Toxicology letters最新文献

英文中文

Lithium attenuates ketamine-induced long-term neurotoxicity through DISC1-mediated GSK-3β/β-catenin and ERK/CREB pathways 锂通过DISC1介导的GSK-3β/β-catenin和ERK/CREB途径减轻氯胺酮诱导的长期神经毒性

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-02-28 DOI: 10.1016/j.toxlet.2025.02.012

Ting-Ting Yang , Zi-Wen Guo , Fang Zhang , Yu Peng , Wei Yu , Guang-Qiang Gao , Hong Tian , Shu-Jun Zhang , Jia-Ren Liu

Ketamine, an antagonist of N-methyl-D-aspartate receptor, is extensively employed in pediatric anesthesia. Multiple studies have shown that repeated ketamine exposure induces neuroapoptosis, synaptic changes and cognitive deficits during neurodevelopment. Therefore, it is essential to elucidate the mechanisms of ketamine-induced neurotoxicity and develop therapies to mitigate its harmful effects. Here, we investigated the role of disrupted in Schizophrenia 1 (DISC1) in ketamine-induced long-term neurotoxicity through a ketamine-exposed neuroapoptosis model. Neonatal rats received 2–5 intraperitoneal injections of ketamine (20 mg/kg b.w.) at 90 min intervals. Another cohort of pups received five intraperitoneal injections of ketamine (20 mg/kg×5 b.w.) with or without lithium (120 mg/kg×5 b.w.) at 90 min intervals over 6 h. Neuroapoptosis, DISC1-associated proteins expression in rats treated with ketamine, lithium, or a combination of both were detected, and the cognitive function of adolescent rats was evaluated by Morris water maze test. The length of dendrites and axons of primary neurons treated with lithium and ketamine were further measured. Results showed that ketamine time-dependently downregulated the levels of DISC1, pGSK-3β, β-catenin, pERK, pCREB and PSD95 in neonatal rats. Lithium could ameliorate neuroapoptosis, cognitive deficits and neurite growth inhibition triggered by ketamine. Mechanistically, lithium upregulated the levels of DISC1, PSD95 and GSK-3β/β-catenin and ERK/CREB signaling-related proteins. Consequently, lithium mitigated ketamine-induced long-term neurotoxicity by elevating DISC1 level and activating the GSK-3β/β-catenin and ERK/CREB signaling pathways.

{"title":"Lithium attenuates ketamine-induced long-term neurotoxicity through DISC1-mediated GSK-3β/β-catenin and ERK/CREB pathways","authors":"Ting-Ting Yang , Zi-Wen Guo , Fang Zhang , Yu Peng , Wei Yu , Guang-Qiang Gao , Hong Tian , Shu-Jun Zhang , Jia-Ren Liu","doi":"10.1016/j.toxlet.2025.02.012","DOIUrl":"10.1016/j.toxlet.2025.02.012","url":null,"abstract":"<div><div>Ketamine, an antagonist of N-methyl-D-aspartate receptor, is extensively employed in pediatric anesthesia. Multiple studies have shown that repeated ketamine exposure induces neuroapoptosis, synaptic changes and cognitive deficits during neurodevelopment. Therefore, it is essential to elucidate the mechanisms of ketamine-induced neurotoxicity and develop therapies to mitigate its harmful effects. Here, we investigated the role of disrupted in Schizophrenia 1 (DISC1) in ketamine-induced long-term neurotoxicity through a ketamine-exposed neuroapoptosis model. Neonatal rats received 2–5 intraperitoneal injections of ketamine (20 mg/kg b.w.) at 90 min intervals. Another cohort of pups received five intraperitoneal injections of ketamine (20 mg/kg×5 b.w.) with or without lithium (120 mg/kg×5 b.w.) at 90 min intervals over 6 h. Neuroapoptosis, DISC1-associated proteins expression in rats treated with ketamine, lithium, or a combination of both were detected, and the cognitive function of adolescent rats was evaluated by Morris water maze test. The length of dendrites and axons of primary neurons treated with lithium and ketamine were further measured. Results showed that ketamine time-dependently downregulated the levels of DISC1, pGSK-3β, β-catenin, pERK, pCREB and PSD95 in neonatal rats. Lithium could ameliorate neuroapoptosis, cognitive deficits and neurite growth inhibition triggered by ketamine. Mechanistically, lithium upregulated the levels of DISC1, PSD95 and GSK-3β/β-catenin and ERK/CREB signaling-related proteins. Consequently, lithium mitigated ketamine-induced long-term neurotoxicity by elevating DISC1 level and activating the GSK-3β/β-catenin and ERK/CREB signaling pathways.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"406 ","pages":"Pages 50-62"},"PeriodicalIF":2.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537656","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

