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}
Pub Date : 2025-10-17DOI: 10.1016/j.toxlet.2025.111744
Lijing Jiang , Fan Wang , Mingwei Huai , Wendi Zhang , Xiaofeng Chen , Chunping Li , Xinsheng Zhang , Bingchen Liu , Yao Su , Minjie Chu , Na Sun , Jiandong Jiao , Wei Wang
Objective
To investigate the association between single nucleotide polymorphisms (SNPs) in autophagy-related genes (ATGs) and susceptibility to silicosis.
Methods
Used silicosis genome-wide association study (GWAS) data and multiple publicly available databases to identify autophagy-associated positive expression quantitative trait locus (eQTL)-SNPs. Candidate positive SNPs were subsequently validated for their association with silicosis susceptibility in an independent population. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to explore the expression of target genes. Finally, gene enrichment analysis was performed to preliminary explore the biological functions and potential pathways associated with the identified susceptibility genes.
Results
A total of 15 SNPs in 10 ATGs were finally obtained after screening. Validation phase results indicated a significant association between the mutant G allele of rs155787 on the Sequestosome 1 (SQSTM1) and an increased risk of silicosis (additive model: odds ratio (OR)= 1.55, 95 % confidence interval (95 % CI): 1.05–2.28, P = 0.027). Combining GWAS and validation phase data, the mutant G allele was correlated with heightened silicosis susceptibility (additive model: OR=1.70, 95 % CI: 1.22–2.36, P = 0.002). The eQTL results indicated that significantly higher SQSTM1 expression in AG and GG genotypes than in AA genotypes (P < 0.05). Bioinformatics analysis revealed that SQSTM1 may bind to a range of autophagy proteins and immunoproteins to activate the biological process of macroautophagy, which influences the development of silicosis.
Conclusion
The rs155787 locus on the SQSTM1 may be associated with silicosis susceptibility, and the mutant G allele may serve as a potential risk factor. Furthermore, the A>G variation at this locus was observed to upregulate SQSTM1 gene expression. Additional large-scale studies are necessary to further validate our findings.
目的：探讨自噬相关基因（ATGs）单核苷酸多态性（snp）与矽肺易感性的关系。方法：利用矽肺全基因组关联研究（GWAS）数据和多个公开数据库，鉴定自噬相关阳性表达数量性状位点(eQTL)- snp。候选阳性snp随后在独立人群中验证了它们与矽肺易感性的关联。采用实时荧光定量聚合酶链反应（qRT-PCR）检测靶基因的表达情况。最后，进行基因富集分析，初步探索与鉴定的易感基因相关的生物学功能和潜在途径。结果：筛选10个atg，最终获得15个snp。验证阶段结果显示，Sequestosome 1 （SQSTM1）上rs155787突变基因G等位基因与矽肺病风险增加之间存在显著关联(加性模型：优势比（OR)=1.55, 95%可信区间（95% CI）： 1.05-2.28, P = 0.027）。结合GWAS和验证期数据，突变G等位基因与矽肺易感性增高相关（加性模型：OR=1.70, 95% CI: 1.22-2.36, P = 0.002）。eQTL结果显示，SQSTM1在AG和GG基因型中的表达量显著高于AA基因型（P < 0.05）。生物信息学分析表明，SQSTM1可能与一系列自噬蛋白和免疫蛋白结合，激活巨噬的生物学过程，影响矽肺的发展。结论：SQSTM1上rs155787位点可能与矽肺易感性相关，突变的G等位基因可能是一个潜在的危险因素。此外，该位点的A>G变异被观察到上调SQSTM1基因的表达。需要更多的大规模研究来进一步验证我们的发现。
{"title":"The single nucleotide polymorphism rs155787 on the autophagy gene of SQSTM1 is associated with silicosis susceptibility: A multi-stage study","authors":"Lijing Jiang , Fan Wang , Mingwei Huai , Wendi Zhang , Xiaofeng Chen , Chunping Li , Xinsheng Zhang , Bingchen Liu , Yao Su , Minjie Chu , Na Sun , Jiandong Jiao , Wei Wang","doi":"10.1016/j.toxlet.2025.111744","DOIUrl":"10.1016/j.toxlet.2025.111744","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the association between single nucleotide polymorphisms (SNPs) in autophagy-related genes (ATGs) and susceptibility to silicosis.</div></div><div><h3>Methods</h3><div>Used silicosis genome-wide association study (GWAS) data and multiple publicly available databases to identify autophagy-associated positive expression quantitative trait locus (eQTL)-SNPs. Candidate positive SNPs were subsequently validated for their association with silicosis susceptibility in an independent population. