational modifications. CAR agonism inhibited YAP ubiquitination but promoted its SUMO1 modification, and had no effect on acetylation, glycosylation, and methylation. Notably, CAR activation enhanced the K63-linked ubiquitination of YAP, facilitating its nuclear translocation, and this effect was dependent on the E3 ligase TRAF6. Furthermore, PIAS4 was identified as a key SUMO E3 ligase, promoting YAP SUMO1 modification upon CAR activation. These findings provide new insights into how CAR regulates YAP activity through post-translational modifications, contributing to the understanding of CAR's role in liver regeneration.
{"title":"Constitutive androstane receptor activation modulates YAP expression and activity through ubiquitination and sumoylation","authors":"Fengting Liang , Shuaishuai Zhang , Wenhong Zhou , Guofang Bi , Xiao Yang , Peng Wang , Shicheng Fan , Shuang Hu , Chenghua Wu , Xiaowen Jiang , Dan Li , Hui Ouyang , Jian-Hong Fang , Huichang Bi","doi":"10.1016/j.toxlet.2025.111728","DOIUrl":"10.1016/j.toxlet.2025.111728","url":null,"abstract":"<div><div>Constitutive Androstane Receptor (CAR) is a member of the nuclear receptor superfamily that significantly contributes to the metabolism of endogenous and exogenous substances and the homeostatic regulation of the body. Yes-associated protein (YAP) is a core component of the Hippo signaling pathway. We have previously demonstrated that CAR activation interacts with YAP and induces the nuclear translocation of YAP, although the specific binding site and regulatory mechanism remain unclear. In this study, we identified the ligand-binding domain (LBD) of CAR as essential for its interaction with YAP, while the WW domain (Tryptophan- Tryptophan domain) of YAP was found to be crucial for CAR binding. We further explored the impact of CAR activation on YAP post-translational modifications. CAR agonism inhibited YAP ubiquitination but promoted its SUMO1 modification, and had no effect on acetylation, glycosylation, and methylation. Notably, CAR activation enhanced the K63-linked ubiquitination of YAP, facilitating its nuclear translocation, and this effect was dependent on the E3 ligase TRAF6. Furthermore, PIAS4 was identified as a key SUMO E3 ligase, promoting YAP SUMO1 modification upon CAR activation. These findings provide new insights into how CAR regulates YAP activity through post-translational modifications, contributing to the understanding of CAR's role in liver regeneration.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111728"},"PeriodicalIF":2.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103011","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 : 2025-11-01Epub Date: 2025-10-17DOI: 10.1016/j.toxlet.2025.111749
Haonan Li , Peng Yue , Qing Shao , Hongqun Qiao
This study aimed to explore the embryo-fetal developmental toxicity and concurrent toxicokinetic characteristics of YWS20045 in rats. Pregnant rats were divided into a solvent control group, three YWS20045 dose groups (4, 16 and 32 mg/kg), and a positive control group (3.5 mg/kg cyclophosphamide). Oral administration was conducted from gestation day (GD) 6–17. Results showed that all dose groups exhibited loose stools, with the high dose group experiencing significant maternal toxicity, including perianal soiling, reduced food intake, weight loss, increased dead fetuses on GD20 and mortality. YWS20045 crossed the placental barrier and accumulated in fetuses at all doses. Doses of 4 mg/kg and above significantly increased fetal rib deformities, affecting fetal growth and development. Toxicokinetic analysis revealed non-proportional increases in Cmax and AUC(0-t) of YWS20045 and its metabolite with dose. The drug was primarily distributed in the liver and lungs, with maternal metabolite mainly in the lungs. Therefore, the relatively safe oral dose of YWS20045 for maternal rats in the embryonic-fetal developmental toxicity study was determined to be 16 mg/kg or lower, whereas doses of 4 mg/kg and above were found to adversely affect fetal growth and development. These findings provide a critical basis for evaluating the reproductive safety of YWS20045 in clinical use.
