Pub Date : 2025-12-01Epub Date: 2025-11-29DOI: 10.1016/j.toxlet.2025.111785
Yuqin Chen , Zixia Hu , Guode Zhao , Mei Li , Ziying Jiang , Liangjia Xu , Jiannan Zheng , Weiwei Li , Ying Peng , Jiang Zheng
Arctigenin (ATG) is an important component isolated from the fruit of the medicinal plant Arctium lappa L., with anti-inflammatory, antiviral and anti-tumor properties. Although ATG has been reported to induce hepatotoxicity in beagle dogs and SD rats, and the underlying mechanisms remained unclear. The aim of this study was to investigate the metabolic activation of ATG and to define the potential correlation between the metabolic activation of ATG and its hepatotoxicity. A quinone methide intermediate was identified in vitro and in vivo, and CYP3A dominated the metabolic activation. ATG was found to show significant cytotoxicity at 50 μM in cultured mouse primary hepatocytes. The ATG-derived quinone methide metabolite assaulted cysteine residue of hepatic protein to form protein covalent binding. The observed protein modification was most likely associated with the cytotoxicity of ATG observed.
{"title":"Metabolic activation, hepatic protein covalent binding, and cytotoxicity of arctigenin","authors":"Yuqin Chen , Zixia Hu , Guode Zhao , Mei Li , Ziying Jiang , Liangjia Xu , Jiannan Zheng , Weiwei Li , Ying Peng , Jiang Zheng","doi":"10.1016/j.toxlet.2025.111785","DOIUrl":"10.1016/j.toxlet.2025.111785","url":null,"abstract":"<div><div>Arctigenin (ATG) is an important component isolated from the fruit of the medicinal plant <em>Arctium lappa</em> L., with anti-inflammatory, antiviral and anti-tumor properties. Although ATG has been reported to induce hepatotoxicity in beagle dogs and SD rats, and the underlying mechanisms remained unclear. The aim of this study was to investigate the metabolic activation of ATG and to define the potential correlation between the metabolic activation of ATG and its hepatotoxicity. A quinone methide intermediate was identified <em>in vitro</em> and <em>in vivo</em>, and CYP3A dominated the metabolic activation. ATG was found to show significant cytotoxicity at 50 μM in cultured mouse primary hepatocytes. The ATG-derived quinone methide metabolite assaulted cysteine residue of hepatic protein to form protein covalent binding. The observed protein modification was most likely associated with the cytotoxicity of ATG observed.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111785"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145655715","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 : 2025-12-01Epub Date: 2025-10-24DOI: 10.1016/j.toxlet.2025.111754
Heba Mohamed Aboubakr , Shimaa Ahmed Alsaeed , Rabab Abdulmoez Amin Eltokhy , Sally Magdy , Nehal Mohammad Helmy , Aziza B. Shalby , Salwa M. Kassem , Mohamed I. Mabrouk , Wagdy K.B. Khalil , Noha Maher Elrewieny
Background
Asthma is a prevalent health condition with significant global impact. Heavy metals, especially lead and cadmium, have been markedly linked to asthma etiology, however, studying their epigenetic mechanisms remains limited.
Aim
to study the association between exposure to lead and cadmium, the methylation of the ADRB2 gene, and the expression of miRNA-146a in adult asthma patients.
Methods
A case-control study included 35 adult asthma patients and 35 sex and age-matched healthy controls. Blood lead, cadmium, ADRB2 5′-UTR methylation and miRNA-146a expression levels were measured for all participants.
Results
Blood cadmium and ADRB2 5′-UTR methylation levels showed significantly higher values, blood lead levels showed higher, but nonsignificant, values, miRNA-146a expression levels showed significantly lower values in asthma patients, compared to controls. Blood cadmium positively correlated with ADRB2 5′-UTR methylation and negatively correlated with miRNA-146a expression. Regression analysis found that blood cadmium, ADRB2 5′-UTR methylation, and miRNA-146a expression levels were associated with asthma occurrence, showing significant odds ratios (95 % CI). Significant novel cutoff values for differentiating between healthy and asthmatic patients were set by ROC curve analysis.
Conclusion
Blood cadmium is significantly linked to asthma, with increased ADRB2 5′-UTR methylation, and reduced miRNA-146a expression. The significant odds ratios and the novel cut off values demonstrate potential clinical applicability, offering promising epigenetic biomarkers for asthma prediction and diagnosis in Egyptian adults. Measures to minimize heavy metals’ environmental exposure are recommended.