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to explore the expression of target genes. Finally, gene enrichment analysis was performed to preliminary explore the biological functions and potential pathways associated with the identified susceptibility genes.</div></div><div><h3>Results</h3><div>A total of 15 SNPs in 10 ATGs were finally obtained after screening. Validation phase results indicated a significant association between the mutant G allele of rs155787 on the Sequestosome 1 (<em>SQSTM1</em>) and an increased risk of silicosis (additive model: odds ratio (OR)= 1.55, 95 % confidence interval (95 % CI): 1.05–2.28, <em>P</em> = 0.027). Combining GWAS and validation phase data, the mutant G allele was correlated with heightened silicosis susceptibility (additive model: OR=1.70, 95 % CI: 1.22–2.36, <em>P</em> = 0.002). The eQTL results indicated that significantly higher <em>SQSTM1</em> expression in AG and GG genotypes than in AA genotypes (<em>P</em> < 0.05). Bioinformatics analysis revealed that <em>SQSTM1</em> may bind to a range of autophagy proteins and immunoproteins to activate the biological process of macroautophagy, which influences the development of silicosis.</div></div><div><h3>Conclusion</h3><div>The rs155787 locus on the <em>SQSTM1</em> may be associated with silicosis susceptibility, and the mutant G allele may serve as a potential risk factor. Furthermore, the A>G variation at this locus was observed to upregulate <em>SQSTM1</em> gene expression. Additional large-scale studies are necessary to further validate our findings.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111744"},"PeriodicalIF":2.9,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329372","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 : 2025-10-17DOI: 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":"2025-10-17","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 : 2025-10-15DOI: 10.1016/j.toxlet.2025.111748
Wenhui Sun , Siyan Huo , Shitian Li , Daifeng Yang , Changsheng Wei , Jieting Zheng , Shanshan Cai
This study aims to elucidate the molecular mechanisms underlying aspartame-associated liver hepatocellular carcinoma (LIHC) by identifying glutathione reductase (GSR) as a key molecular target. Through a combination of network toxicology analysis and Mendelian randomization, GSR was implicated as a critical protein involved in the pathogenesis of aspartame-associated LIHC. Functional annotation using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that GSR is predominantly involved in energy metabolism, particularly lipid metabolism and glycolysis, both of which are central to tumorigenesis in LIHC. Elevated GSR expression was observed in LIHC tumor tissues, correlating with poor clinical outcomes including reduced overall survival (OS) and recurrence-free survival (RFS). Furthermore, genetic analyses revealed significant alterations in GSR, including mutations and copy number variations, in various cancer types, with specific relevance to immune regulatory gene networks. Molecular dynamics simulations demonstrated a robust binding affinity between aspartame and GSR, with favorable binding interactions, suggesting a stable protein-ligand complex. Additionally, functional assays confirmed that GSR modulates tumor cell proliferation via regulation of glycolytic enzyme activity, indicating its pivotal role in metabolic reprogramming during LIHC progression. These findings collectively highlight GSR as a promising biomarker and therapeutic target in the context of aspartame-associated hepatocellular carcinoma, with implications for targeted intervention in cancer treatment.