Modernizing toxicology: The importance of accessible NAM training

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-02-25 DOI: 10.1016/j.toxlet.2025.02.011

Eryn Slankster-Schmierer

Current toxicology curricula and certifications are heavily reliant on animal-based research and lack mandatory education and training in New Approach Methodologies (NAMs). Traditional animal-based toxicological methods come with many concerns, including translatability and reproducibility, which NAMs are aptly positioned to address. The NAM Use for Regulatory Application (NURA) program aims to bridge this educational gap by providing training to toxicologists, method developers, regulators, and legislators on the use of NAMs, helping to build confidence in NAM use and facilitate the shift to more human-based methods.

引用次数: 0

Discovery of non-steroidal aldo-keto reductase 1D1 inhibitors through automated screening and in vitro evaluation

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-02-21 DOI: 10.1016/j.toxlet.2025.02.009

Jacek Kȩdzierski , Rianne E. van Diest , Julien A. Allard , Alex Odermatt , Martin Smieško

Steroid hormones regulate a wide range of physiological processes in the human body. However, exposure to xenobiotics can disrupt the hormonal balance by inhibition of enzymes involved in hormone synthesis or metabolism. Aldo-keto reductase 1D1 (AKR1D1) plays a key role in bile acid and steroid hormone metabolism by catalyzing the reduction of the double bond between C4 and C5 atoms of Δ(4)-steroids. In our previous work, we developed a model to screen for steroid-like xenobiotics that inhibit AKR1D1. In the current study, we used this model to screen for novel non-steroidal inhibitors. By applying an automatized screening approach, based on molecular docking and scoring in combination with post-docking refinement, 45 compounds were detected as potential hits and selected for in vitro evaluation. Among them, zardaverine was identified as the most potent inhibitor, with an IC₅₀ value of 2.32 ± 1.27 μM. Other moderate inhibitors included carbamazepine, larotrectinib, endosulfan II, megastigmatrienone A, and mizolastine. The structural diversity of the identified inhibitors demonstrates that the binding site of AKR1D1 is rather promiscuous and can accommodate a broad range of ligands. These findings underscore the importance of toxicity screening and potential to identify structurally different AKR1D1 inhibitors.

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引用次数: 0

Zanamivir alleviates ethanol intoxication through activating catalase 扎那米韦通过激活过氧化氢酶减轻乙醇中毒。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-02-21 DOI: 10.1016/j.toxlet.2025.02.010

Zhanghui Guan , Dong Tian , Menghan Wang , Xinrui Meng , Jia Kang , Zhuozhou Hu , Haoxuan Xu , Xiaomei Ma , Tingting Jin , Xiaoshan Gao , Yixuan Zhang , Youquan Gu , Xiaohua Liu , Xinping Chen

Objectives

Acute alcohol intoxication is characterized as high morbidity and mortality. To explore new chemicals to relieve ethanol intoxication, we tried to explore the activators of catalase (CAT), an enzyme responsible for oxidization of ethanol into acetaldehyde to accelerate ethanol removal.

Methods

We identified zanamivir, an antiviral agent, activated CAT in vitro after screening of clinical chemicals. Then, female KunMing mice were administrated with a single dose of ethanol to induce acute alcoholism model. The behavioral changes were recorded, besides, the serum ethanol derivatives and redox- associated with indexes in mouse liver were detected.

