Pub Date : 2026-01-29DOI: 10.1016/j.toxlet.2026.111849
Anhui Ning , Feng Shao , Qingzheng Yang , Yiqian Ren , Shenxuan Zhou , Jinfeng Lin , Minjie Chu , Yan Zhang
Wide exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS) poses a great risk to human reproductive health. Reproductive longevity is a major factor influencing the female reproductive cycle and affects women's healthy ageing. However, few studies have comprehensively evaluated the correlation between serum PFAS concentrations and female reproductive age, including menarche, reproductive longevity, and menopause. The purpose of this research is to investigate the correlation between serum PFAS levels and female reproductive age using linear regression models based on the National Health and Nutrition Examination Survey (NHANES) database. A total of 4743 participants were included in this analysis, and the results showed that age at menopause was inversely associated with perfluorooctanoic acid (PFOA) (β = −0.77, 95 % CI = −1.36, −0.18, P = 0.01), perfluorohexane sulfonic acid (PFHxS) (β = −1.07, 95 % CI = −1.53, −0.60, P < 0.001) and perfluorooctane sulfonic acid (PFOS) (β = −0.84, 95 % CI = −1.30, −0.38, P < 0.001). Moreover, the results showed that PFOS (β = −0.89, 95 % CI = −1.36, −0.42, P < 0.001), PFHxS (β = −1.08, 95 % CI = −1.55, −0.60, P < 0.001), and PFOA (β = −0.68, 95 % CI = −1.28, −0.08, P = 0.03) exposure were inversely related to reproductive longevity in women, exhibiting a strong dose-response trend. Evidence from the study indicates that exposure to PFAS may raise the risk of shortened reproductive longevity in women.
广泛接触全氟烷基和多氟烷基物质（PFAS）对人类生殖健康构成巨大风险。生殖寿命是影响女性生殖周期和妇女健康老龄化的主要因素。然而，很少有研究全面评估血清PFAS浓度与女性生育年龄（包括月经初潮、生殖寿命和更年期）的相关性。本研究基于美国国家健康与营养调查（NHANES）数据库，采用线性回归模型探讨血清PFAS水平与女性生育年龄的相关性。共有4743名参与者被包含在这一分析,结果表明,绝经的年龄呈负相关并酸(PFOA)(β=−0.77,95 % CI =−1.36−0.18,P = 0.01),perfluorohexane磺酸(PFHxS)(β=−1.07,95 % CI =−1.53−0.60,P & lt; 0.001)和perfluorooctane磺酸(卵圆孔未闭)(β=−0.84,95 % CI =−1.30−0.38,P & lt; 0.001)。此外,结果表明,卵圆孔未闭(β=−0.89,95 % CI =−1.36−0.42,P & lt; 0.001),PFHxS(β=−1.08,95 % CI =−1.55−0.60,P & lt; 0.001),和全氟辛酸及其盐类(PFOA)(β=−0.68,95 % CI =−1.28−0.08,P = 0.03)接触是女性生殖寿命成反比,表现出强烈的剂量反应的趋势。研究证据表明，接触PFAS可能会增加女性生殖寿命缩短的风险。
{"title":"Association between perfluoroalkyl and polyfluoroalkyl substances exposure and reproductive longevity for female in the United States: A population-based study","authors":"Anhui Ning , Feng Shao , Qingzheng Yang , Yiqian Ren , Shenxuan Zhou , Jinfeng Lin , Minjie Chu , Yan Zhang","doi":"10.1016/j.toxlet.2026.111849","DOIUrl":"10.1016/j.toxlet.2026.111849","url":null,"abstract":"<div><div>Wide exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS) poses a great risk to human reproductive health. Reproductive longevity is a major factor influencing the female reproductive cycle and affects women's healthy ageing. However, few studies have comprehensively evaluated the correlation between serum PFAS concentrations and female reproductive age, including menarche, reproductive longevity, and menopause. The purpose of this research is to investigate the correlation between serum PFAS levels and female reproductive age using linear regression models based on the National Health and Nutrition Examination Survey (NHANES) database. A total of 4743 participants were included in this analysis, and the results showed that age at menopause was inversely associated with perfluorooctanoic acid (PFOA) (β = −0.77, 95 % CI = −1.36, −0.18, P = 0.01), perfluorohexane sulfonic acid (PFHxS) (β = −1.07, 95 % CI = −1.53, −0.60, P < 0.001) and perfluorooctane sulfonic acid (PFOS) (β = −0.84, 95 % CI = −1.30, −0.38, P < 0.001). Moreover, the results showed that PFOS (β = −0.89, 95 % CI = −1.36, −0.42, P < 0.001), PFHxS (β = −1.08, 95 % CI = −1.55, −0.60, P < 0.001), and PFOA (β = −0.68, 95 % CI = −1.28, −0.08, P = 0.03) exposure were inversely related to reproductive longevity in women, exhibiting a strong dose-response trend. Evidence from the study indicates that exposure to PFAS may raise the risk of shortened reproductive longevity in women.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111849"},"PeriodicalIF":2.9,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081125","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 : 2026-01-29DOI: 10.1016/j.toxlet.2026.111846
Xiaoxiao Liu , Xinyu Tao , Mengting Cheng , Hao Yan , Zhifei Xu , Bo Yang , Qiaojun He , Peihua Luo , Fangjie Yan , Jiangxia Du
