Pub Date : 2025-11-05DOI: 10.1016/j.toxlet.2025.111769
Mohd Fazal Ur Rehman , Mohammad Muaz Khan , Mohammad Mansoob Khan
Microplastics (MPs) and nanoplastics (NPs) have emerged as critical environmental contaminants with potential adverse effects on human health. This review examines the various ways MPs and NPs can be spread in the environment and their potential impact on humans. They can be introduced into the environment through multiple sources, like synthetic textiles, cosmetics, packaging, and industrial processes. These particles enter the human body through ingestion, inhalation, and skin contact, and they deposit in various tissues, including the lungs, kidneys, and gastrointestinal tract. Additionally, they can cross embryonic layers and reach the placenta. They can cause inflammation, oxidative stress, metabolic disorders, genotoxicity, and immunotoxic effects upon interaction, as confirmed by in-vivo and in-vitro studies. Furthermore, long-term exposure to MPs and NPs causes various complications to the human body, including metabolic disorders or even the development of cancers. Despite the presence of much evidence, a significant gap remains in fully understanding the mechanism of toxicity posed by MPs and NPs exposure and its long-term health outcomes. There is an urgent need for extensive investigations and improvement in standardized methods to evaluate the human health impact of MPs and NPs. This review explores current evidence on exposure pathways, bioaccumulation mechanisms, and health outcomes and identifies critical knowledge gaps.
{"title":"Impact of microplastics and nanoplastics on human health: Mechanistic insights and exposure pathways","authors":"Mohd Fazal Ur Rehman , Mohammad Muaz Khan , Mohammad Mansoob Khan","doi":"10.1016/j.toxlet.2025.111769","DOIUrl":"10.1016/j.toxlet.2025.111769","url":null,"abstract":"<div><div>Microplastics (MPs) and nanoplastics (NPs) have emerged as critical environmental contaminants with potential adverse effects on human health. This review examines the various ways MPs and NPs can be spread in the environment and their potential impact on humans. They can be introduced into the environment through multiple sources, like synthetic textiles, cosmetics, packaging, and industrial processes. These particles enter the human body through ingestion, inhalation, and skin contact, and they deposit in various tissues, including the lungs, kidneys, and gastrointestinal tract. Additionally, they can cross embryonic layers and reach the placenta. They can cause inflammation, oxidative stress, metabolic disorders, genotoxicity, and immunotoxic effects upon interaction, as confirmed by in-vivo and in-vitro studies. Furthermore, long-term exposure to MPs and NPs causes various complications to the human body, including metabolic disorders or even the development of cancers. Despite the presence of much evidence, a significant gap remains in fully understanding the mechanism of toxicity posed by MPs and NPs exposure and its long-term health outcomes. There is an urgent need for extensive investigations and improvement in standardized methods to evaluate the human health impact of MPs and NPs. This review explores current evidence on exposure pathways, bioaccumulation mechanisms, and health outcomes and identifies critical knowledge gaps.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111769"},"PeriodicalIF":2.9,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472083","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 : 2025-11-04DOI: 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":"2025-11-04","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}
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":"2025-11-01","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 : 2025-10-24DOI: 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":"2025-10-24","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 : 2025-10-24DOI: 10.1016/j.toxlet.2025.111755
Sili Chen , Liqin Xiong , Xinlan Wu , Lu Chen , Junwei Zhang , Guanqing Jiang , Xin Li , Qiaoyuan Yang
We investigated the toxicity of benzo[ghi]perylene (BghiP), a prevalent polycyclic aromatic hydrocarbon (PAH). Transcriptome analysis of control and BghiP-exposed human bronchial epithelial cells (BEAS-2B) led to the identification of a novel chimeric RNA (chRNA), TVP23C-CDRT4, whose expression is significantly downregulated by BghiP in vitro and in vivo. Funcionally, overexpression of TVP23C-CDRT4 inhibited BghiP-induced cell proliferation and DNA damage, whereas its knockdown exacerbated these detrimental effects. Mechanistically, TVP23C-CDRT4 acts as a molecular decoy for miR-24–3p. Thus, BghiP-induced suppression of TVP23C-CDRT4 unveils a novel mechanism of PAH toxicity, highlighting its anti-proliferative and genome-protective roles relevant to the early stages of carcinogenesis.