Results

We observed that zanamivir augmented CAT activity to reduce blood ethanol concentration. Mechanically, zanamivir enhanced superoxide dismutase (SOD) activity and glutathione (GSH) amount, meanwhile it decreased the concentration of malondialdehyde (MDA), thereby mitigating oxidative damage induced by ethanol consumption. Accordingly, zanamivir relieved drunkenness in mouse ethanol intoxication model, and simultaneously suppressed aspartate transferase (AST), alanine transaminase (ALT) and lactic acid (LD) accumulation to protect hepatic function and tissue.

Significance

Collectively, our work suggests that zanamivir should be repurposed for countering alcohol intoxication in clinic.

{"title":"Zanamivir alleviates ethanol intoxication through activating catalase","authors":"Zhanghui Guan , Dong Tian , Menghan Wang , Xinrui Meng , Jia Kang , Zhuozhou Hu , Haoxuan Xu , Xiaomei Ma , Tingting Jin , Xiaoshan Gao , Yixuan Zhang , Youquan Gu , Xiaohua Liu , Xinping Chen","doi":"10.1016/j.toxlet.2025.02.010","DOIUrl":"10.1016/j.toxlet.2025.02.010","url":null,"abstract":"<div><h3>Objectives</h3><div>Acute alcohol intoxication is characterized as high morbidity and mortality. To explore new chemicals to relieve ethanol intoxication, we tried to explore the activators of catalase (CAT), an enzyme responsible for oxidization of ethanol into acetaldehyde to accelerate ethanol removal.</div></div><div><h3>Methods</h3><div>We identified zanamivir, an antiviral agent, activated CAT in vitro after screening of clinical chemicals. Then, female KunMing mice were administrated with a single dose of ethanol to induce acute alcoholism model. The behavioral changes were recorded, besides, the serum ethanol derivatives and redox- associated with indexes in mouse liver were detected.</div></div><div><h3>Results</h3><div>We observed that zanamivir augmented CAT activity to reduce blood ethanol concentration. Mechanically, zanamivir enhanced superoxide dismutase (SOD) activity and glutathione (GSH) amount, meanwhile it decreased the concentration of malondialdehyde (MDA), thereby mitigating oxidative damage induced by ethanol consumption. Accordingly, zanamivir relieved drunkenness in mouse ethanol intoxication model, and simultaneously suppressed aspartate transferase (AST), alanine transaminase (ALT) and lactic acid (LD) accumulation to protect hepatic function and tissue.</div></div><div><h3>Significance</h3><div>Collectively, our work suggests that zanamivir should be repurposed for countering alcohol intoxication in clinic.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"406 ","pages":"Pages 40-49"},"PeriodicalIF":2.9,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484038","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

Iodoacetamide triggers ovarian dysfunction in mice through TGF-β signaling pathway and apoptosis

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-02-14 DOI: 10.1016/j.toxlet.2025.02.005

Chenyu Xiao , Qianru Li , Meiqi Li , Yongshu Han , Hubin Xu , Haimin Jiang , Suer Zhang , Zhen Jin , Leilei Gao

Iodoacetamide (IAcAm) is a harmful disinfection by-product. Studies have demonstrated that IAcAm can produce toxic effects in various tissues; however, its effect on female reproductive function remains unclear. To explore the effects of IAcAm on ovaries, we constructed a female mouse IAcAm toxicity model of free drinking model. The findings indicated that IAcAm exposure for five weeks did not affect the body growth of mice but increased the ovary/body weight ratio. At the tissue level, the numbers of atretic follicles increased. After the exposure, ovarian and blood samples were collected for analysis. IAcAm exposure caused changes in serum sex hormone levels, with an increase in follicle-stimulating hormone concentration(follicle-stimulating hormone) and a decrease in anti-Müllerian hormone concentration (anti-Müllerian hormone). Subsequent investigations revealed that IAcAm activated the transforming growth factor-β (TGF-β) signaling pathway and promoted ovarian fibrosis in mice. Simultaneously, IAcAm stimulated the granulosa cell apoptosis pathway and promoted granulosa cell apoptosis. Moreover, IAcAm interfered with mitochondrial function and increased reactive oxygen species, leading to a decrease in oocyte developmental potential. In conclusion, IAcAm exposure causes ovarian inflammation and leads to mitochondrial dysfunction in oocytes, affecting follicle maturation and reducing oocyte quality.