Crizotinib, a first-in-class ALK/ROS1/MET inhibitor, has been shown to significantly improve outcomes in advanced non-small cell lung cancer (NSCLC); however, its clinical utility remains limited by multisystem toxicities. This review synthesizes evidence regarding crizotinib-induced adverse effects—such as hepatotoxicity, cardiotoxicity, and interstitial lung disease—along with associated clinical management strategies. Through a systematic examination of the molecular mechanisms and multifactorial determinants of toxicity, this work aims to enhance understanding of the limitations associated with crizotinib’s clinical applicability. Although most toxicities are manageable through dose adjustments, prophylactic monitoring, and adjunct therapies, unresolved mechanistic questions and rare, severe adverse events underscore the need for further research. By integrating molecular insights with practical approaches, this review underscores the essential balance between therapeutic efficacy and toxicity risks, thereby informing personalized treatment decisions and facilitating the development of safer targeted therapies. The synthesis of current knowledge is intended to optimize the clinical application of crizotinib and to foster innovative strategies for toxicity management within the evolving paradigms of NSCLC treatment.
{"title":"Mechanisms and management of crizotinib-induced toxicity in non-small cell lung cancer","authors":"Xiaoxiao Liu , Xinyu Tao , Mengting Cheng , Hao Yan , Zhifei Xu , Bo Yang , Qiaojun He , Peihua Luo , Fangjie Yan , Jiangxia Du","doi":"10.1016/j.toxlet.2026.111846","DOIUrl":"10.1016/j.toxlet.2026.111846","url":null,"abstract":"<div><div>Crizotinib, a first-in-class ALK/ROS1/MET inhibitor, has been shown to significantly improve outcomes in advanced non-small cell lung cancer (NSCLC); however, its clinical utility remains limited by multisystem toxicities. This review synthesizes evidence regarding crizotinib-induced adverse effects—such as hepatotoxicity, cardiotoxicity, and interstitial lung disease—along with associated clinical management strategies. Through a systematic examination of the molecular mechanisms and multifactorial determinants of toxicity, this work aims to enhance understanding of the limitations associated with crizotinib’s clinical applicability. Although most toxicities are manageable through dose adjustments, prophylactic monitoring, and adjunct therapies, unresolved mechanistic questions and rare, severe adverse events underscore the need for further research. By integrating molecular insights with practical approaches, this review underscores the essential balance between therapeutic efficacy and toxicity risks, thereby informing personalized treatment decisions and facilitating the development of safer targeted therapies. The synthesis of current knowledge is intended to optimize the clinical application of crizotinib and to foster innovative strategies for toxicity management within the evolving paradigms of NSCLC treatment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111846"},"PeriodicalIF":2.9,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081063","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 : 2026-01-28DOI: 10.1016/j.toxlet.2026.111844
Maike Felipe Santos Barbetta , Giovanni Stoppa Baviera , Leandro Oka-Duarte , Icaro Salgado Perovani , Anderson Rodrigo Moraes de Oliveira
Diclofop (DF) is the main chiral metabolite of diclofop-methyl (DFM), a widely used herbicide for grass weed control. While DFM toxicity is documented, little is known about DF, despite its persistence. This study evaluated the enantioselective inhibition by racemic DF and its enantiomers over the major cytochrome P450 (CYP) isoforms present in human liver microsomes. The inhibition screening showed that (+)-DF preferentially inhibited CYP1A2, CYP2C9, CYP2E1, and CYP3A4/5, whereas (−)-DF was more active against CYP2C19 and CYP3A4/5. IC50 and kinetic studies confirmed moderate inhibition without time-dependent effect. DF competitively inhibited CYP2C9 with a Ki value of 2.13 µmol L−1. Finally, R1 factor estimations indicated that in vivo inhibition is unlikely even at exposure levels up to 100-fold above the acceptable daily intake. These results highlight the enantioselective inhibitory potential of a pesticide metabolite and its relevance for pesticide–drug interactions and human toxicity.