{"title":"Epigenetic effects of cadmium and lead in asthma: Cadmium-specific associations with ADRB2 methylation and miRNA-146a expression in Egyptian Adults","authors":"Heba Mohamed Aboubakr , Shimaa Ahmed Alsaeed , Rabab Abdulmoez Amin Eltokhy , Sally Magdy , Nehal Mohammad Helmy , Aziza B. Shalby , Salwa M. Kassem , Mohamed I. Mabrouk , Wagdy K.B. Khalil , Noha Maher Elrewieny","doi":"10.1016/j.toxlet.2025.111754","DOIUrl":"10.1016/j.toxlet.2025.111754","url":null,"abstract":"<div><h3>Background</h3><div>Asthma is a prevalent health condition with significant global impact. Heavy metals, especially lead and cadmium, have been markedly linked to asthma etiology, however, studying their epigenetic mechanisms remains limited.</div></div><div><h3>Aim</h3><div>to study the association between exposure to lead and cadmium, the methylation of the ADRB2 gene, and the expression of miRNA-146a in adult asthma patients.</div></div><div><h3>Methods</h3><div>A case-control study included 35 adult asthma patients and 35 sex and age-matched healthy controls. Blood lead, cadmium, ADRB2 5′-UTR methylation and miRNA-146a expression levels were measured for all participants.</div></div><div><h3>Results</h3><div>Blood cadmium and ADRB2 5′-UTR methylation levels showed significantly higher values, blood lead levels showed higher, but nonsignificant, values, miRNA-146a expression levels showed significantly lower values in asthma patients, compared to controls. Blood cadmium positively correlated with ADRB2 5′-UTR methylation and negatively correlated with miRNA-146a expression. Regression analysis found that blood cadmium, ADRB2 5′-UTR methylation, and miRNA-146a expression levels were associated with asthma occurrence, showing significant odds ratios (95 % CI). Significant novel cutoff values for differentiating between healthy and asthmatic patients were set by ROC curve analysis.</div></div><div><h3>Conclusion</h3><div>Blood cadmium is significantly linked to asthma, with increased ADRB2 5′-UTR methylation, and reduced miRNA-146a expression. The significant odds ratios and the novel cut off values demonstrate potential clinical applicability, offering promising epigenetic biomarkers for asthma prediction and diagnosis in Egyptian adults. Measures to minimize heavy metals’ environmental exposure are recommended.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111754"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370493","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 : 2025-12-01Epub Date: 2025-11-04DOI: 10.1016/j.toxlet.2025.111771
W. Steiling , H. Assaf Vandecasteele , F. Boisleve , T. Burke , D. Keller , G. Pappa , A. Gurjanov , A. Giusti , A.M. Bowden
Consumer products such as cosmetic spray products must be safe. Strict rules to ensure this for cosmetic spray products are established by the EU Cosmetic Products Regulation, as well as by scientific advisory panels. In this article several default values are proposed from the literature to improve the consistency and accuracy of inhalation exposure assessments performed for cosmetic spray products. The use of these default values is given for the most relevant spray product types currently on the EU market. The use of well-known exposure calculation models (e.g. one-box and two-box models) are discussed for their applicability to estimate consumer inhalation exposure to certain spray product types. The availability of measured data from experimental studies is limited due to the complication caused by parameters such as technical product information relating to droplet/particle sizing of the airborne product. In some cases, there is reliance on conservative, worst-case input values (e.g., spray time and the amount released from the product container) for exposure assessment of individual product uses. Where the authors have identified data gaps for certain parameters for specific product types during the literature review, recommendations are provided for additional consolidated default values to promote the safety assessment.