{"title":"Iodoacetamide triggers ovarian dysfunction in mice through TGF-β signaling pathway and apoptosis","authors":"Chenyu Xiao , Qianru Li , Meiqi Li , Yongshu Han , Hubin Xu , Haimin Jiang , Suer Zhang , Zhen Jin , Leilei Gao","doi":"10.1016/j.toxlet.2025.02.005","DOIUrl":"10.1016/j.toxlet.2025.02.005","url":null,"abstract":"<div><div>Iodoacetamide (IAcAm) is a harmful disinfection by-product. Studies have demonstrated that IAcAm can produce toxic effects in various tissues; however, its effect on female reproductive function remains unclear. To explore the effects of IAcAm on ovaries, we constructed a female mouse IAcAm toxicity model of free drinking model. The findings indicated that IAcAm exposure for five weeks did not affect the body growth of mice but increased the ovary/body weight ratio. At the tissue level, the numbers of atretic follicles increased. After the exposure, ovarian and blood samples were collected for analysis. IAcAm exposure caused changes in serum sex hormone levels, with an increase in follicle-stimulating hormone concentration(follicle-stimulating hormone) and a decrease in anti-Müllerian hormone concentration (anti-Müllerian hormone). Subsequent investigations revealed that IAcAm activated the transforming growth factor-β (TGF-β) signaling pathway and promoted ovarian fibrosis in mice. Simultaneously, IAcAm stimulated the granulosa cell apoptosis pathway and promoted granulosa cell apoptosis. Moreover, IAcAm interfered with mitochondrial function and increased reactive oxygen species, leading to a decrease in oocyte developmental potential. In conclusion, IAcAm exposure causes ovarian inflammation and leads to mitochondrial dysfunction in oocytes, affecting follicle maturation and reducing oocyte quality.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"406 ","pages":"Pages 9-19"},"PeriodicalIF":2.9,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433887","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

Mitophagy impairment drives microglia activation and results in cognitive deficits in neonatal mice following sevoflurane exposure

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-02-13 DOI: 10.1016/j.toxlet.2025.02.008

Piao Zhang , Rui-Juan Cheng , Qiao-Ling Yang , Yan Gong , Yan Xu , Ling-Min Chen , Li Zhou , Chun-Ling Jiang

Sevoflurane exposure induces cognitive deficits in neonatal mice. Mitophagy was closely correlated to sevoflurane inhalation induced neurotoxicity in developing brains. However, the underlying mechanisms have not been fully elucidated. In this study, we attempted to clarify the role of mitophagy in neonatal mice undergoing sevoflurane exposure. BV2 microglial cells were cultured, and mcherry-EGFP-LC3B adenovirus were transfected. The results showed that the fluorescence intensity of GFP was markedly increased after sevoflurane exposure, and rapamycin administration could mitigate this effect. The mitophagy flux test showed that sevoflurane exposure reduced the degree of colocalization between Mito-Traker and Lyso-Traker fluorescent, while which was elevated by rapamycin treatment. The immunofluorescence assay suggested that sevoflurane inhalation resulted in the significant decrease of autolysosome formation, which was sharply enhanced in SEV group after rapamycin treatment. Meanwhile, sevoflurane inhalation shifted microglial M1/M2 phenotypic polarization, and rapamycin administration reversed this status. Moreover, the degree of colocalization among Iba-1, Synaptophysin (Syn) and lysosomal-associated membrane protein 1 (Lamp1) was increased after sevoflurane exposure, and that was reduced following rapamycin treatment. The behavioral performance was worse after sevoflurane inhalation in neonatal mice, and rapamycin treatment effectively improved the cognitive outcome. Collectively, these findings demonstrated that mitophagy impairment induced by sevoflurane exposure promoted microglia M1 phenotypic polarization and enlarged phagocytosis, and resulted in cognitive deficits, while rapamycin administration effectively reversed this tendency.