{"title":"Enantioselective CYP inhibition by diclofop, the active metabolite of diclofop-methyl: Mechanism and relevance for human exposure","authors":"Maike Felipe Santos Barbetta , Giovanni Stoppa Baviera , Leandro Oka-Duarte , Icaro Salgado Perovani , Anderson Rodrigo Moraes de Oliveira","doi":"10.1016/j.toxlet.2026.111844","DOIUrl":"10.1016/j.toxlet.2026.111844","url":null,"abstract":"<div><div>Diclofop (DF) is the main chiral metabolite of diclofop-methyl (DFM), a widely used herbicide for grass weed control. While DFM toxicity is documented, little is known about DF, despite its persistence. This study evaluated the enantioselective inhibition by racemic DF and its enantiomers over the major cytochrome P450 (CYP) isoforms present in human liver microsomes. The inhibition screening showed that (+)-DF preferentially inhibited CYP1A2, CYP2C9, CYP2E1, and CYP3A4/5, whereas (−)-DF was more active against CYP2C19 and CYP3A4/5. IC<sub>50</sub> and kinetic studies confirmed moderate inhibition without time-dependent effect. DF competitively inhibited CYP2C9 with a K<sub>i</sub> value of 2.13 µmol L<sup>−1</sup>. Finally, R<sub>1</sub> factor estimations indicated that <em>in vivo</em> inhibition is unlikely even at exposure levels up to 100-fold above the acceptable daily intake. These results highlight the enantioselective inhibitory potential of a pesticide metabolite and its relevance for pesticide–drug interactions and human toxicity.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111844"},"PeriodicalIF":2.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146094273","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 : 2026-01-28DOI: 10.1016/j.toxlet.2026.111845
Amanda Rebonatto Oltramari , Alice Santos Da Silva , Marina Machado Cabrera , Geisson Marcos Nardi , Fátima Regina Mena Barreto Silva , Gabriel Adan Araújo Leite
Statins are widely used to manage lipid disorders and reduce cardiovascular risk in humans. Rosuvastatin, one of the most effective statins, decreases cholesterol biosynthesis and exerts pleiotropic effects. However, recent studies indicate potential reproductive toxicity associated with statin use in animal and human studies. This study aimed to evaluate the reproductive parameters and fertility in adult female Swiss mice exposed to relevant doses of rosuvastatin. Female mice were divided into three experimental groups: control (0.9 % saline solution), 1.5 mg/kg of rosuvastatin, and 5.5 mg/kg of rosuvastatin. The treatments were administered via gavage from postnatal day (PND) 80 to PND 110, and the reproductive and developmental parameters, as well as the general health status of the animals, were assessed. There was a reduction in total serum cholesterol and triglyceride levels, a reduced total number of antral follicles, and an increased ovarian follicular atresia, as confirmed by increased cleaved caspase-9 and caspase-3 immunostaining in the granulosa cells of antral follicles, in the rosuvastatin-treated females. However, no adverse effects were observed in body mass gain and the hepatic markers of non-pregnant females. The treatment with rosuvastatin preceding gestation reduced pregnancy rate and increased post-implantation losses, resorptions, and fetal mortality, especially at the lower dose. In summary, the exposure to rosuvastatin during adulthood may compromise follicular dynamics and reduce female reproductive performance. These outcomes reinforce the need for caution in the use of statins by women of reproductive age.