{"title":"Molecular mechanisms by which benzo[ghi]perylene promotes cell proliferation and DNA damage via downregulation of the chimeric RNA TVP23C-CDRT4/miR-24–3p axis","authors":"Sili Chen , Liqin Xiong , Xinlan Wu , Lu Chen , Junwei Zhang , Guanqing Jiang , Xin Li , Qiaoyuan Yang","doi":"10.1016/j.toxlet.2025.111755","DOIUrl":"10.1016/j.toxlet.2025.111755","url":null,"abstract":"<div><div>We investigated the toxicity of benzo[ghi]perylene (BghiP), a prevalent polycyclic aromatic hydrocarbon (PAH). Transcriptome analysis of control and BghiP-exposed human bronchial epithelial cells (BEAS-2B) led to the identification of a novel chimeric RNA (chRNA), TVP23C-CDRT4, whose expression is significantly downregulated by BghiP in vitro and in vivo. Funcionally, overexpression of TVP23C-CDRT4 inhibited BghiP-induced cell proliferation and DNA damage, whereas its knockdown exacerbated these detrimental effects. Mechanistically, TVP23C-CDRT4 acts as a molecular decoy for miR-24–3p. Thus, BghiP-induced suppression of TVP23C-CDRT4 unveils a novel mechanism of PAH toxicity, highlighting its anti-proliferative and genome-protective roles relevant to the early stages of carcinogenesis.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111755"},"PeriodicalIF":2.9,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145420019","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 : 2025-10-23DOI: 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":"2025-10-23","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}
Pub Date : 2025-10-22DOI: 10.1016/j.toxlet.2025.111751
Runzi Yang , Jing Li, Rui Liu, Tingting Ren, Nan Wang, Liangyuan Xu, Jianmin Ma
Aim
To analyze the effects of various urinary metals on cataract using National Health and Nutrition Examination Survey data.
Methods
Multivariate logistic regression was used to analyze the relationship between nine urinary metals and cataract. Weighted quantile sum (WQS) was used to analyze the positive and negative effects of various metals on cataract. The global and independent effects were analyzed using Bayesian kernel machine regression (BKMR). Network pharmacological analysis was used to explore the mechanism of metals on cataract.
Results
A total of 2207 participants were participated in the study. After excluding the influence of covariates, it was found that the concentrations of Ba, Sb, and Tl were significantly correlated with the prevalence of cataract. WQS showed that Cd, Pb, and Ba had the strongest negative effects on cataracts, while Tu and Co had the strongest positive effects. BKMR showed that the overall effect of nine urinary metals had no significant relationship with cataract, there was a significant positive correlation between Co and cataract, and a significant negative correlation between Pb and cataract under certain conditions. Co and cataract interact through various pathways, including Interleukin-4 and Interleukin-13 signaling. AKT1 may be the key protein in the correlation.
Conclusion
Urinary metal concentrations may be associated with the risk of ocular outcomes. While our findings suggest potential links between Co and cataract, these results should be interpreted with caution due to the cross-sectional nature of the data. Further longitudinal studies are needed to confirm these associations and to explore possible threshold levels for clinical or public health monitoring.
{"title":"Urinary metal mixtures and cataract: Findings from a U.S. population-based study and network pharmacology analysis","authors":"Runzi Yang , Jing Li, Rui Liu, Tingting Ren, Nan Wang, Liangyuan Xu, Jianmin Ma","doi":"10.1016/j.toxlet.2025.111751","DOIUrl":"10.1016/j.toxlet.2025.111751","url":null,"abstract":"<div><h3>Aim</h3><div>To analyze the effects of various urinary metals on cataract using National Health and Nutrition Examination Survey data.</div></div><div><h3>Methods</h3><div>Multivariate logistic regression was used to analyze the relationship between nine urinary metals and cataract. Weighted quantile sum (WQS) was used to analyze the positive and negative effects of various metals on cataract. The global and independent effects were analyzed using Bayesian kernel machine regression (BKMR). Network pharmacological analysis was used to explore the mechanism of metals on cataract.</div></div><div><h3>Results</h3><div>A total of 2207 participants were participated in the study. After excluding the influence of covariates, it was found that the concentrations of Ba, Sb, and Tl were significantly correlated with the prevalence of cataract. WQS showed that Cd, Pb, and Ba had the strongest negative effects on cataracts, while Tu and Co had the strongest positive effects. BKMR showed that the overall effect of nine urinary metals had no significant relationship with cataract, there was a significant positive correlation between Co and cataract, and a significant negative correlation between Pb and cataract under certain conditions. Co and cataract interact through various pathways, including Interleukin-4 and Interleukin-13 signaling. AKT1 may be the key protein in the correlation.</div></div><div><h3>Conclusion</h3><div>Urinary metal concentrations may be associated with the risk of ocular outcomes. While our findings suggest potential links between Co and cataract, these results should be interpreted with caution due to the cross-sectional nature of the data. Further longitudinal studies are needed to confirm these associations and to explore possible threshold levels for clinical or public health monitoring.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111751"},"PeriodicalIF":2.9,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368913","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 : 2025-10-21DOI: 10.1016/j.toxlet.2025.111752
