Toxicology letters最新文献_第6页

The single nucleotide polymorphism rs155787 on the autophagy gene of SQSTM1 is associated with silicosis susceptibility: A multi-stage study SQSTM1自噬基因rs155787单核苷酸多态性与矽肺易感性相关：一项多阶段研究

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-10-17 DOI: 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":"2025-12-01","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}

引用次数: 0

Prenatal exposure profiles to Benzophenones and their impacts on thyroid hormones 二苯甲酮产前暴露概况及其对甲状腺激素的影响。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-10-14 DOI: 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.

目的：产前接触二苯甲酮及其潜在健康影响的研究仍然不够充分，特别是在孕妇等弱势群体中。考虑到这些内分泌干扰化学物质（EDCs）可能对新生儿健康造成的风险，特别是与甲状腺激素调节有关，缺乏研究令人担忧。本研究旨在通过测量生活在阿尔及尔的妇女产前接触二苯甲酮的概况来解决这一研究差距。具体来说，它旨在探讨脐带血中二苯甲酮水平与分娩时甲状腺激素水平中断之间的关系。此外，该研究还调查了女性接触特定来源与由此产生的内源性二苯甲酮水平之间的可能联系。方法：采用问卷调查收集必要信息后，对154对女性新生儿进行描述性研究。采集脐血，电化学发光法检测TSH和甲状腺激素（FT3、FT4）， LC-MS/MS法检测二苯甲酮（BP-1、BP-2、BP-3）。结果：BP-1、BP-2和BP-3的检出率分别为29.87%、0%和48.05%。BP-1和BP-3的平均浓度分别为0.330和0.787µg/g。脐带血中FT3水平与BP-3浓度呈显著负相关（β= -0.237）， FT4水平与产前BP-1浓度呈负相关（β= -1.028）。值得注意的是，产前接触二苯甲酮对出生结果没有显着改变。较低水平的BP-1与孕妇阅读化妆品成分标签的倾向有显著关联（P= 0.024）。结论：在阿尔及利亚的孕妇人群中，通过胎盘血液高暴露于BP-1和BP-3与甲状腺激素（FT4和FT3分别）水平的改变有关。这两种化合物似乎对甲状腺功能的影响逐渐减弱。这种变化可能对母亲健康和儿童发育，特别是对神经系统产生不利影响。

{"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":"2025-12-01","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}

引用次数: 0

Transgenerational toxicity of tralomethrin in zebrafish: Parental exposure induces developmental defects in offspring 氯氰菊酯对斑马鱼的跨代毒性：亲代接触诱发后代发育缺陷。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-11-18 DOI: 10.1016/j.toxlet.2025.111777

Yueping Huang , Wenmin Feng , Jinli Zhang , Yafang Shi , Peng Xiao , Wenhua Li

Tralomethrin (TRA), a widely used type II pyrethroid insecticide, belongs to a class of pesticides frequently detected in aquatic environments, raising concerns about its potential chronic and transgenerational toxicity. This study aimed to evaluate the long-term effects of environmentally relevant concentrations of TRA (0.05, 0.5, and 5 μg/L) on adult zebrafish and their offspring. Adult zebrafish were exposed to TRA for 150 days, during which phenotypic observations, histological assessments, biochemical assays, transcriptomic profiling, and developmental evaluations of F1 progeny were conducted. Following TRA exposure, male zebrafish exhibited increased body weight, and a significant decline in spawning rate was observed. Histological and biochemical analyses revealed gill and ovarian abnormalities, accompanied by oxidative stress and apoptosis in ovarian tissues. Transcriptomic analysis of TRA-exposed ovaries revealed gene enrichment in glutathione metabolism and signaling pathways including Hedgehog and Wnt, reflecting oxidative stress and developmental disruption. In the F1 generation, TRA exposure led to decreased survival and hatching rates, along with developmental abnormalities including pericardial edema, spinal curvature, and impaired swim bladder inflation. Gene expression analyses of swim bladder marker genes and regulatory pathways further corroborated TRA-induced disruption in organogenesis. Overall, these findings demonstrate that chronic TRA exposure can induce multi-level toxic effects in zebrafish, including reproductive impairment and transgenerational developmental defects. This study highlights the urgent need to assess the ecological risks of pyrethroid pesticides and to incorporate long-term and transgenerational endpoints into environmental risk assessment.