{"title":"Rosuvastatin exposure during adulthood increases ovarian follicular atresia and reduces reproductive performance in female mice","authors":"Amanda Rebonatto Oltramari , Alice Santos Da Silva , Marina Machado Cabrera , Geisson Marcos Nardi , Fátima Regina Mena Barreto Silva , Gabriel Adan Araújo Leite","doi":"10.1016/j.toxlet.2026.111845","DOIUrl":"10.1016/j.toxlet.2026.111845","url":null,"abstract":"<div><div>Statins are widely used to manage lipid disorders and reduce cardiovascular risk in humans. Rosuvastatin, one of the most effective statins, decreases cholesterol biosynthesis and exerts pleiotropic effects. However, recent studies indicate potential reproductive toxicity associated with statin use in animal and human studies. This study aimed to evaluate the reproductive parameters and fertility in adult female Swiss mice exposed to relevant doses of rosuvastatin. Female mice were divided into three experimental groups: control (0.9 % saline solution), 1.5 mg/kg of rosuvastatin, and 5.5 mg/kg of rosuvastatin. The treatments were administered via gavage from postnatal day (PND) 80 to PND 110, and the reproductive and developmental parameters, as well as the general health status of the animals, were assessed. There was a reduction in total serum cholesterol and triglyceride levels, a reduced total number of antral follicles, and an increased ovarian follicular atresia, as confirmed by increased cleaved caspase-9 and caspase-3 immunostaining in the granulosa cells of antral follicles, in the rosuvastatin-treated females. However, no adverse effects were observed in body mass gain and the hepatic markers of non-pregnant females. The treatment with rosuvastatin preceding gestation reduced pregnancy rate and increased post-implantation losses, resorptions, and fetal mortality, especially at the lower dose. In summary, the exposure to rosuvastatin during adulthood may compromise follicular dynamics and reduce female reproductive performance. These outcomes reinforce the need for caution in the use of statins by women of reproductive age.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111845"},"PeriodicalIF":2.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081126","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}
Tributyl phosphate (TBP) can lead to abnormal hepatic lipid metabolism. Inflammation triggered by the cGAS-STING may be involved in it. Within this research, we investigated the involved mechanisms of TBP-induced lipid metabolic disorders. Rats and BRL-3A cells are used as models to determine the liver toxicity of TBP. Aspirin was used to alleviate the inflammation induced by TBP. RU.521 and H151 were employed to inhibit the activation of cGAS-STING. HE staining was applied to observe liver injury. The mitochondrial structure was observed with transmission electron microscopy. The quantification of lipid levels was achieved through colorimetry. The concentrations of inflammatory factors were assessed by ELISA. The expression levels of genes involved in lipid metabolism and cGAS-STING signaling pathway were detected by Q-PCR and western blot. TBP induced hepatocyte swelling and disorganized cord structures of rat livers. Following exposure to TBP, there is an elevation in the concentrations of triglycerides (TG) and total cholesterol (T-CHO), and the mRNA and protein expression levels of FASN, SREBP2, and PPARγ also showed a significant increase(P < 0.05). TBP exposure enhanced interleukin-6 (IL-6) production and this effect is reversed by aspirin treatment(P < 0.05). In BRL-3A cells, inhibiting cGAS-STING signaling pathway decreased the IL-6 concentrations and reversed the lipid accumulation caused by TBP(P < 0.05). Taken together, our results suggest TBP induced histopathological damage in rat livers, including hepatocyte swelling and disorganized cord structures. It also caused alterations in mitochondrial structure. Moreover, TBP can mediate inflammatory responses via the cGAS-STING, which in turn leads to hepatic lipid accumulation.
{"title":"Tributyl phosphate disrupts hepatic lipid metabolism via cGAS-STING signal pathway mediated inflammation","authors":"Liwei Yang, Zhili Ge, Xuehan Ding, Jingjing Shi, Jiaxin Zhang, Tianyou Wang, Huibin Jiang, Xinyu Zhang, Liting Zhou","doi":"10.1016/j.toxlet.2026.111847","DOIUrl":"10.1016/j.toxlet.2026.111847","url":null,"abstract":"<div><div>Tributyl phosphate (TBP) can lead to abnormal hepatic lipid metabolism. Inflammation triggered by the cGAS-STING may be involved in it. Within this research, we investigated the involved mechanisms of TBP-induced lipid metabolic disorders. Rats and BRL-3A cells are used as models to determine the liver toxicity of TBP. Aspirin was used to alleviate the inflammation induced by TBP. RU.521 and H151 were employed to inhibit the activation of cGAS-STING. HE staining was applied to observe liver injury. The mitochondrial structure was observed with transmission electron microscopy. The quantification of lipid levels was achieved through colorimetry. The concentrations of inflammatory factors were assessed by ELISA. The expression levels of genes involved in lipid metabolism and cGAS-STING signaling pathway were