Steven Lockhart , Yasser Tabana , Seyed Amirhossein Tabatabaei Dakhili , Dinesh Babu , Newton H. Tran , Othman Eldalal , Frederick G. West , John R. Ussher , Khaled H. Barakat , Richard P. Fahlman , Arno G. Siraki
Schizophrenia affects a significant proportion of individuals, wherein a subset of patients is described as treatment-resistant. Clozapine (CLOZ) is an atypical antipsychotic, which is reserved for these patients and is superior in its anti-suicidal activity. However, it carries numerous serious warnings and is well-known for its risk of drug-induced agranulocytosis. The mechanism of toxicity is unclear and could be due to CLOZ’s protein covalent binding and off-target effects through its reactive metabolites produced from neutrophil myeloperoxidase (MPO) activity. We hypothesize that identifying and analyzing the protein-CLOZ adducts will contribute to our understanding of toxicity pathways. We have developed a novel clickable CLOZ (Click-CLOZ) derivative and have designed click chemistry protocols for protein identification. The HL-60 (human promyelocytic leukemia) cell line and isolated human neutrophils express MPO significantly and were used to identify the protein covalent targets of Click-CLOZ. In HL-60 cells, LC/MS analysis revealed many Click-CLOZ-bound proteins (compared to the vehicle control). Some captured proteins were known for their roles in DNA replication, immune responses and oxidative stress, such as cathepsin G, MPO, ribophorin I and P1-MCM3. In neutrophils, Click-CLOZ-bound proteins included MPO, S100, and DEFA1B, which are also associated with neutrophil-mediated oxidative stress and immune responses. In conclusion, the application of click chemistry proteomics has facilitated a novel approach to identify multiple CLOZ-bound protein targets that will be used to advance our understanding of the toxicity of CLOZ.
{"title":"A chemoproteomic strategy for identifying protein covalent binding targets of clozapine: An approach for advancing clozapine toxicity research","authors":"Steven Lockhart , Yasser Tabana , Seyed Amirhossein Tabatabaei Dakhili , Dinesh Babu , Newton H. Tran , Othman Eldalal , Frederick G. West , John R. Ussher , Khaled H. Barakat , Richard P. Fahlman , Arno G. Siraki","doi":"10.1016/j.toxlet.2025.111752","DOIUrl":"10.1016/j.toxlet.2025.111752","url":null,"abstract":"<div><div>Schizophrenia affects a significant proportion of individuals, wherein a subset of patients is described as treatment-resistant. Clozapine (CLOZ) is an atypical antipsychotic, which is reserved for these patients and is superior in its anti-suicidal activity. However, it carries numerous serious warnings and is well-known for its risk of drug-induced agranulocytosis. The mechanism of toxicity is unclear and could be due to CLOZ’s protein covalent binding and off-target effects through its reactive metabolites produced from neutrophil myeloperoxidase (MPO) activity. We hypothesize that identifying and analyzing the protein-CLOZ adducts will contribute to our understanding of toxicity pathways. We have developed a novel clickable CLOZ (Click-CLOZ) derivative and have designed click chemistry protocols for protein identification. The HL-60 (human promyelocytic leukemia) cell line and isolated human neutrophils express MPO significantly and were used to identify the protein covalent targets of Click-CLOZ. In HL-60 cells, LC/MS analysis revealed many Click-CLOZ-bound proteins (compared to the vehicle control). Some captured proteins were known for their roles in DNA replication, immune responses and oxidative stress, such as cathepsin G, MPO, ribophorin I and P1-MCM3. In neutrophils, Click-CLOZ-bound proteins included MPO, S100, and DEFA1B, which are also associated with neutrophil-mediated oxidative stress and immune responses. In conclusion, the application of click chemistry proteomics has facilitated a novel approach to identify multiple CLOZ-bound protein targets that will be used to advance our understanding of the toxicity of CLOZ.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111752"},"PeriodicalIF":2.9,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355742","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 : 2025-10-21DOI: 10.1016/j.toxlet.2025.111753
Lu Meng , Yan Hu , Xuzi Zhao , Zhecheng Wang , Yue Wang , Ning Zhang , Shanshan Guo , Xinying Wang , Dongyan Gao , Yan Zhao , Jihong Yao
Background
Alcohol-associated liver disease (ALD), one of the most frequent chronic liver diseases globally, is characterized by steatosis. HMG-CoA reductase-degrading protein 1 (HRD1) participates in the endoplasmic reticulum-associated protein degradation pathway through the recognition, translocation, and ubiquitination of substrate proteins. HRD1 is implicated in endoplasmic reticulum stress, oxidative stress and cell metabolism; however, the function of HRD1 in ALD remains unclear.