{"title":"Recommendations for the calculation of inhalation exposure to cosmetic spray products: A comprehensive review","authors":"W. Steiling , H. Assaf Vandecasteele , F. Boisleve , T. Burke , D. Keller , G. Pappa , A. Gurjanov , A. Giusti , A.M. Bowden","doi":"10.1016/j.toxlet.2025.111771","DOIUrl":"10.1016/j.toxlet.2025.111771","url":null,"abstract":"<div><div>Consumer products such as cosmetic spray products must be safe. Strict rules to ensure this for cosmetic spray products are established by the EU Cosmetic Products Regulation, as well as by scientific advisory panels. In this article several default values are proposed from the literature to improve the consistency and accuracy of inhalation exposure assessments performed for cosmetic spray products. The use of these default values is given for the most relevant spray product types currently on the EU market. The use of well-known exposure calculation models (e.g. one-box and two-box models) are discussed for their applicability to estimate consumer inhalation exposure to certain spray product types. The availability of measured data from experimental studies is limited due to the complication caused by parameters such as technical product information relating to droplet/particle sizing of the airborne product. In some cases, there is reliance on conservative, worst-case input values (e.g., spray time and the amount released from the product container) for exposure assessment of individual product uses. Where the authors have identified data gaps for certain parameters for specific product types during the literature review, recommendations are provided for additional consolidated default values to promote the safety assessment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111771"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459866","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}
O,O-Dimethyl O-(2,2-dichlorovinyl) phosphate (DDVP), commonly referred to as dichlorvos, is one of the most widely used organophosphorus insecticides for agricultural and domestic pest control, especially in low- and middle-income countries, due to its low cost and effectiveness. While acute neurotoxicity through the irreversible inhibition of AChE and subsequent cholinergic overstimulation is well documented, there is growing evidence that DDVP exerts broader chronic effects, particularly those involving the neurovascular system. Specifically, endothelial dysfunction and disruption of the bloodbrain barrier have been shown to be early events that link vascular injury to neurodegeneration. These databases included PubMed, Scopus, Web of Science, ScienceDirect, EMBASE, and the Toxicology Data Network. The terms used in the search included "dichlorvos," "DDVP," "organophosphate pesticide," "neurotoxicity," "endothelial dysfunction," "bloodbrain barrier," "neurodegeneration," "oxidative stress," and "crosstalk." The inclusion criterion was peer-reviewed studies published in English between 2000 and 2025, which involved in vivo and in vitro experimental studies that reported DDVP-induced neurovascular toxicity. Studies not related to DDVP, publications in languages other than English, and non-peer-reviewed sources were excluded. Studies suggest that DDVP impairs endothelial integrity through disrupting the homeostasis of oxidative stress, nitric oxide, and inflammatory signalling. This type of endothelial insult impairs selectivity in BBB permeability, enabling the infiltration of circulating toxins and cytokines into the central nervous system, thus promoting neuronal apoptosis, mitochondrial dysfunction, and neuroinflammation. These findings suggest that the neurotoxicity of DDVP extends beyond synaptic cholinergic mechanisms but includes neurovascular-crosstalk-driven degeneration. This review synthesizes current mechanistic insights into DDVP-induced neurovascular toxicity and recognizes the neurovascular unit as a critical target in organophosphate poisoning. Elucidation of the interplay between endothelial dysfunction and neuronal injury opens new avenues for risk assessment, preventive strategies, and therapeutic interventions for pesticide-related neurodegenerative disorders.
O，O-二甲基O-（2,2-二氯乙烯基）磷酸盐（DDVP），通常被称为敌敌畏，是农业和家庭病虫害防治中使用最广泛的有机磷杀虫剂之一，特别是在低收入和中等收入国家，因为它的成本低，效果好。尽管对乙酰胆碱酯酶的不可逆抑制和随后的胆碱能过度刺激引起的急性神经毒性已得到充分证明，但越来越多的证据表明，DDVP具有更广泛的慢性效应，特别是涉及神经血管系统的慢性效应。具体而言，内皮功能障碍和血脑屏障的破坏已被证明是血管损伤与神经变性相关的早期事件。这些数据库包括PubMed、Scopus、Web of Science、ScienceDirect、EMBASE和毒理学数据网络。搜索中使用的术语包括“敌敌畏”、“敌敌畏”、“有机磷农药”、“神经毒性”、“内皮功能障碍”、“血脑屏障”、“神经变性”、“氧化应激”和“相声”。纳入标准是2000年至2025年间以英文发表的同行评议研究，涉及报道ddvp诱导的神经血管毒性的体内和体外实验研究。与DDVP无关的研究、非英语语言的出版物和非同行评议来源被排除在外。研究表明，DDVP通过破坏氧化应激、一氧化氮和炎症信号的稳态来损害内皮细胞的完整性。这种类型的内皮损伤损害血脑屏障通透性的选择性，使循环毒素和细胞因子渗入中枢神经系统，从而促进神经元凋亡、线粒体功能障碍和神经炎症。这些发现表明，DDVP的神经毒性超出了突触胆碱能机制，但包括神经血管串扰驱动的变性。这篇综述综合了目前ddvp诱导的神经血管毒性的机制见解，并认识到神经血管单位是有机磷中毒的关键靶点。阐明内皮功能障碍和神经元损伤之间的相互作用，为农药相关神经退行性疾病的风险评估、预防策略和治疗干预开辟了新的途径。