detected by Q-PCR and western blot. TBP induced hepatocyte swelling and disorganized cord structures of rat livers. Following exposure to TBP, there is an elevation in the concentrations of triglycerides (TG) and total cholesterol (T-CHO), and the mRNA and protein expression levels of FASN, SREBP2, and PPARγ also showed a significant increase(<em>P</em> < 0.05). TBP exposure enhanced interleukin-6 (IL-6) production and this effect is reversed by aspirin treatment(<em>P</em> < 0.05). In BRL-3A cells, inhibiting cGAS-STING signaling pathway decreased the IL-6 concentrations and reversed the lipid accumulation caused by TBP(<em>P</em> < 0.05). Taken together, our results suggest TBP induced histopathological damage in rat livers, including hepatocyte swelling and disorganized cord structures. It also caused alterations in mitochondrial structure. Moreover, TBP can mediate inflammatory responses via the cGAS-STING, which in turn leads to hepatic lipid accumulation.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111847"},"PeriodicalIF":2.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081127","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}
The development of robust human in vitro models is crucial for advancing neurotoxicology and reducing animal testing. Human-induced pluripotent stem cell (hiPSC)-derived neuronal models hold great promise, but still show limitations in recapitulating certain neurodevelopmental processes. Currently, rodent primary cultures remain the gold standard for studying complex processes such as synaptogenesis. A key mechanism in glutamatergic synapse maturation is the GluN2B/GluN2A switch, which promotes the recruitment of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, increasing the structural and functional complexity of the synaptic spines. This study characterizes the development of the glutamatergic machinery in hiPSC-derived neurons, focusing on the expression and maturation of N-methyl-D-aspartate (NMDA) and AMPA receptors. The increase of neuronal markers and the reduction of progenitor markers confirmed the differentiation efficiency. However, discrepancies emerged between transcriptional and protein profiles of key receptor subunits. GluN2A mRNA levels increased over time, while protein levels remained similar to those of neural progenitor cells (NPCs). Conversely, the GluN3A transcript increased at 30 and 60 days in vitro (DIV), while protein abundance decreased. Similar transcript–protein mismatches were observed for some AMPA receptor subunits. These results suggest that this model does not reach full glutamatergic maturity within the tested timeframe. Therefore, optimizing differentiation conditions (such as extending culture duration or adding maturation cues) may be necessary to better reproduce receptor dynamics. Finally, this study highlights the need to integrate protein-level analyses with transcriptional data to improve the reliability of hiPSC-derived neuronal models for neurotoxicity and NMDA receptor–mediated excitotoxicity studies.
{"title":"Transcript-protein discrepancy of glutamatergic receptor subunits in human iPSC-derived neurons: Implications for neurotoxicity testing","authors":"Melania Maria Serafini , Miriam Midali , Giacomo Grumelli , Alessandro Cutarelli , Marina Marinovich , Luciano Conti , Barbara Viviani","doi":"10.1016/j.toxlet.2026.111834","DOIUrl":"10.1016/j.toxlet.2026.111834","url":null,"abstract":"<div><div>The development of robust human in vitro models is crucial for advancing neurotoxicology and reducing animal testing. Human-induced pluripotent stem cell (hiPSC)-derived neuronal models hold great promise, but still show limitations in recapitulating certain neurodevelopmental processes. Currently, rodent primary cultures remain the gold standard for studying complex processes such as synaptogenesis. A key mechanism in glutamatergic synapse maturation is the GluN2B/GluN2A switch, which promotes the recruitment of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, increasing the structural and functional complexity of the synaptic spines. This study characterizes the development of the glutamatergic machinery in hiPSC-derived neurons, focusing on the expression and maturation of N-methyl-<span>D</span>-aspartate (NMDA) and AMPA receptors. The increase of neuronal markers and the reduction of progenitor markers confirmed the differentiation efficiency. However, discrepancies emerged between transcriptional and protein profiles of key receptor subunits. GluN2A mRNA levels increased over time, while protein levels remained similar to those of neural progenitor cells (NPCs). Conversely, the GluN3A transcript increased at 30 and 60 days in vitro (DIV), while protein abundance decreased. Similar transcript–protein mismatches were observed for some AMPA receptor subunits. These results suggest that this model does not reach full glutamatergic maturity within the tested timeframe. Therefore, optimizing differentiation conditions (such as extending culture duration or adding maturation cues) may be necessary to better reproduce receptor dynamics. Finally, this study highlights the need to integrate protein-level analyses with transcriptional data to improve the reliability of hiPSC-derived neuronal models for neurotoxicity and NMDA receptor–mediated excitotoxicity studies.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111834"},"PeriodicalIF":2.9,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146067245","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 : 2026-01-24DOI: 10.1016/j.toxlet.2026.111833