{"title":"Evaluating the role of glutathione reductase in aspartame-induced liver hepatocellular carcinoma: A molecular network and prognostic approach","authors":"Wenhui Sun , Siyan Huo , Shitian Li , Daifeng Yang , Changsheng Wei , Jieting Zheng , Shanshan Cai","doi":"10.1016/j.toxlet.2025.111748","DOIUrl":"10.1016/j.toxlet.2025.111748","url":null,"abstract":"<div><div>This study aims to elucidate the molecular mechanisms underlying aspartame-associated liver hepatocellular carcinoma (LIHC) by identifying glutathione reductase (GSR) as a key molecular target. Through a combination of network toxicology analysis and Mendelian randomization, GSR was implicated as a critical protein involved in the pathogenesis of aspartame-associated LIHC. Functional annotation using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that GSR is predominantly involved in energy metabolism, particularly lipid metabolism and glycolysis, both of which are central to tumorigenesis in LIHC. Elevated GSR expression was observed in LIHC tumor tissues, correlating with poor clinical outcomes including reduced overall survival (OS) and recurrence-free survival (RFS). Furthermore, genetic analyses revealed significant alterations in GSR, including mutations and copy number variations, in various cancer types, with specific relevance to immune regulatory gene networks. Molecular dynamics simulations demonstrated a robust binding affinity between aspartame and GSR, with favorable binding interactions, suggesting a stable protein-ligand complex. Additionally, functional assays confirmed that GSR modulates tumor cell proliferation via regulation of glycolytic enzyme activity, indicating its pivotal role in metabolic reprogramming during LIHC progression. These findings collectively highlight GSR as a promising biomarker and therapeutic target in the context of aspartame-associated hepatocellular carcinoma, with implications for targeted intervention in cancer treatment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111748"},"PeriodicalIF":2.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313989","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 : 2025-10-15DOI: 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":"2025-10-15","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}
Pub Date : 2025-10-14DOI: 10.1016/j.toxlet.2025.111746
Khelfi Abderrezak , Alsayed Ahmad Dana , Azzouz Mohamed
Purpose
Prenatal exposure to Benzophenones and their potential health impacts remain insufficiently studied, particularly among vulnerable populations such as pregnant women. The lack of research is concerning given the suspected risks these endocrine-disrupting chemicals (EDCs) may pose to neonatal health, especially in relation to thyroid hormone regulation. This study seeks to address this research gap by measuring prenatal exposure profiles to Benzophenones in women living in Algiers. Specifically, it aims to explore the associations between Benzophenone levels in umbilical cord blood and disruptions in thyroid hormone levels at the time of delivery. Additionally, the study investigates the possible link between women's exposure to specific sources and the resulting endogenous levels of Benzophenones.
Methods
This was a descriptive study carried out on 154 paired mother-newborns after gathering necessary information using a questionnaire. Umbilical cord blood was collected and TSH and thyroid hormones (FT3 and FT4) were measured by electrochemiluminescence while Benzophenones (BP-1, BP-2, and BP-3) were detected by LC-MS/MS.
Results
BP-1, BP-2, and BP-3 were detected in 29.87 %, 0 %, and 48.05 % of analyzed samples. Mean concentrations were 0.330 and 0.787 µg/g for BP-1 and BP-3, respectively. Significant negative association was found between levels of FT3 and concentrations of BP-3 in cord blood (β= -0.237), as well as a negative association between levels of FT4 and prenatal concentrations of BP-1 (β= -1.028). Notably, prenatal exposure to Benzophenones did not exhibit significant alterations on birth outcomes. A significant association linked lower levels of BP-1 with the tendency to read ingredient labels on cosmetic products by pregnant women (P = 0.024).
Conclusion
In this Algerian population of parturient women, high exposure profiles to BP-1 and BP-3 through placental blood were associated with altered levels of thyroid hormones (FT4 and FT3, respectively). It appears these two compounds exert a diminishing effect on thyroid function. Such changes may involve adverse effects on maternal health and child development, especially on the nervous system.