{"title":"Mitophagy impairment drives microglia activation and results in cognitive deficits in neonatal mice following sevoflurane exposure","authors":"Piao Zhang , Rui-Juan Cheng , Qiao-Ling Yang , Yan Gong , Yan Xu , Ling-Min Chen , Li Zhou , Chun-Ling Jiang","doi":"10.1016/j.toxlet.2025.02.008","DOIUrl":"10.1016/j.toxlet.2025.02.008","url":null,"abstract":"<div><div>Sevoflurane exposure induces cognitive deficits in neonatal mice. Mitophagy was closely correlated to sevoflurane inhalation induced neurotoxicity in developing brains. However, the underlying mechanisms have not been fully elucidated. In this study, we attempted to clarify the role of mitophagy in neonatal mice undergoing sevoflurane exposure. BV2 microglial cells were cultured, and mcherry-EGFP-LC3B adenovirus were transfected. The results showed that the fluorescence intensity of GFP was markedly increased after sevoflurane exposure, and rapamycin administration could mitigate this effect. The mitophagy flux test showed that sevoflurane exposure reduced the degree of colocalization between Mito-Traker and Lyso-Traker fluorescent, while which was elevated by rapamycin treatment. The immunofluorescence assay suggested that sevoflurane inhalation resulted in the significant decrease of autolysosome formation, which was sharply enhanced in SEV group after rapamycin treatment. Meanwhile, sevoflurane inhalation shifted microglial M1/M2 phenotypic polarization, and rapamycin administration reversed this status. Moreover, the degree of colocalization among Iba-1, Synaptophysin (Syn) and lysosomal-associated membrane protein 1 (Lamp1) was increased after sevoflurane exposure, and that was reduced following rapamycin treatment. The behavioral performance was worse after sevoflurane inhalation in neonatal mice, and rapamycin treatment effectively improved the cognitive outcome. Collectively, these findings demonstrated that mitophagy impairment induced by sevoflurane exposure promoted microglia M1 phenotypic polarization and enlarged phagocytosis, and resulted in cognitive deficits, while rapamycin administration effectively reversed this tendency.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"406 ","pages":"Pages 20-30"},"PeriodicalIF":2.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426258","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

The effects of citalopram and sertraline on adipogenesis and lipogenesis in 3T3-L1 cells

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-02-13 DOI: 10.1016/j.toxlet.2025.02.007

Deniz Bozdag , Bita Entezari , Hande Gurer-Orhan

Selective serotonin reuptake inhibitors (SSRIs), widely used antidepressants, have been associated with metabolic adverse effects, including weight gain and disrupted lipid metabolism. This study investigates the potential adipogenic and lipogenic effects of two commonly prescribed SSRIs, citalopram (CIT) and sertraline (SER), using the murine 3T3-L1 preadipocyte cell line. Key markers, such as adiponectin secretion, G3PDH activity, and the expression of critical transcription factors (PPARγ, CEBPα, SREBP1) and lipogenic enzymes (FASN, LPL), were evaluated. Furthermore, assessment of intracellular lipid accumulation via Oil Red O staining was used as a measure for enhanced adipogenesis. The results show that CIT significantly increased adiponectin secretion and G3PDH activity, with comparable potency to the positive control, rosiglitazone. Both SSRIs upregulated the transcription of key adipogenic genes but displayed discrepancies in protein expression. Despite these molecular changes, neither CIT nor SER promoted lipid accumulation, indicating disruption of adipogenic and lipogenic processes without direct stimulation of fat storage. These findings underscore the complexity of SSRI-induced metabolic effects and the need for further studies to evaluate their long-term impact.

{"title":"The effects of citalopram and sertraline on adipogenesis and lipogenesis in 3T3-L1 cells","authors":"Deniz Bozdag , Bita Entezari , Hande Gurer-Orhan","doi":"10.1016/j.toxlet.2025.02.007","DOIUrl":"10.1016/j.toxlet.2025.02.007","url":null,"abstract":"<div><div>Selective serotonin reuptake inhibitors (SSRIs), widely used antidepressants, have been associated with metabolic adverse effects, including weight gain and disrupted lipid metabolism. This study investigates the potential adipogenic and lipogenic effects of two commonly prescribed SSRIs, citalopram (CIT) and sertraline (SER), using the murine 3T3-L1 preadipocyte cell line. Key markers, such as adiponectin secretion, G3PDH activity, and the expression of critical transcription factors (PPARγ, CEBPα, SREBP1) and lipogenic enzymes (FASN, LPL), were evaluated. Furthermore, assessment of intracellular lipid accumulation via Oil Red O staining was used as a measure for enhanced adipogenesis. The results show that CIT significantly increased adiponectin secretion and G3PDH activity, with comparable potency to the positive control, rosiglitazone. Both SSRIs upregulated the transcription of key adipogenic genes but displayed discrepancies in protein expression. Despite these molecular changes, neither CIT nor SER promoted lipid accumulation, indicating disruption of adipogenic and lipogenic processes without direct stimulation of fat storage. These findings underscore the complexity of SSRI-induced metabolic effects and the need for further studies to evaluate their long-term impact.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"405 ","pages":"Pages 67-75"},"PeriodicalIF":2.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143422114","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