{"title":"Neurovascular toxicity of dichlorvos: Crosstalk between endothelial dysfunction and neurodegeneration","authors":"Igbayilola Yusuff Dimeji , Ngabea Murtala , Adekola Saheed Ayodeji , Hmaidu Lawan Jabba","doi":"10.1016/j.toxlet.2025.111775","DOIUrl":"10.1016/j.toxlet.2025.111775","url":null,"abstract":"<div><div>O,O-Dimethyl O-(2,2-dichlorovinyl) phosphate (DDVP), commonly referred to as dichlorvos, is one of the most widely used organophosphorus insecticides for agricultural and domestic pest control, especially in low- and middle-income countries, due to its low cost and effectiveness. While acute neurotoxicity through the irreversible inhibition of AChE and subsequent cholinergic overstimulation is well documented, there is growing evidence that DDVP exerts broader chronic effects, particularly those involving the neurovascular system. Specifically, endothelial dysfunction and disruption of the blood<img>brain barrier have been shown to be early events that link vascular injury to neurodegeneration. These databases included PubMed, Scopus, Web of Science, ScienceDirect, EMBASE, and the Toxicology Data Network. The terms used in the search included \"dichlorvos,\" \"DDVP,\" \"organophosphate pesticide,\" \"neurotoxicity,\" \"endothelial dysfunction,\" \"blood<img>brain barrier,\" \"neurodegeneration,\" \"oxidative stress,\" and \"crosstalk.\" The inclusion criterion was peer-reviewed studies published in English between 2000 and 2025, which involved in vivo and in vitro experimental studies that reported DDVP-induced neurovascular toxicity. Studies not related to DDVP, publications in languages other than English, and non-peer-reviewed sources were excluded. Studies suggest that DDVP impairs endothelial integrity through disrupting the homeostasis of oxidative stress, nitric oxide, and inflammatory signalling. This type of endothelial insult impairs selectivity in BBB permeability, enabling the infiltration of circulating toxins and cytokines into the central nervous system, thus promoting neuronal apoptosis, mitochondrial dysfunction, and neuroinflammation. These findings suggest that the neurotoxicity of DDVP extends beyond synaptic cholinergic mechanisms but includes neurovascular-crosstalk-driven degeneration. This review synthesizes current mechanistic insights into DDVP-induced neurovascular toxicity and recognizes the neurovascular unit as a critical target in organophosphate poisoning. Elucidation of the interplay between endothelial dysfunction and neuronal injury opens new avenues for risk assessment, preventive strategies, and therapeutic interventions for pesticide-related neurodegenerative disorders.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111775"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530686","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 : 2025-12-01Epub Date: 2025-11-28DOI: 10.1016/j.toxlet.2025.111781
Xin-xin Zhu , Wei-wei Zhang , Ming-yue Hao , Zheng-ya Chen , Bai-fan Wan , Ming-hui Niu , Xiu-liang Li , Jian-hua Wei , Su-ya Liu , Shuang-ling Mi , Hua Wang , De-xiang Xu , Lan Gao
1-Nitropyrene (1-NP), a representative reproductive toxicant enriched in nitro-PAHs, is a known reproductive toxicant. Although our previous studies demonstrated that 1-NP impairs testosterone synthesis, its effects on other critical processes in testosterone biosynthesis, particularly cholesterol metabolism, remain unknown. Using in vivo and in vitro models, we investigated 1-NP’s effects on cholesterol homeostasis and steroidogenesis. Mice were exposed to 1-NP (0, 1.25, 5 mg/kg), a mouse Leydig tumor cell line (MLTC-1) were treated with 0.1, 1 μM 1-NP along with hCG stimulation. IBMX was used for intervention experiment. Key assays included ELISA, qPCR, Western blot, filipin staining, and cholesterol/testosterone quantification. This study demonstrates that 1-NP exposure significantly depletes intracellular free cholesterol without altering total cholesterol, leading to testosterone reduction. Mechanistically, 1-NP decreases cAMP levels, impairing PKA nuclear translocation and CREB Ser133 phosphorylation, thereby downregulating the cholesterol synthesis rate-limiting enzyme HMGCR at both transcriptional and translational levels. Critically, phosphodiesterase inhibitor IBMX rescues cAMP levels, reverses HMGCR suppression, and restores free cholesterol pools and testosterone synthesis, establishing that 1-NP induces endocrine disruption via a novel cholesterol metabolic pathway. While limitations exist, this work redefines 1-NP toxicity as "metabolic sabotage" of specialized endocrine pathways, providing a framework for signal-pathway-targeted interventions against pollution-associated endocrine disruption.