Tianyu Li , Zhichen Tang , Yaping Song , Min Su , Xiao Liu , Fuping Li , Xing Wei , Xiaolei Luo , Bin Zhou , Yanyun Wang , Lin Zhang
Busulfan combined with cyclophosphamide (BuCy) is a common conditioning regimen before hematopoietic stem cell transplantation, but it causes severe gonadotoxicity, with nearly half of male patients suffering from irreversible infertility. Existing mouse models mostly use busulfan alone, which does not fully mimic clinical treatment. Here, we applied a BuCy treatment regimen in mice and performed a longitudinal characterization of testicular injury and recovery. BuCy treatment caused marked testicular atrophy in mice, severely disrupted seminiferous tubule architecture, and dramatically reduced sperm count and motility, with partial recovery at later time points. ScRNA-seq revealed a stepwise decline in germ cell populations, with spermatogonia disappearing earlier than spermatogonial stem cells (SSCs). In addition, we observed the highest number of differentially expressed genes (DEGs) at day 28. Functional enrichment highlighted disruptions in spermatogenesis, RNA metabolism, and chromatin regulation. This study systematically characterized the long-term, multi-time-point dynamics of BuCy-induced testicular damage and recovery in mice, with single-cell transcriptomic profiling providing complementary observations at the cellular level.
{"title":"Busulfan plus cyclophosphamide induced spermatogenic dysfunction and recovery: A dynamic change perspective","authors":"Tianyu Li , Zhichen Tang , Yaping Song , Min Su , Xiao Liu , Fuping Li , Xing Wei , Xiaolei Luo , Bin Zhou , Yanyun Wang , Lin Zhang","doi":"10.1016/j.toxlet.2026.111833","DOIUrl":"10.1016/j.toxlet.2026.111833","url":null,"abstract":"<div><div>Busulfan combined with cyclophosphamide (BuCy) is a common conditioning regimen before hematopoietic stem cell transplantation, but it causes severe gonadotoxicity, with nearly half of male patients suffering from irreversible infertility. Existing mouse models mostly use busulfan alone, which does not fully mimic clinical treatment. Here, we applied a BuCy treatment regimen in mice and performed a longitudinal characterization of testicular injury and recovery. BuCy treatment caused marked testicular atrophy in mice, severely disrupted seminiferous tubule architecture, and dramatically reduced sperm count and motility, with partial recovery at later time points. ScRNA-seq revealed a stepwise decline in germ cell populations, with spermatogonia disappearing earlier than spermatogonial stem cells (SSCs). In addition, we observed the highest number of differentially expressed genes (DEGs) at day 28. Functional enrichment highlighted disruptions in spermatogenesis, RNA metabolism, and chromatin regulation. This study systematically characterized the long-term, multi-time-point dynamics of BuCy-induced testicular damage and recovery in mice, with single-cell transcriptomic profiling providing complementary observations at the cellular level.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111833"},"PeriodicalIF":2.9,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053874","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}
Drug-induced liver injury (DILI) is one of the most common adverse drug effects and a major cause of drug development failure. However, preclinically identifying drugs that cause liver injury remains difficult and represents a major challenge in drug development. MicroRNAs (miRNAs) have been proposed as biomarkers for the early detection of DILI owing to the dynamic changes in their expression in response to hepatotoxic insults. Therefore, identifying human-specific miRNAs that change early in response to diverse hepatotoxicants may enable a practical screening approach for drug development. Here, we evaluated whether hepatic miRNA responses can distinguish hepatotoxic from non-hepatotoxic drugs using a highly humanized liver chimeric mouse model (PXB-mouse). We administered eight hepatotoxic compounds (hTOX) and three non-hepatotoxic compounds (non-hTOX) to PXB-mice and performed a comprehensive analysis of the changes in hepatic RNA expression. PXB-mice exposed to hTOX exhibited an increased expression of liver mRNAs which were related to early activation of transcriptional pathways induced by liver damage. Among the miRNAs that exhibited expression changes exclusively in the hTOX-treated group but not in the non-hTOX group compared to the controls, we identified miR-4306 and miR-1237 as potential candidates of human-specific miRNAs whose expression was changed only after hTOX treatment. Although further validation studies are warranted, our findings suggest that detection of miR-4306 and miR-1237 in PXB-mice may help discriminate hepatotoxic from non-hepatotoxic drug exposure.