{"title":"Embryo-fetal developmental toxicity and toxicokinetics studies of YWS20045 orally administered to pregnant rats","authors":"Haonan Li , Peng Yue , Qing Shao , Hongqun Qiao","doi":"10.1016/j.toxlet.2025.111749","DOIUrl":"10.1016/j.toxlet.2025.111749","url":null,"abstract":"<div><div>This study aimed to explore the embryo-fetal developmental toxicity and concurrent toxicokinetic characteristics of YWS20045 in rats. Pregnant rats were divided into a solvent control group, three YWS20045 dose groups (4, 16 and 32 mg/kg), and a positive control group (3.5 mg/kg cyclophosphamide). Oral administration was conducted from gestation day (GD) 6–17. Results showed that all dose groups exhibited loose stools, with the high dose group experiencing significant maternal toxicity, including perianal soiling, reduced food intake, weight loss, increased dead fetuses on GD<sub>20</sub> and mortality. YWS20045 crossed the placental barrier and accumulated in fetuses at all doses. Doses of 4 mg/kg and above significantly increased fetal rib deformities, affecting fetal growth and development. Toxicokinetic analysis revealed non-proportional increases in C<sub>max</sub> and AUC<sub>(0-t)</sub> of YWS20045 and its metabolite with dose. The drug was primarily distributed in the liver and lungs, with maternal metabolite mainly in the lungs. Therefore, the relatively safe oral dose of YWS20045 for maternal rats in the embryonic-fetal developmental toxicity study was determined to be 16 mg/kg or lower, whereas doses of 4 mg/kg and above were found to adversely affect fetal growth and development. These findings provide a critical basis for evaluating the reproductive safety of YWS20045 in clinical use.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111749"},"PeriodicalIF":2.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329989","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 : 2025-11-01Epub Date: 2025-10-09DOI: 10.1016/j.toxlet.2025.111742
Richa Soni , Santasabuj Das , Gopal Shankar Sahni , Dweipayan Goswami , Deepak Verma , Bikash Das , Palak Parmar
Every year, annual outbreaks of AES occur in lychee-growing regions: previously healthy children suddenly succumb to Acute Encephalitis Syndrome (AES). Initial suspicions pointed towards the seemingly innocent lychee fruit and its inherent toxins, Hypoglycin A and MCPG. However, the toxin-alone hypothesis is challenged by the fact that lychees are safely consumed globally. This discrepancy suggests that the development of severe illness is not caused by the toxins alone but requires specific host vulnerabilities, such as malnutrition, and co-factors like the consumption of unripe fruit on an empty stomach. This has prompted the consideration of alternative hypotheses. These include the role of pesticide contamination in orchards, potential bat-borne viral infections, and environmental stressors that may shift with seasons and geography. The striking differences in illness patterns observed in Bihar (India), Bangladesh, and Vietnam further complicate the picture. Moreover, documented reports of children falling ill with AES without any reported lychee consumption cast doubt on a singular explanation. This review delves into the heart of this enduring medical enigma, critically dissecting the compelling arguments and critical caveats surrounding each potential cause. This review critically evaluates the evidence for the multifaceted theories behind lychee-associated AES and challenges established assumptions. The analysis indicates a multifactorial etiology is responsible for this recurring childhood tragedy.