{"title":"1-NP hijacks endocrine-metabolic checkpoints and disrupts testicular steroidogenesis by suppressing the cAMP-PKA-CREB-HMGCR axis","authors":"Xin-xin Zhu , Wei-wei Zhang , Ming-yue Hao , Zheng-ya Chen , Bai-fan Wan , Ming-hui Niu , Xiu-liang Li , Jian-hua Wei , Su-ya Liu , Shuang-ling Mi , Hua Wang , De-xiang Xu , Lan Gao","doi":"10.1016/j.toxlet.2025.111781","DOIUrl":"10.1016/j.toxlet.2025.111781","url":null,"abstract":"<div><div>1-Nitropyrene (1-NP), a representative reproductive toxicant enriched in nitro-PAHs, is a known reproductive toxicant. Although our previous studies demonstrated that 1-NP impairs testosterone synthesis, its effects on other critical processes in testosterone biosynthesis, particularly cholesterol metabolism, remain unknown. Using <em>in vivo</em> and <em>in vitro</em> models, we investigated 1-NP’s effects on cholesterol homeostasis and steroidogenesis. Mice were exposed to 1-NP (0, 1.25, 5 mg/kg), a mouse Leydig tumor cell line (MLTC-1) were treated with 0.1, 1 μM 1-NP along with hCG stimulation. IBMX was used for intervention experiment. Key assays included ELISA, qPCR, Western blot, filipin staining, and cholesterol/testosterone quantification. This study demonstrates that 1-NP exposure significantly depletes intracellular free cholesterol without altering total cholesterol, leading to testosterone reduction. Mechanistically, 1-NP decreases cAMP levels, impairing PKA nuclear translocation and CREB Ser133 phosphorylation, thereby downregulating the cholesterol synthesis rate-limiting enzyme HMGCR at both transcriptional and translational levels. Critically, phosphodiesterase inhibitor IBMX rescues cAMP levels, reverses HMGCR suppression, and restores free cholesterol pools and testosterone synthesis, establishing that 1-NP induces endocrine disruption via a novel cholesterol metabolic pathway. While limitations exist, this work redefines 1-NP toxicity as \"metabolic sabotage\" of specialized endocrine pathways, providing a framework for signal-pathway-targeted interventions against pollution-associated endocrine disruption.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111781"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649337","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 : 2025-12-01Epub Date: 2025-11-14DOI: 10.1016/j.toxlet.2025.111776
Karen B. Méndez-Rodríguez , Francisco J. Pérez-Vázquez , Evelyn Van Brussel , Ana K. González-Palomo , Axel Reyes-Zavala , Kelvin Saldaña-Villanueva
Children engaged in precarious labor activities may experience exposure to environmental contaminants, including heavy metals, particularly in marginalized communities. Limited evidence exists regarding the potential hematological implications of such exposures in pediatric populations. A cross-sectional study was conducted among 50 children (<18 years) from three communities in San Luis Potosí, Mexico, engaged in informal recycling (Zone B), artisanal brickmaking (Zone C), or artisanal stone-carving (Zone A). Urinary concentrations of 15 metals were determined by ICP–MS, and hematological parameters were assessed using an automated analyzer. Associations were examined using nonparametric statistics, age-adjusted correlations, Bayesian Kendall’s Tau analysis, and post hoc power evaluation. Distinct urinary metal profiles and hematological parameters were observed across the study zones. Zone B showed higher concentrations of Cr, Co, Ni, Al, and Sn, whereas As was elevated in Zone C. Hematological differences included higher WBC, lymphocyte, granulocyte counts, and MPV in Zone C. Age-adjusted correlations identified associations of As with WBC, lymphocyte, and granulocyte counts; Co with platelet indices; and negative correlations of Ni, Al, and Sn with several hematological variables. Bayesian analysis confirmed robust associations for Co with WBC, Al with granulocytes, and Sn with MPV. This study provides exploratory evidence of associations between urinary metal concentrations and hematological parameters in children engaged in precarious labor activities. While preliminary, the findings underscore the importance of child-focused public health strategies and support the need for larger, longitudinal studies to validate these associations and clarify their implications.