Aims
We aimed to explore the contribution and underlying molecular mechanism of HRD1 in alcoholic liver disease.
Methods
Mice were administered adeno-associated virus 9 encoding HRD1- or ACSL3-specific shRNA via intravenous injection, followed by feeding with a Lieber–DeCarli liquid diet containing 5 % ethanol. HepG2 cells were transfected with either HRD1 siRNA or HRD1 overexpression plasmids prior to ethanol exposure.
Results
Hepatic HRD1 expression was significantly increased under alcohol conditions. Hepatocyte-specific HRD1 knockdown markedly attenuated alcohol-induced hepatic injury, inflammation, oxidative stress and lipid metabolism disorders in vivo. Additionally, similar results were shown in vitro. Mechanistically, acyl-CoA synthetase long chain family member 3 (ACSL3), a key regulator known to ameliorate hepatic steatosis, was identified as a novel substrate of HRD1. HRD1 facilitates the ubiquitination and degradation of ACSL3. Interestingly, HRD1 knockdown significantly suppressed fatty acid synthesis and promoted fatty acid oxidation, which was reversed by ACSL3 silencing both in vivo and in vitro.
Conclusion
In summary, HRD1 functions as a key mediator of ALD by ubiquitinating ACSL3, thereby promoting lipid dyshomeostasis, and aggravating ALD. Our findings reveal novel mechanistic insights into HRD1 and identify ACSL3 as a new downstream target of HRD1 to facilitate ALD treatment.
{"title":"HRD1 promotes chronic alcoholic liver disease by mediating ACSL3 ubiquitination and degradation","authors":"Lu Meng , Yan Hu , Xuzi Zhao , Zhecheng Wang , Yue Wang , Ning Zhang , Shanshan Guo , Xinying Wang , Dongyan Gao , Yan Zhao , Jihong Yao","doi":"10.1016/j.toxlet.2025.111753","DOIUrl":"10.1016/j.toxlet.2025.111753","url":null,"abstract":"<div><h3>Background</h3><div>Alcohol-associated liver disease (ALD), one of the most frequent chronic liver diseases globally, is characterized by steatosis. HMG-CoA reductase-degrading protein 1 (HRD1) participates in the endoplasmic reticulum-associated protein degradation pathway through the recognition, translocation, and ubiquitination of substrate proteins. HRD1 is implicated in endoplasmic reticulum stress, oxidative stress and cell metabolism; however, the function of HRD1 in ALD remains unclear.</div></div><div><h3>Aims</h3><div>We aimed to explore the contribution and underlying molecular mechanism of HRD1 in alcoholic liver disease.</div></div><div><h3>Methods</h3><div>Mice were administered adeno-associated virus 9 encoding HRD1- or ACSL3-specific shRNA via intravenous injection, followed by feeding with a Lieber–DeCarli liquid diet containing 5 % ethanol. HepG2 cells were transfected with either HRD1 siRNA or HRD1 overexpression plasmids prior to ethanol exposure.</div></div><div><h3>Results</h3><div>Hepatic HRD1 expression was significantly increased under alcohol conditions. Hepatocyte-specific HRD1 knockdown markedly attenuated alcohol-induced hepatic injury, inflammation, oxidative stress and lipid metabolism disorders in vivo. Additionally, similar results were shown in vitro. Mechanistically, acyl-CoA synthetase long chain family member 3 (ACSL3), a key regulator known to ameliorate hepatic steatosis, was identified as a novel substrate of HRD1. HRD1 facilitates the ubiquitination and degradation of ACSL3. Interestingly, HRD1 knockdown significantly suppressed fatty acid synthesis and promoted fatty acid oxidation, which was reversed by ACSL3 silencing both in vivo and in vitro.</div></div><div><h3>Conclusion</h3><div>In summary, HRD1 functions as a key mediator of ALD by ubiquitinating ACSL3, thereby promoting lipid dyshomeostasis, and aggravating ALD. Our findings reveal novel mechanistic insights into HRD1 and identify ACSL3 as a new downstream target of HRD1 to facilitate ALD treatment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111753"},"PeriodicalIF":2.9,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145340720","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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