Aristolochic acid-induced DNA adduct formation triggers acute DNA damage response in rat kidney proximal tubular cells 马兜铃酸诱导的 DNA 加合物形成引发大鼠肾近端肾小管细胞的急性 DNA 损伤反应

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-02-13 DOI: 10.1016/j.toxlet.2025.02.006

Miyu Komatsu, Takeshi Funakoshi, Toshihiko Aki, Kana Unuma

Aristolochic acid nephropathy (AAN) is a form of acute kidney injury triggered by the ingestion of aristolochic acid (AA), characterized by significant degeneration and loss of cells in the proximal tubules. Previous reports of AA-induced acute kidney injury have reported that AA-induced cytotoxicity can occur within a short period, up to 24 h; however, there are few reports on the relationship between AA-DNA adduct formation and cytotoxic mechanism during the acute phase. In this study, we aimed to elucidate the toxicological mechanisms in the initial phase of AA exposure by examining the effects of AA on NRK-52E rat proximal tubular cells within 24 h. We detected the formation of AA-DNA adducts as early as 4 h post-exposure, indicating that 50 μM of AA causes DNA damage. The DNA damage response pathway was activated, peaking at 8 h post-exposure. Additionally, we observed an increasing trend of G1 phase cell cycle arrest after 8 h, followed by a significant decline in cell viability at 16 h. These findings suggest that 50 μM of AA induces rapid DNA damage in NRK-52E cells, primarily through the formation of AA-DNA adducts, ultimately leading to G1 phase cell cycle arrest.

{"title":"Aristolochic acid-induced DNA adduct formation triggers acute DNA damage response in rat kidney proximal tubular cells","authors":"Miyu Komatsu, Takeshi Funakoshi, Toshihiko Aki, Kana Unuma","doi":"10.1016/j.toxlet.2025.02.006","DOIUrl":"10.1016/j.toxlet.2025.02.006","url":null,"abstract":"<div><div>Aristolochic acid nephropathy (AAN) is a form of acute kidney injury triggered by the ingestion of aristolochic acid (AA), characterized by significant degeneration and loss of cells in the proximal tubules. Previous reports of AA-induced acute kidney injury have reported that AA-induced cytotoxicity can occur within a short period, up to 24 h; however, there are few reports on the relationship between AA-DNA adduct formation and cytotoxic mechanism during the acute phase. In this study, we aimed to elucidate the toxicological mechanisms in the initial phase of AA exposure by examining the effects of AA on NRK-52E rat proximal tubular cells within 24 h. We detected the formation of AA-DNA adducts as early as 4 h post-exposure, indicating that 50 μM of AA causes DNA damage. The DNA damage response pathway was activated, peaking at 8 h post-exposure. Additionally, we observed an increasing trend of G1 phase cell cycle arrest after 8 h, followed by a significant decline in cell viability at 16 h. These findings suggest that 50 μM of AA induces rapid DNA damage in NRK-52E cells, primarily through the formation of AA-DNA adducts, ultimately leading to G1 phase cell cycle arrest.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"406 ","pages":"Pages 1-8"},"PeriodicalIF":2.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426256","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

Neurotoxic implications of gliotoxin and ochratoxin A in SH-SY5Y cells: ROS-induced apoptosis and genotoxicity

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-02-12 DOI: 10.1016/j.toxlet.2025.02.004