氯氰菊酯（Tralomethrin， TRA）是一种广泛使用的II型拟除虫菊酯杀虫剂，属于在水生环境中经常检测到的一类农药，其潜在的慢性和跨代毒性引起了人们的关注。本研究旨在评估环境相关浓度的TRA（0.05、0.5和5μg/L）对成年斑马鱼及其后代的长期影响。将成年斑马鱼暴露于TRA 150天，在此期间进行表型观察、组织学评估、生化分析、转录组分析和F1后代发育评估。暴露于TRA后，雄性斑马鱼体重增加，产卵率显著下降。组织学和生化分析显示鳃和卵巢异常，伴有卵巢组织氧化应激和细胞凋亡。转录组学分析显示，暴露于tra的卵巢中谷胱甘肽代谢和包括Hedgehog和Wnt在内的信号通路的基因富集，反映了氧化应激和发育中断。在F1代中，TRA暴露导致成活率和孵化率下降，并伴有发育异常，包括心包水肿、脊柱弯曲和鳔膨胀受损。对鱼鳔标记基因和调控途径的基因表达分析进一步证实了tra在器官发生中诱导的破坏。总的来说，这些发现表明，长期暴露于TRA可以诱导斑马鱼的多层次毒性作用，包括生殖损伤和跨代发育缺陷。这项研究强调了评估拟除虫菊酯类杀虫剂的生态风险的迫切需要，并将长期和跨代终点纳入环境风险评估。

{"title":"Transgenerational toxicity of tralomethrin in zebrafish: Parental exposure induces developmental defects in offspring","authors":"Yueping Huang , Wenmin Feng , Jinli Zhang , Yafang Shi , Peng Xiao , Wenhua Li","doi":"10.1016/j.toxlet.2025.111777","DOIUrl":"10.1016/j.toxlet.2025.111777","url":null,"abstract":"<div><div>Tralomethrin (TRA), a widely used type II pyrethroid insecticide, belongs to a class of pesticides frequently detected in aquatic environments, raising concerns about its potential chronic and transgenerational toxicity. This study aimed to evaluate the long-term effects of environmentally relevant concentrations of TRA (0.05, 0.5, and 5 μg/L) on adult zebrafish and their offspring. Adult zebrafish were exposed to TRA for 150 days, during which phenotypic observations, histological assessments, biochemical assays, transcriptomic profiling, and developmental evaluations of F1 progeny were conducted. Following TRA exposure, male zebrafish exhibited increased body weight, and a significant decline in spawning rate was observed. Histological and biochemical analyses revealed gill and ovarian abnormalities, accompanied by oxidative stress and apoptosis in ovarian tissues. Transcriptomic analysis of TRA-exposed ovaries revealed gene enrichment in glutathione metabolism and signaling pathways including Hedgehog and Wnt, reflecting oxidative stress and developmental disruption. In the F1 generation, TRA exposure led to decreased survival and hatching rates, along with developmental abnormalities including pericardial edema, spinal curvature, and impaired swim bladder inflation. Gene expression analyses of swim bladder marker genes and regulatory pathways further corroborated TRA-induced disruption in organogenesis. Overall, these findings demonstrate that chronic TRA exposure can induce multi-level toxic effects in zebrafish, including reproductive impairment and transgenerational developmental defects. This study highlights the urgent need to assess the ecological risks of pyrethroid pesticides and to incorporate long-term and transgenerational endpoints into environmental risk assessment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111777"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557697","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}

引用次数: 0

Comprehensive estrogenicity assessment of 4-methylbenzophenone via in vivo, in vitro, and in silico approaches within an integrated testing strategy framework 在综合测试策略框架内，通过体内、体外和计算机方法对4-甲基二苯甲酮的综合雌激素性进行评估。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-11-29 DOI: 10.1016/j.toxlet.2025.111784