{"title":"Prenatal exposure profiles to Benzophenones and their impacts on thyroid hormones","authors":"Khelfi Abderrezak , Alsayed Ahmad Dana , Azzouz Mohamed","doi":"10.1016/j.toxlet.2025.111746","DOIUrl":"10.1016/j.toxlet.2025.111746","url":null,"abstract":"<div><h3>Purpose</h3><div>Prenatal exposure to Benzophenones and their potential health impacts remain insufficiently studied, particularly among vulnerable populations such as pregnant women. The lack of research is concerning given the suspected risks these endocrine-disrupting chemicals (EDCs) may pose to neonatal health, especially in relation to thyroid hormone regulation. This study seeks to address this research gap by measuring prenatal exposure profiles to Benzophenones in women living in Algiers. Specifically, it aims to explore the associations between Benzophenone levels in umbilical cord blood and disruptions in thyroid hormone levels at the time of delivery. Additionally, the study investigates the possible link between women's exposure to specific sources and the resulting endogenous levels of Benzophenones.</div></div><div><h3>Methods</h3><div>This was a descriptive study carried out on 154 paired mother-newborns after gathering necessary information using a questionnaire. Umbilical cord blood was collected and TSH and thyroid hormones (FT3 and FT4) were measured by electrochemiluminescence while Benzophenones (BP-1, BP-2, and BP-3) were detected by LC-MS/MS.</div></div><div><h3>Results</h3><div>BP-1, BP-2, and BP-3 were detected in 29.87 %, 0 %, and 48.05 % of analyzed samples. Mean concentrations were 0.330 and 0.787 µg/g for BP-1 and BP-3, respectively. Significant negative association was found between levels of FT3 and concentrations of BP-3 in cord blood (β= <strong>-</strong>0.237), as well as a negative association between levels of FT4 and prenatal concentrations of BP-1 (β= <strong>-</strong>1.028). Notably, prenatal exposure to Benzophenones did not exhibit significant alterations on birth outcomes. A significant association linked lower levels of BP-1 with the tendency to read ingredient labels on cosmetic products by pregnant women (P = 0.024).</div></div><div><h3>Conclusion</h3><div>In this Algerian population of parturient women, high exposure profiles to BP-1 and BP-3 through placental blood were associated with altered levels of thyroid hormones (FT4 and FT3, respectively). It appears these two compounds exert a diminishing effect on thyroid function. Such changes may involve adverse effects on maternal health and child development, especially on the nervous system.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111746"},"PeriodicalIF":2.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145309412","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}
Humans are exposed to microplastics through three routes: oral, dermal, and respiratory. These tiny polymer particles enter the body and accumulate in various organs. One of the most sensitive organs to microplastics is the female reproductive system. In this review, manuscripts that investigated the effects of various microplastics on the hypothalamic-pituitary-ovarian axis in laboratory animals were collected with relevant keywords. This axis plays an important role in the function of the female reproductive system. Effects on endpoints of this axis, including hormonal changes, gene expression, and histopathological changes, were assessed. The most studied microplastic was polystyrene. Hormone levels were measured in all studies. In almost all studies, 17β-estradiol was decreased. Apoptosis and oxidative stress-induced damage in the ovaries were also observed in some studies. The results summarized from the manuscript emphasize the adverse effects of microplastics, especially polystyrene microplastics, on the female reproductive system following exposure.
{"title":"A systematic review on the effect of microplastics on the hypothalamus-pituitary-ovary axis based on animal studies","authors":"Saeed Shahsavari , Behrouz Akbari-Adergani , Hamed Shafaroodi , Nader Akbari , Burhan Basaran , Melina Sadighara , Parisa Sadighara","doi":"10.1016/j.toxlet.2025.111745","DOIUrl":"10.1016/j.toxlet.2025.111745","url":null,"abstract":"<div><div>Humans are exposed to microplastics through three routes: oral, dermal, and respiratory. These tiny polymer particles enter the body and accumulate in various organs. One of the most sensitive organs to microplastics is the female reproductive system. In this review, manuscripts that investigated the effects of various microplastics on the hypothalamic-pituitary-ovarian axis in laboratory animals were collected with relevant keywords. This axis plays an important role in the function of the female reproductive system. Effects on endpoints of this axis, including hormonal changes, gene expression, and histopathological changes, were assessed. The most studied microplastic was polystyrene. Hormone levels were measured in all studies. In almost all studies, 17β-estradiol was decreased. Apoptosis and oxidative stress-induced damage in the ovaries were also observed in some studies. The results summarized from the manuscript emphasize the adverse effects of microplastics, especially polystyrene microplastics, on the female reproductive system following exposure.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111745"},"PeriodicalIF":2.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145309365","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 : 2025-10-13DOI: 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":"2025-10-13","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}
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