{"title":"MicroRNA-based discrimination of hepatotoxic and non-hepatotoxic drugs using a humanized liver mouse model","authors":"Naoto Okada , Hatsune Enomoto , Ryota Goto , Hidehisa Tachiki , Takashi Kitahara","doi":"10.1016/j.toxlet.2026.111832","DOIUrl":"10.1016/j.toxlet.2026.111832","url":null,"abstract":"<div><div>Drug-induced liver injury (DILI) is one of the most common adverse drug effects and a major cause of drug development failure. However, preclinically identifying drugs that cause liver injury remains difficult and represents a major challenge in drug development. MicroRNAs (miRNAs) have been proposed as biomarkers for the early detection of DILI owing to the dynamic changes in their expression in response to hepatotoxic insults. Therefore, identifying human-specific miRNAs that change early in response to diverse hepatotoxicants may enable a practical screening approach for drug development. Here, we evaluated whether hepatic miRNA responses can distinguish hepatotoxic from non-hepatotoxic drugs using a highly humanized liver chimeric mouse model (PXB-mouse). We administered eight hepatotoxic compounds (hTOX) and three non-hepatotoxic compounds (non-hTOX) to PXB-mice and performed a comprehensive analysis of the changes in hepatic RNA expression. PXB-mice exposed to hTOX exhibited an increased expression of liver mRNAs which were related to early activation of transcriptional pathways induced by liver damage. Among the miRNAs that exhibited expression changes exclusively in the hTOX-treated group but not in the non-hTOX group compared to the controls, we identified miR-4306 and miR-1237 as potential candidates of human-specific miRNAs whose expression was changed only after hTOX treatment. Although further validation studies are warranted, our findings suggest that detection of miR-4306 and miR-1237 in PXB-mice may help discriminate hepatotoxic from non-hepatotoxic drug exposure.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111832"},"PeriodicalIF":2.9,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023571","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 : 2026-01-20DOI: 10.1016/j.toxlet.2026.111835
Guoping Li , Xiaohong Du , Xinqiao Wang , Xiaojie Han , Mengnan Peng , Chen Nan
Objective
This study aimed to explore the role of mitochondrial biogenesis in methanol-induced neurobehavioral impairments in rats and elucidate the potential neurotoxic mechanisms of methanol exposure.
Methods
Forty-eight healthy Sprague-Dawley rats (200 ± 20 g), equally stratified by sex, were randomized into four groups: a control group (0 g/m³) and low- (25.344 g/m³), medium- (50.688 g/m³), and high-dose (101.376 g/m³) methanol exposure groups. Rats were exposed via inhalation for 2 h/day, 7 days/week for 4 weeks. Neurobehavioral changes were evaluated using the Morris water maze (MWM) and open field test (OFT). Cortical histopathology was examined via H&E staining. Mitochondrial DNA (mtDNA) content was quantified by qPCR, and ATP levels were measured using a commercial assay kit. Western blotting was performed to assess the expression of mitochondrial biogenesis-related proteins (COX IV, PGC-1α, NRF1, and TFAM).
Results
Methanol-exposed rats exhibited significantly prolonged escape latency and fewer platform crossings in the MWM (P < 0.05). OFT results demonstrated reduced central zone activity duration, total distance traveled, and central zone entries (P < 0.05). H&E staining revealed neuronal loss and structural disorganization in the cortex. Additionally, mtDNA content and ATP levels were significantly decreased in medium- and high-dose groups (P < 0.05). Western blot analysis confirmed downregulation of COX IV, PGC-1α, NRF1, and TFAM (P < 0.05), indicating suppressed mitochondrial biogenesis.
Conclusion
Methanol exposure disrupts mitochondrial biogenesis in rat cortical neurons, leading to reduced mitochondrial content and ATP production, which may contribute to the observed neurobehavioral deficits. These findings provide mechanistic insights into methanol-induced neurotoxicity.