Darlene Mae D. Ortiz, Ngoc Minh-Hong Hoang, Handule Lee, Kwangsik Park

4-Methylbenzophenone (4-MBP) is extensively used as a photoinitiator in ultraviolet-cured printing inks and food packaging. This study comprehensively evaluated its estrogenic activity using an Integrated Testing Strategy (ITS) incorporating in vivo, in vitro, and in silico methodologies. Repeated oral administration of 4-MBP at 300 mg/kg (lowest observed effect concentration, LOEC) in ovariectomized rats significantly increased relative uterine weight (0.11 ± 0.01 % vs. 0.05 ± 0.00 % in controls) and serum estradiol levels elevated serum estradiol levels (4-fold over vehicle control). Histological analysis confirmed estrogenic alterations, including epithelial thickening, glandular degeneration, and stromal inflammation. Although estrogen receptor α (ERα) expression remained unchanged, aromatase (CYP19) was significantly upregulated in uterine tissue, suggesting that enhanced estrogen biosynthesis plays a key role in the effects elicited by 4-MBP. In vitro assays showed that 4-MBP activated ER transcription in HeLa9903 cells with a maximum relative proliferative capacity (RPCmax) of about 200 % compared with 1 nM 17β-estradiol, and significantly induced MCF-7 cell proliferation at 10⁻⁵ M, coinciding with peak CYP19 mRNA expression. CYP19 expression was also increased at the mRNA and protein levels, and evidence of post-transcriptional regulation was observed at higher concentrations (10 µM). In silico molecular docking and dynamic simulations corroborated these findings demonstrating strong binding affinities of 4-MBP to ERα (docking score as low as −8.7 kcal/mol) and ERβ. Our results indicate that 4-MBP exerts estrogenic effects by elevating estrogen synthesis and inducing direct ER transcriptional activation. These findings highlight the utility of ITS for evaluating endocrine-disrupting chemicals and emphasize the need for regulatory consideration of 4-MBP and structurally related compounds in consumer products.

4-甲基二苯甲酮（4-MBP）作为光引发剂广泛应用于紫外光固化印刷油墨和食品包装中。本研究使用综合测试策略（its）综合体内，体外和计算机方法全面评估其雌激素活性。去卵巢大鼠反复口服4-MBP 300mg/kg（最低观察效应浓度，LOEC）显著增加相对子宫重量（对照组为0.11±0.01%，对照组为0.05±0.00%），血清雌二醇水平升高（比对照提高4倍）。组织学分析证实雌激素改变，包括上皮增厚、腺体变性和间质炎症。虽然雌激素受体α (ERα)表达不变，但子宫组织中芳香化酶（CYP19）显著上调，提示雌激素生物合成增强在4-MBP诱导的作用中起关键作用。体外实验显示，4-MBP激活HeLa9903细胞内质网转录，与1nM 17β-雌二醇相比，最大相对增殖能力（RPCmax）约为200%，并显著诱导MCF-7细胞在10⁻- 35 M时增殖，与CYP19 mRNA表达高峰一致。在mRNA和蛋白水平上CYP19的表达也增加，并且在较高浓度（10µM）下观察到转录后调节的证据。硅分子对接和动态模拟证实了这些发现，表明4-MBP与ERα（对接评分低至-8.7kcal/mol）和ERβ具有很强的结合亲和力。我们的研究结果表明，4-MBP通过提高雌激素合成和诱导内质网直接转录激活来发挥雌激素作用。这些发现强调了ITS在评估内分泌干扰化学物质方面的效用，并强调了在消费品中对4-MBP和结构相关化合物进行监管的必要性。