Raquel Penalva-Olcina, Cristina Juan, Mónica Fernández-Franzón, Ana Juan-García

Gliotoxin (GTX) and ochratoxin A (OTA) are naturally produced toxins by fungi and are known for their potential health risks. With the aim of shed some light on the mechanisms by which GTX, OTA, and their combination exert toxicity at neuronal level, the following in vitro studies were conducted in SH-SY5Y cells: a) intracellular ROS monitorization by the H2-DCFDA assay b) study of the expression of pro-apoptotic genes Bcl2, Casp-3, and Bax by RT-qPCR c) study of the apoptotic-necrotic progression of SH-SY5Y cells by flow cytometry; d) study of the genotoxic potential through the in vitro micronucleus (MN) assay also by flow cytometry following OECD TG 487 guidelines. ROS production was increased when cells were exposed to mycotoxins at all scenarios tested highlighting the effects of GTX. Regarding gene expression, increases of Bax and Casp-3 genes at 1.3- and 3- folds respectively were observed when cells were exposed to GTX at 0.75 μM, with a more prominent increase after exposure to the binary combination [GTX + OTA] at [0.2 + 0.1] µM, increasing 3 and 5-folds more, respectively when compared to the control. MN formation increased a 30 % compared to control when exposed to GTX at 0.4 μM, 43 % for OTA at 0.8 μM, with the highest increase observed when cells were exposed to the combination [GTX + OTA] at [0.2 + 1.5] μM, obtaining a 65 % more MN formation. Based on the results obtained, we can conclude that for the proposed scenarios of exposure to GTX, OTA, and their combination, genotoxic effects together with oxidative effects at neuronal level in SH-SY5Y cell line, were found to play a key role in their mechanisms of toxic action.

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引用次数: 0

Toxicological mode-of-action and developmental toxicity of different carbon chain length PFAS

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-02-09 DOI: 10.1016/j.toxlet.2025.02.003

Kamlesh Sodani , Bas Ter Braak , Sabine Hartvelt , Mark Boelens , Amer Jamalpoor , Sandeep Mukhi

Per-and polyfluoro alkyl substances (PFAS), also known as “forever chemicals”, are deemed as highly toxic with similar toxicological mode-of-action (MoA) and potency. However, varying carbon chain length and functional head-group of PFAS can affect their physicochemical properties, resulting in different toxicological properties. To assess PFAS toxicological MoA and to distinguish between high toxic PFAS and the low-toxic analogs, we tested a set of eight PFAS with varying carbon chain length (C2-C10) in the ToxProfiler assay. ToxProfiler is a human in vitro assay containing seven fluorescent reporters to visualize and quantify activation of the major cellular stress pathways: oxidative stress, cell cycle stress, endoplasmic reticulum (ER) stress, autophagy, ion stress, protein stress and inflammation. In addition, we evaluated teratogenicity potential of long-chain PFAS perfluorooctanoic acid (PFOA; C8), and the ultrashort-chain PFAS trifluoroacetic acid (TFA; C2) in ReproTracker, a human induced pluripotent stem cell (hiPSCs)-based assay in which differentiation into cardiomyocytes, hepatocytes, and neural rosettes is followed to identify developmental toxicity hazards of new drugs and chemicals. In this study, we identified long-chain PFAS (C8-C10), such as PFOA (C8) to be more cytotoxic than ultrashort-chain PFAS and to predominantly induce ER and oxidative stress at 130 µM. PFAS with a carbon chain length of C4-C7 primarily induced autophagy (300 µM) in ToxProfiler. Ultrashort-chain PFAS trifluoroacetic acid (TFA; C2) and perfluoropropionic acid (PFPrA; C3) did not activate any of the ToxProfiler stress response reporters and were not cytotoxic at their maximum tested concentrations (10 mM). In concordance, exposure of differentiating cells to PFOA in ReproTracker led to a concentration-dependent decrease in the hepatocyte-specific and neuroectodermal biomarker genes and disrupted their morphology at 30 and 60 µM, respectively. TFA had no significant effect on biomarker expression, nor on the morphology/functionality of the three differentiated cells. Altogether, we demonstrated that the carbon chain length of PFAS can determine their in vitro toxicity and ultrashort-chain PFAS (TFA) were found to be less toxic when compared to long-chain PFAS.

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