{"title":"Hematological effects of chronic heavy metal exposure in children from marginalized occupational communities in Mexico","authors":"Karen B. Méndez-Rodríguez , Francisco J. Pérez-Vázquez , Evelyn Van Brussel , Ana K. González-Palomo , Axel Reyes-Zavala , Kelvin Saldaña-Villanueva","doi":"10.1016/j.toxlet.2025.111776","DOIUrl":"10.1016/j.toxlet.2025.111776","url":null,"abstract":"<div><div>Children engaged in precarious labor activities may experience exposure to environmental contaminants, including heavy metals, particularly in marginalized communities. Limited evidence exists regarding the potential hematological implications of such exposures in pediatric populations. A cross-sectional study was conducted among 50 children (<18 years) from three communities in San Luis Potosí, Mexico, engaged in informal recycling (Zone B), artisanal brickmaking (Zone C), or artisanal stone-carving (Zone A). Urinary concentrations of 15 metals were determined by ICP–MS, and hematological parameters were assessed using an automated analyzer. Associations were examined using nonparametric statistics, age-adjusted correlations, Bayesian Kendall’s Tau analysis, and post hoc power evaluation. Distinct urinary metal profiles and hematological parameters were observed across the study zones. Zone B showed higher concentrations of Cr, Co, Ni, Al, and Sn, whereas As was elevated in Zone C. Hematological differences included higher WBC, lymphocyte, granulocyte counts, and MPV in Zone C. Age-adjusted correlations identified associations of As with WBC, lymphocyte, and granulocyte counts; Co with platelet indices; and negative correlations of Ni, Al, and Sn with several hematological variables. Bayesian analysis confirmed robust associations for Co with WBC, Al with granulocytes, and Sn with MPV. This study provides exploratory evidence of associations between urinary metal concentrations and hematological parameters in children engaged in precarious labor activities. While preliminary, the findings underscore the importance of child-focused public health strategies and support the need for larger, longitudinal studies to validate these associations and clarify their implications.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111776"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534776","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 : 2025-12-01Epub Date: 2025-11-26DOI: 10.1016/j.toxlet.2025.111783
Xinfang Tan , Jinglan Li , Yang Peng , Guoli Huang , Lijuan Yu , Guocheng Hu , Liangliang Xu
In recent years, decabromodiphenyl ethane (DBDPE), a type of brominated flame retardant, has gained popularity in industry as an alternative to decabromodiphenyl ether (BDEs). However, DBDPE exposure poses environmental pollution and primarily impacts muscle contraction and the reproductive endocrine system. The cellular implications and underlying mechanisms of DBDPE's effects on muscle remain poorly understood. In the present study, we investigated the effect of DBDPE on myoblast differentiation, apoptosis, as well as the potential mechanisms involved. The results demonstrated that exposure to DBDPE disrupted the differentiation of myotubes, inhibited cell proliferation, and increased levels of reactive oxygen species (ROS), ultimately leading to cell death. In addition, the RNAseq analysis revealed that DBDPE mainly affected the biological processes in mitochondria related to oxidative phosphorylation, ATP synthesis coupled electron transport, etc. Then we demonstrated that DBDPE inhibited mitochondrial membrane potential and ATP production, implying DBDPE resulted in mitochondrial dysfunction in C2C12 cells. Mechanistically, we showed that PI3K/AKT/mTOR signaling pathway was inhibited by DBDPE in C2C12 cells. And the apoptosis rate was significantly increased by DBDPE as demonstrated by increased active caspase-3 and TUNEL signal. Taken together, these findings suggest that low-dose exposure to DBDPE hampers myogenic differentiation and mitochondrial function, and increased cellular apoptosis through PI3K/AKT/mTOR signaling pathway, providing important insights for understanding its environmental toxic effects and conducting risk assessments.
{"title":"DBDPE inhibits myogenic differentiation of C2C12 cells through inhibiting mitochondrial function and PI3K/AKT/mTOR signaling pathway","authors":"Xinfang Tan , Jinglan Li , Yang Peng , Guoli Huang , Lijuan Yu , Guocheng Hu , Liangliang Xu","doi":"10.1016/j.toxlet.2025.111783","DOIUrl":"10.1016/j.toxlet.2025.111783","url":null,"abstract":"<div><div>In recent years, decabromodiphenyl ethane (DBDPE), a type of brominated flame retardant, has gained popularity in industry as an alternative to decabromodiphenyl ether (BDEs). However, DBDPE exposure poses environmental pollution and primarily impacts muscle contraction and the reproductive endocrine system. The cellular implications and underlying mechanisms of DBDPE's effects on muscle remain poorly understood. In the present study, we investigated the effect of DBDPE on myoblast differentiation, apoptosis, as well as the potential mechanisms involved. The results demonstrated that exposure to DBDPE disrupted the differentiation of myotubes, inhibited cell proliferation, and increased levels of reactive oxygen species (ROS), ultimately leading to cell death. In addition, the RNAseq analysis revealed that DBDPE mainly affected the biological processes in mitochondria related to oxidative phosphorylation, ATP synthesis coupled electron transport, etc. Then we demonstrated that DBDPE inhibited mitochondrial membrane potential and ATP production, implying DBDPE resulted in mitochondrial dysfunction in C2C12 cells. Mechanistically, we showed that PI3K/AKT/mTOR signaling pathway was inhibited by DBDPE in C2C12 cells. And the apoptosis rate was significantly increased by DBDPE as demonstrated by increased active caspase-3 and TUNEL signal. Taken together, these findings suggest that low-dose exposure to DBDPE hampers myogenic differentiation and mitochondrial function, and increased cellular apoptosis through PI3K/AKT/mTOR signaling pathway, providing important insights for understanding its environmental toxic effects and conducting risk assessments.