{"title":"Comprehensive estrogenicity assessment of 4-methylbenzophenone via in vivo, in vitro, and in silico approaches within an integrated testing strategy framework","authors":"Darlene Mae D. Ortiz, Ngoc Minh-Hong Hoang, Handule Lee, Kwangsik Park","doi":"10.1016/j.toxlet.2025.111784","DOIUrl":"10.1016/j.toxlet.2025.111784","url":null,"abstract":"<div><div>4-Methylbenzophenone (4-MBP) is extensively used as a photoinitiator in ultraviolet-cured printing inks and food packaging. This study comprehensively evaluated its estrogenic activity using an Integrated Testing Strategy (ITS) incorporating <em>in vivo, in vitro</em>, and <em>in silico</em> methodologies. Repeated oral administration of 4-MBP at 300 mg/kg (lowest observed effect concentration, LOEC) in ovariectomized rats significantly increased relative uterine weight (0.11 ± 0.01 % vs. 0.05 ± 0.00 % in controls) and serum estradiol levels elevated serum estradiol levels (4-fold over vehicle control). Histological analysis confirmed estrogenic alterations, including epithelial thickening, glandular degeneration, and stromal inflammation. Although estrogen receptor α (ERα) expression remained unchanged, aromatase (CYP19) was significantly upregulated in uterine tissue, suggesting that enhanced estrogen biosynthesis plays a key role in the effects elicited by 4-MBP. <em>In vitro</em> assays showed that 4-MBP activated ER transcription in HeLa9903 cells with a maximum relative proliferative capacity (RPCmax) of about 200 % compared with 1 nM 17β-estradiol, and significantly induced MCF-7 cell proliferation at 10⁻⁵ M, coinciding with peak CYP19 mRNA expression. CYP19 expression was also increased at the mRNA and protein levels, and evidence of post-transcriptional regulation was observed at higher concentrations (10 µM). <em>In silico</em> molecular docking and dynamic simulations corroborated these findings demonstrating strong binding affinities of 4-MBP to ERα (docking score as low as −8.7 kcal/mol) and ERβ. Our results indicate that 4-MBP exerts estrogenic effects by elevating estrogen synthesis and inducing direct ER transcriptional activation. These findings highlight the utility of ITS for evaluating endocrine-disrupting chemicals and emphasize the need for regulatory consideration of 4-MBP and structurally related compounds in consumer products.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111784"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649362","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}

引用次数: 0

Co-exposure to low levels of DEHP, procymidone, Cd2 + , Pb2+, and 1-nitropyrene may damage mouse ovary and uterus via Hippo pathway and circPVT1 共同暴露于低水平DEHP、原胺酮、Cd2+、Pb2+和1-硝基芘可通过Hippo通路和circPVT1损伤小鼠卵巢和子宫。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-11-19 DOI: 10.1016/j.toxlet.2025.111770

Yushan Li , Hui Nie , Shiyun He , Jiaxin Zhang , Hu Fu , Yongfei Zhu

High doses of Di-(2-ethylhexyl) phthalate (DEHP), procymidone (PCM), Cd²⁺, Pb²⁺, and 1-nitropyrene (1-NP) induce reproductive toxicity in female experimental animals. However, evidence regarding female reproductive toxicity at low levels of combined exposure (co-exposure) to these substances is lacking. In this study, these environmental chemicals, which met or minimally exceeded the relevant standards, were administered simultaneously to 4-week-old female mice. After 21 days of exposure, the mice were kept feeding for 1 week and then sacrificed. Subsequently, their blood, ovaries, and uteri were taken. Co-exposure to concentrations ≥ 1/3 of the maximum allowable concentration (MAC) for each of these chemicals, as per relevant standards, was revealed to impair ovarian and uterine development in mice. This exposure activated the Hippo pathway, resulting in a decrease in ERα and circPVT1, and an elevation of miR-149. Co-exposure to these compounds in levels marginally lower than the MACs of each chemical also elevated cleaved CASPASE-3 levels. These changes showed a dose–response relationship. Joint exposure to these substances at values ≥ 1/3 of each average concentration in the blood could elicit similar biological effects in the ovaries and uteri cultured in vitro. Therefore, this study hypothesized that co-exposure to low levels of these environmental chemicals results in ovarian and uterine impairment in mice and that this damage may be linked to the activation of the Hippo pathway, downregulation of ERα and circPVT1, and upregulation of miR-149.

高剂量邻苯二甲酸二（2-乙基己基）酯（DEHP）、原胺酮（PCM）、Cd2+、Pb2+和1-硝基芘（1-NP）对雌性实验动物具有生殖毒性。然而，缺乏关于低水平联合暴露（共同暴露）于这些物质的女性生殖毒性的证据。在本研究中，这些环境化学物质达到或最低超过相关标准，同时给予4周龄的雌性小鼠。暴露21 d后，饲养1周后处死。随后，采集了他们的血液、卵巢和子宫。根据相关标准，这些化学物质中每一种的最大允许浓度(MAC)≥1/3的浓度共同暴露会损害小鼠卵巢和子宫的发育。这种暴露激活了Hippo通路，导致ERα和circPVT1降低，miR-149升高。以略低于每种化学物质的MACs水平共同暴露于这些化合物中也会提高裂解CASPASE-3水平。这些变化呈剂量-反应关系。在体外培养的卵巢和子宫中，当这些物质在血液中浓度≥各平均浓度的1/3时，联合暴露在这些物质中也会产生类似的生物学效应。因此，本研究假设，共同暴露于低水平的这些环境化学物质会导致小鼠卵巢和子宫损伤，这种损伤可能与Hippo通路的激活、ERα和circPVT1的下调以及miR-149的上调有关。