{"title":"Is lychee-associated encephalopathy in children a straightforward case of toxicity or a complex metabolic and environmental cascade?","authors":"Richa Soni , Santasabuj Das , Gopal Shankar Sahni , Dweipayan Goswami , Deepak Verma , Bikash Das , Palak Parmar","doi":"10.1016/j.toxlet.2025.111742","DOIUrl":"10.1016/j.toxlet.2025.111742","url":null,"abstract":"<div><div>Every year, annual outbreaks of AES occur in lychee-growing regions: previously healthy children suddenly succumb to Acute Encephalitis Syndrome (AES). Initial suspicions pointed towards the seemingly innocent lychee fruit and its inherent toxins, Hypoglycin A and MCPG. However, the toxin-alone hypothesis is challenged by the fact that lychees are safely consumed globally. This discrepancy suggests that the development of severe illness is not caused by the toxins alone but requires specific host vulnerabilities, such as malnutrition, and co-factors like the consumption of unripe fruit on an empty stomach. This has prompted the consideration of alternative hypotheses. These include the role of pesticide contamination in orchards, potential bat-borne viral infections, and environmental stressors that may shift with seasons and geography. The striking differences in illness patterns observed in Bihar (India), Bangladesh, and Vietnam further complicate the picture. Moreover, documented reports of children falling ill with AES without any reported lychee consumption cast doubt on a singular explanation. This review delves into the heart of this enduring medical enigma, critically dissecting the compelling arguments and critical caveats surrounding each potential cause. This review critically evaluates the evidence for the multifaceted theories behind lychee-associated AES and challenges established assumptions. The analysis indicates a multifactorial etiology is responsible for this recurring childhood tragedy.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111742"},"PeriodicalIF":2.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259214","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 : 2025-11-01Epub Date: 2025-09-29DOI: 10.1016/j.toxlet.2025.111732
Xiaoming Shen, Chuanqing Bao
Background
Bisphenol A (BPA) is a widespread endocrine-disrupting chemical found in consumer products. While BPA exposure has been associated with various health risks, its specific impact on colorectal cancer (CRC) progression and underlying mechanisms remain poorly understood.
Methods
In this five-year retrospective cohort study, we analyzed 63 CRC patients selected from an initial cohort of 574. Urinary BPA was quantified using HPLC-MS/MS, and patients were stratified into normal (n = 15), low (n = 30), and high (n = 18) BPA exposure groups. Flow cytometry and immunohistochemistry profiled immune cell populations in blood and tumor tissues. Multivariate regression analyses identified relationships between BPA exposure, metabolic parameters, and clinical outcomes.
Results
BPA levels showed significant inverse correlations with HDL/LDL ratio (p = 0.010) and positive correlations with BMI (p = 0.028). Patients with high BPA exposure demonstrated significantly higher rates of metastasis (61.1 % vs. 10 % in low exposure and 0 % in normal exposure groups, p < 0.001) and shorter overall survival (median 20 months vs. 51 months in low exposure group, p = 0.034). Flow cytometric analysis revealed dose-dependent reductions in circulating CD8 + T cells, CD4 + T cells, and NK cells with increasing BPA exposure. Immunohistochemical analysis showed pronounced decreases in tumor-infiltrating CD8 + T lymphocytes correlating with BPA exposure levels (p = 0.0027). High BPA exposure was also significantly associated with increased post-surgical infection rates (OR=1.9, 95 % CI: 1.1–3.1).
Conclusion
These preliminary findings suggest BPA exposure represents a potential risk factor for CRC progression, likely mediated through metabolic alterations and immunosuppression within the tumor microenvironment. Environmental exposures may significantly influence cancer outcomes through immune-metabolic pathways, though further validation in larger cohorts is warranted.
{"title":"Bisphenol A exposure associates with colorectal cancer metastasis and immunosuppression: A five-year cohort study","authors":"Xiaoming Shen, Chuanqing Bao","doi":"10.1016/j.toxlet.2025.111732","DOIUrl":"10.1016/j.toxlet.2025.111732","url":null,"abstract":"<div><h3>Background</h3><div>Bisphenol A (BPA) is a widespread endocrine-disrupting chemical found in consumer products. While BPA exposure has been associated with various health risks, its specific impact on colorectal cancer (CRC) progression and underlying mechanisms remain poorly understood.</div></div><div><h3>Methods</h3><div>In this five-year retrospective cohort study, we analyzed 63 CRC patients selected from an initial cohort of 574. Urinary BPA was quantified using HPLC-MS/MS, and patients were stratified into normal (n = 15), low (n = 30), and high (n = 18) BPA exposure groups. Flow cytometry and immunohistochemistry profiled immune cell populations in blood and tumor tissues. Multivariate regression analyses identified relationships between BPA exposure, metabolic parameters, and clinical outcomes.