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111783"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623655","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 : 2025-12-01Epub Date: 2025-10-23DOI: 10.1016/j.toxlet.2025.111750
Tianyin Lin , Huan Luo , Jingqiu Sun , Chen Dong , Xinyu Hong , Ping Xiao , Gonghua Tao
Conventional two-dimensional (2D) cell culture models for genotoxicity testing often yield false-positive results due to their limited metabolic capacity and lack of tissue architecture. Three-dimensional (3D) reconstructed human skin models offer a more physiologically relevant alternative for evaluating genotoxicity. In this study, the reproducibility, dose–response, and predictive performance of the micronucleus test (MNT) and comet assay were systematically assessed using 3D skin models EpiSkin-MNT and T-Skin. A panel of reference chemicals, including both genotoxic and non-genotoxic agents, was tested. Cytotoxicity was measured using ATP and adenylate kinase (AK) assays; genotoxicity endpoints included micronucleus frequency and comet assay parameters such as tail intensity and tail moment. Both assays exhibited clear dose-dependent increases in genotoxic markers for positive controls, while negative controls showed no significant response. Use of the DNA repair inhibitor aphidicolin in the comet assay enhanced the sensitivity of DNA damage detection. The integration of 3D skin models with MNT and comet assays provides a robust, reproducible, and physiologically relevant platform for genotoxicity assessment, supporting the transition from animal-based methods and aligning with regulatory trends.
{"title":"Investigating the application of 3D skin models in micronucleus assay and comet assay","authors":"Tianyin Lin , Huan Luo , Jingqiu Sun , Chen Dong , Xinyu Hong , Ping Xiao , Gonghua Tao","doi":"10.1016/j.toxlet.2025.111750","DOIUrl":"10.1016/j.toxlet.2025.111750","url":null,"abstract":"<div><div>Conventional two-dimensional (2D) cell culture models for genotoxicity testing often yield false-positive results due to their limited metabolic capacity and lack of tissue architecture. Three-dimensional (3D) reconstructed human skin models offer a more physiologically relevant alternative for evaluating genotoxicity. In this study, the reproducibility, dose–response, and predictive performance of the micronucleus test (MNT) and comet assay were systematically assessed using 3D skin models EpiSkin-MNT and T-Skin. A panel of reference chemicals, including both genotoxic and non-genotoxic agents, was tested. Cytotoxicity was measured using ATP and adenylate kinase (AK) assays; genotoxicity endpoints included micronucleus frequency and comet assay parameters such as tail intensity and tail moment. Both assays exhibited clear dose-dependent increases in genotoxic markers for positive controls, while negative controls showed no significant response. Use of the DNA repair inhibitor aphidicolin in the comet assay enhanced the sensitivity of DNA damage detection. The integration of 3D skin models with MNT and comet assays provides a robust, reproducible, and physiologically relevant platform for genotoxicity assessment, supporting the transition from animal-based methods and aligning with regulatory trends.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111750"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370533","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}
Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant recognized for its environmental persistence, bioaccumulation and toxicological potential, raising concerns about its hazardous effects on both ecological systems and human health. Our research investigated the hepatotoxicity of TBBPA at environmentally relevant concentrations (1–100 nM) using transformed human liver epithelial-2 (THLE-2) cells. Results demonstrated that TBBPA exposure induced cell alterations in cell density, nuclear irregularities and fibrosis-like extensions. Transcriptomic analysis revealed significant perturbations in pathways related to metabolism, cellular stress responses, inflammatory responses, cell proliferation, substance transport and degradation. Further investigations revealed the most obvious gene expression profile changes at 1 nM TBBPA exposure, however, higher concentrations (10 nM and 100 nM) of TBBPA appeared to cause more severe hepatotoxicity. RT-qPCR and molecular docking experiments confirmed the changed gene expression and TBBPA-Protein binding. These findings elucidate complex mechanisms of TBBPA-induced effects in hepatocytes, highlighting the environmental health risks of TBBPA.