{"title":"Co-exposure to low levels of DEHP, procymidone, Cd2 + , Pb2+, and 1-nitropyrene may damage mouse ovary and uterus via Hippo pathway and circPVT1","authors":"Yushan Li , Hui Nie , Shiyun He , Jiaxin Zhang , Hu Fu , Yongfei Zhu","doi":"10.1016/j.toxlet.2025.111770","DOIUrl":"10.1016/j.toxlet.2025.111770","url":null,"abstract":"<div><div>High doses of Di-(2-ethylhexyl) phthalate (DEHP), procymidone (PCM), Cd<sup>2+</sup>, Pb<sup>2+</sup>, and 1-nitropyrene (1-NP) induce reproductive toxicity in female experimental animals. However, evidence regarding female reproductive toxicity at low levels of combined exposure (co-exposure) to these substances is lacking. In this study, these environmental chemicals, which met or minimally exceeded the relevant standards, were administered simultaneously to 4-week-old female mice. After 21 days of exposure, the mice were kept feeding for 1 week and then sacrificed. Subsequently, their blood, ovaries, and uteri were taken. Co-exposure to concentrations ≥ 1/3 of the maximum allowable concentration (MAC) for each of these chemicals, as per relevant standards, was revealed to impair ovarian and uterine development in mice. This exposure activated the Hippo pathway, resulting in a decrease in ERα and circPVT1, and an elevation of miR-149. Co-exposure to these compounds in levels marginally lower than the MACs of each chemical also elevated cleaved CASPASE-3 levels. These changes showed a dose–response relationship. Joint exposure to these substances at values ≥ 1/3 of each average concentration in the blood could elicit similar biological effects in the ovaries and uteri cultured in vitro. Therefore, this study hypothesized that co-exposure to low levels of these environmental chemicals results in ovarian and uterine impairment in mice and that this damage may be linked to the activation of the Hippo pathway, downregulation of ERα and circPVT1, and upregulation of miR-149.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"414 ","pages":"Article 111770"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145574723","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}

引用次数: 0

Corrigendum to “Ibuprofen induces hepatic Cyp7a1 expression in mice via the intestinal FXR-FGF15 signaling” [Toxicology Letters 398 (2024) 1–12] “布洛芬通过肠道FXR-FGF15信号诱导小鼠肝脏Cyp7a1表达”的更正[毒理学快报398 (2024)1-12]

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-10-31 DOI: 10.1016/j.toxlet.2025.111766

Huixiang Li , Hui Xiong , Xue Wang , Tong Xu , Chunze Zhang , Weihua Zhang , Youcai Zhang

引用次数: 0

Impact of microplastics and nanoplastics on human health: Mechanistic insights and exposure pathways 微塑料和纳米塑料对人体健康的影响：机理见解和暴露途径。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-11-05 DOI: 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.

微塑料（MPs）和纳米塑料（NPs）已成为对人类健康具有潜在不利影响的重要环境污染物。本文综述了MPs和NPs在环境中传播的各种途径及其对人类的潜在影响。它们可以通过多种来源进入环境，如合成纺织品、化妆品、包装和工业过程。这些颗粒通过摄入、吸入和皮肤接触进入人体，并沉积在各种组织中，包括肺、肾和胃肠道。此外，它们可以穿过胚胎层到达胎盘。经体内和体外研究证实，它们在相互作用时可引起炎症、氧化应激、代谢紊乱、遗传毒性和免疫毒性作用。此外，长期暴露于MPs和NPs会给人体带来各种并发症，包括代谢紊乱甚至癌症的发展。尽管存在大量证据，但在充分了解多磺酸盐和非磺酸盐暴露造成的毒性机制及其长期健康后果方面仍存在重大差距。迫切需要进行广泛的调查和改进标准化方法，以评估MPs和NPs对人类健康的影响。本综述探讨了目前关于暴露途径、生物积累机制和健康结果的证据，并确定了关键的知识空白。

{"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":"2025-12-01","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}

引用次数: 0

A chemoproteomic strategy for identifying protein covalent binding targets of clozapine: An approach for advancing clozapine toxicity research 确定氯氮平蛋白共价结合靶点的化学蛋白质组学策略：一种推进氯氮平毒性研究的方法。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-10-21 DOI: 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.