</div></div><div><h3>Results</h3><div>BPA levels showed significant inverse correlations with HDL/LDL ratio (p = 0.010) and positive correlations with BMI (p = 0.028). Patients with high BPA exposure demonstrated significantly higher rates of metastasis (61.1 % vs. 10 % in low exposure and 0 % in normal exposure groups, p < 0.001) and shorter overall survival (median 20 months vs. 51 months in low exposure group, p = 0.034). Flow cytometric analysis revealed dose-dependent reductions in circulating CD8 + T cells, CD4 + T cells, and NK cells with increasing BPA exposure. Immunohistochemical analysis showed pronounced decreases in tumor-infiltrating CD8 + T lymphocytes correlating with BPA exposure levels (p = 0.0027). High BPA exposure was also significantly associated with increased post-surgical infection rates (OR=1.9, 95 % CI: 1.1–3.1).</div></div><div><h3>Conclusion</h3><div>These preliminary findings suggest BPA exposure represents a potential risk factor for CRC progression, likely mediated through metabolic alterations and immunosuppression within the tumor microenvironment. Environmental exposures may significantly influence cancer outcomes through immune-metabolic pathways, though further validation in larger cohorts is warranted.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111732"},"PeriodicalIF":2.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207662","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 : 2025-11-01Epub Date: 2025-10-15DOI: 10.1016/j.toxlet.2025.111747
Shikha, Keerti Gautam, Muskan Sharma
This review provides a comprehensive analysis of the toxicology, mechanistic pathways, and regulatory evaluations of 4-methylimidazole (4-MI), a nitrogen-containing compound formed during caramel coloring production and industrial synthesis. The study aimed to consolidate evidence on health risks and clarify regulatory inconsistencies. Experimental models show that 4-MI induces hepatotoxicity via oxidative stress, mitochondrial dysfunction, and inflammation, leading to liver cell damage. Neurotoxicity includes behavioral changes, brain mitochondrial injury, and teratogenic effects. Reproductive toxicity has been observed in rodents and zebrafish, impairing sperm function, hormone production, and embryonic development. Although cytotoxic and genotoxic effects—such as DNA damage and chromosomal aberrations—have been reported, standard mutagenicity assays largely remain negative, contributing to regulatory uncertainty. California classifies 4-MI as a possible carcinogen with strict exposure limits, while EFSA finds genotoxic evidence insufficient. Emerging studies also link 4-MI to disruptions in glucose and lipid metabolism, raising concerns about chronic low-dose dietary exposure. Overall, these findings highlight significant public health risks and the urgent need for further toxicodynamic research to inform harmonized regulations and more accurate risk assessments.
{"title":"Toxicological evaluation of 4-methylimidazole: Research advances, health concerns and regulatory perspectives","authors":"Shikha, Keerti Gautam, Muskan Sharma","doi":"10.1016/j.toxlet.2025.111747","DOIUrl":"10.1016/j.toxlet.2025.111747","url":null,"abstract":"<div><div>This review provides a comprehensive analysis of the toxicology, mechanistic pathways, and regulatory evaluations of 4-methylimidazole (4-MI), a nitrogen-containing compound formed during caramel coloring production and industrial synthesis. The study aimed to consolidate evidence on health risks and clarify regulatory inconsistencies. Experimental models show that 4-MI induces hepatotoxicity via oxidative stress, mitochondrial dysfunction, and inflammation, leading to liver cell damage. Neurotoxicity includes behavioral changes, brain mitochondrial injury, and teratogenic effects. Reproductive toxicity has been observed in rodents and zebrafish, impairing sperm function, hormone production, and embryonic development. Although cytotoxic and genotoxic effects—such as DNA damage and chromosomal aberrations—have been reported, standard mutagenicity assays largely remain negative, contributing to regulatory uncertainty. California classifies 4-MI as a possible carcinogen with strict exposure limits, while EFSA finds genotoxic evidence insufficient. Emerging studies also link 4-MI to disruptions in glucose and lipid metabolism, raising concerns about chronic low-dose dietary exposure. Overall, these findings highlight significant public health risks and the urgent need for further toxicodynamic research to inform harmonized regulations and more accurate risk assessments.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111747"},"PeriodicalIF":2.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313935","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号