{"title":"Environmental relevant concentrations of TBBPA cause complex toxicological mechanisms","authors":"Yuxing Liao , Yilin Wang , Hao Dong , YaJie Lin , Yuxi Xiao , Rummana Jaman , Mohith Mohan , Farheen Azim , Rui Lu , Tengji Zhao , Jiao Zhu , Guiyuan Chen , Conglin Zhang , Jiaqi Zhou","doi":"10.1016/j.toxlet.2025.111767","DOIUrl":"10.1016/j.toxlet.2025.111767","url":null,"abstract":"<div><div>Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant recognized for its environmental persistence, bioaccumulation and toxicological potential, raising concerns about its hazardous effects on both ecological systems and human health. Our research investigated the hepatotoxicity of TBBPA at environmentally relevant concentrations (1–100 nM) using transformed human liver epithelial-2 (THLE-2) cells. Results demonstrated that TBBPA exposure induced cell alterations in cell density, nuclear irregularities and fibrosis-like extensions. Transcriptomic analysis revealed significant perturbations in pathways related to metabolism, cellular stress responses, inflammatory responses, cell proliferation, substance transport and degradation. Further investigations revealed the most obvious gene expression profile changes at 1 nM TBBPA exposure, however, higher concentrations (10 nM and 100 nM) of TBBPA appeared to cause more severe hepatotoxicity. RT-qPCR and molecular docking experiments confirmed the changed gene expression and TBBPA-Protein binding. These findings elucidate complex mechanisms of TBBPA-induced effects in hepatocytes, highlighting the environmental health risks of TBBPA.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111767"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145432128","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 : 2025-12-01Epub Date: 2025-11-22DOI: 10.1016/j.toxlet.2025.111780
Junhao Wang , Chunbei Liu , Fangtong Gu , Yufeng Gu , Haihong Hao
Aditoprim (ADP) is a novel dihydrofolate reductase inhibitor. It has potent antibacterial activity, low toxicity, and no mutagenicity. These characteristics position it as a promising candidate for further research in clinical veterinary medicine and its effect on humans. Therefore, this research aimed to investigate the impact of ADP on human microbiota. ADP (0, 1, 16, and 128 mg/L) was added to chemostats containing human intestinal flora. Microflora communities, short-chain fatty acids (SCFAs), and the rate of antibiotic resistance were monitored at different time points before and after the administration of ADP. Salmonella Typhimurium inoculation was used to assess the gut microbiota’s colonization barrier over a period of three days. The results indicate long-term exposure to higher levels of ADP (16 and 128 mg/L) disrupted the colonization barrier of intestinal flora and increased the proportion of resistant bacteria. 16S rRNA sequencing data indicate that high levels of ADP caused significant changes in gut microbiota, especially Bacteroides fragilis and Bacteroides uniformis. This study assessed the microbiological safety of ADP in vitro for the first time by simulating the human gut microbiota environment. The findings showed that 1 mg/L was the no observable adverse effect concentration, and the microbiological acceptable daily intake was determined to be 91.67 µg/kg.BW/day.
{"title":"Microbiological toxicology of the new antibiotic aditoprim on human intestinal microbiota","authors":"Junhao Wang , Chunbei Liu , Fangtong Gu , Yufeng Gu , Haihong Hao","doi":"10.1016/j.toxlet.2025.111780","DOIUrl":"10.1016/j.toxlet.2025.111780","url":null,"abstract":"<div><div>Aditoprim (ADP) is a novel dihydrofolate reductase inhibitor. It has potent antibacterial activity, low toxicity, and no mutagenicity. These characteristics position it as a promising candidate for further research in clinical veterinary medicine and its effect on humans. Therefore, this research aimed to investigate the impact of ADP on human microbiota. ADP (0, 1, 16, and 128 mg/L) was added to chemostats containing human intestinal flora. Microflora communities, short-chain fatty acids (SCFAs), and the rate of antibiotic resistance were monitored at different time points before and after the administration of ADP. <em>Salmonella</em> Typhimurium inoculation was used to assess the gut microbiota’s colonization barrier over a period of three days. The results indicate long-term exposure to higher levels of ADP (16 and 128 mg/L) disrupted the colonization barrier of intestinal flora and increased the proportion of resistant bacteria. 16S rRNA sequencing data indicate that high levels of ADP caused significant changes in gut microbiota, especially <em>Bacteroides fragilis</em> and <em>Bacteroides uniformis</em>. This study assessed the microbiological safety of ADP <em>in vitro</em> for the first time by simulating the human gut microbiota environment. The findings showed that 1 mg/L was the no observable adverse effect concentration, and the microbiological acceptable daily intake was determined to be 91.67 µg/kg.BW/day.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111780"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145597598","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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