精神分裂症影响很大比例的个体，其中一部分患者被描述为治疗抵抗。氯氮平是一种非典型抗精神病药，保留给这些患者使用，在抗自杀活性方面具有优势。然而，它带有许多严重的警告，并因其药物性粒细胞缺乏症的风险而闻名。毒性机制尚不清楚，可能是由于氯氮平的蛋白质共价结合和脱靶效应，通过其反应性代谢物产生的中性粒细胞过氧化物酶（MPO）活性。我们假设鉴定和分析蛋白质-氯氮平加合物将有助于我们对毒性途径的理解。我们开发了一种新的可点击氯氮平（click - cloz）衍生物，并设计了用于蛋白质鉴定的点击化学方案。HL-60（人早幼粒细胞白血病）细胞系和分离的人中性粒细胞显著表达MPO，并用于鉴定Click-CLOZ的蛋白共价靶点。在HL-60细胞中，LC/MS分析发现了许多click - cloz结合蛋白（与载体对照相比）。一些捕获的蛋白质因其在DNA复制、免疫反应和氧化应激中的作用而闻名，如组织蛋白酶G、MPO、核蛋白I和P1-MCM3。在中性粒细胞中，Click-CLOZ结合蛋白包括MPO、S100和DEFA1B，它们也与中性粒细胞介导的氧化应激和免疫反应有关。总之，点击化学蛋白质组学的应用促进了一种新的方法来识别多个氯氮平结合蛋白靶点，这将有助于我们进一步了解氯氮平的毒性。

{"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":"2025-12-01","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}

引用次数: 0

Corrigendum to “TLR2-ERK signaling pathway regulates expression of galectin-3 in a murine model of OVA-induced allergic airway inflammation” [Toxicol. Lett. 397 (2024) 55–66] “TLR2-ERK信号通路调节ova诱导的小鼠过敏性气道炎症模型中半乳糖凝集素-3的表达”的更正[毒理学杂志]。Lett. 397(2024) 55-66]。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-11-03 DOI: 10.1016/j.toxlet.2025.111768

Yunxiang Lv , Guiyun Jiang , Yanru Jiang , Caiqiu Peng , Wei Li

引用次数: 0

HRD1 promotes chronic alcoholic liver disease by mediating ACSL3 ubiquitination and degradation HRD1通过介导ACSL3泛素化和降解促进慢性酒精性肝病

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-10-21 DOI: 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.

酒精相关性肝病（ALD）是全球最常见的慢性肝病之一，其特征是脂肪变性。HMG-CoA还原酶降解蛋白1 （HRD1）通过底物蛋白的识别、易位和泛素化参与内质网相关蛋白降解途径。HRD1参与内质网应激、氧化应激和细胞代谢；然而，HRD1在ALD中的功能尚不清楚。目的探讨HRD1在酒精性肝病中的作用及其分子机制。方法小鼠静脉注射编码HRD1-或acsl3特异性shRNA的腺相关病毒9，饲喂含5 %乙醇的Lieber-DeCarli液体饲料。在乙醇暴露之前，用HRD1 siRNA或HRD1过表达质粒转染HepG2细胞。结果酒精作用下肝脏HRD1表达明显升高。肝细胞特异性HRD1敲低可显著减轻体内酒精诱导的肝损伤、炎症、氧化应激和脂质代谢紊乱。此外，在体外也显示出类似的结果。从机制上说，酰基辅酶a合成酶长链家族成员3 （ACSL3）是已知改善肝脂肪变性的关键调节因子，被确定为HRD1的新底物。HRD1促进ACSL3的泛素化和降解。有趣的是，HRD1敲低显著抑制脂肪酸合成并促进脂肪酸氧化，而ACSL3沉默在体内和体外均可逆转这一作用。综上所述，HRD1通过泛素化ACSL3而成为ALD的关键介质，从而促进脂质失衡，加重ALD。我们的研究结果揭示了HRD1的新机制，并确定ACSL3是HRD1促进ALD治疗的新下游靶点。

{"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":"2025-12-01","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}

引用次数: 0