{"title":"Role of mitochondrial biogenesis in methanol-induced neurobehavioral changes in rats","authors":"Guoping Li , Xiaohong Du , Xinqiao Wang , Xiaojie Han , Mengnan Peng , Chen Nan","doi":"10.1016/j.toxlet.2026.111835","DOIUrl":"10.1016/j.toxlet.2026.111835","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to explore the role of mitochondrial biogenesis in methanol-induced neurobehavioral impairments in rats and elucidate the potential neurotoxic mechanisms of methanol exposure.</div></div><div><h3>Methods</h3><div>Forty-eight healthy Sprague-Dawley rats (200 ± 20 g), equally stratified by sex, were randomized into four groups: a control group (0 g/m³) and low- (25.344 g/m³), medium- (50.688 g/m³), and high-dose (101.376 g/m³) methanol exposure groups. Rats were exposed via inhalation for 2 h/day, 7 days/week for 4 weeks. Neurobehavioral changes were evaluated using the Morris water maze (MWM) and open field test (OFT). Cortical histopathology was examined via H&E staining. Mitochondrial DNA (mtDNA) content was quantified by qPCR, and ATP levels were measured using a commercial assay kit. Western blotting was performed to assess the expression of mitochondrial biogenesis-related proteins (COX IV, PGC-1α, NRF1, and TFAM).</div></div><div><h3>Results</h3><div>Methanol-exposed rats exhibited significantly prolonged escape latency and fewer platform crossings in the MWM (P < 0.05). OFT results demonstrated reduced central zone activity duration, total distance traveled, and central zone entries (P < 0.05). H&E staining revealed neuronal loss and structural disorganization in the cortex. Additionally, mtDNA content and ATP levels were significantly decreased in medium- and high-dose groups (P < 0.05). Western blot analysis confirmed downregulation of COX IV, PGC-1α, NRF1, and TFAM (P < 0.05), indicating suppressed mitochondrial biogenesis.</div></div><div><h3>Conclusion</h3><div>Methanol exposure disrupts mitochondrial biogenesis in rat cortical neurons, leading to reduced mitochondrial content and ATP production, which may contribute to the observed neurobehavioral deficits. These findings provide mechanistic insights into methanol-induced neurotoxicity.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111835"},"PeriodicalIF":2.9,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146026269","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 : 2026-01-13DOI: 10.1016/j.toxlet.2026.111828
Ukbe Sirayder, Cihangir Acik
Aim
This study aimed to evaluate the effects of occupational lead exposure on exercise capacity, oxidative stress, and pulmonary function using a multisystemic approach.
Methods
A total of 48 lead-exposed and 51 control male workers participated in this cross-sectional study. Incremental Shuttle Walk Test (ISWT), spirometry, blood lead levels (ICP-MS), and oxidative stress markers (MDA, FRAP) were assessed. Correlation and stepwise linear regression analyses were performed.
Results
The exposed group showed significantly lower ISWT distances (p < 0.001, Cohen’s d = 0.93), higher dyspnea and fatigue scores (p < 0.01), elevated MDA (d = 2.99), and reduced FRAP levels (d = 0.64). FVC (%) was significantly lower (p < 0.001, d = 1.48), while FEV₁/FVC ratio was higher (p < 0.001, d = 1.46). Regression analyses revealed that lead exposure duration significantly predicted reduced ISWT distance (β = –0.299, p = 0.039), increased dyspnea (β = 0.591, p < 0.001), general fatigue (β = 0.476, p = 0.001), and lower FVC (β = –0.353, p = 0.014).
Conclusion
Occupational lead exposure is associated with impaired exercise performance and pulmonary function. While oxidative stress contributes to this impairment, cumulative exposure duration emerged as the most consistent predictor. This is the first study to integratively evaluate the impact of lead on maximal exercise capacity alongside biochemical and respiratory parameters, offering novel insights into its systemic physiological burden.
目的本研究旨在通过多系统方法评估职业性铅暴露对运动能力、氧化应激和肺功能的影响。方法对48名铅暴露男性工人和51名正常男性工人进行横断面研究。评估增量穿梭行走试验（ISWT）、肺活量测定、血铅水平（ICP-MS）和氧化应激标志物（MDA、FRAP）。进行相关分析和逐步线性回归分析。结果暴露组ISWT距离显著缩短（p <； 0.001,Cohen’s d = 0.93），呼吸困难和疲劳评分显著升高（p <； 0.01），MDA升高（d = 2.99）， FRAP水平显著降低（d = 0.64）。FVC（%）显著降低（p <； 0.001,d = 1.48），而FEV 1 /FVC比率较高（p <； 0.001,d = 1.46）。回归分析显示，铅暴露时间显著预测ISWT距离缩短（β = -0.299, p = 0.039）、呼吸困难增加（β = 0.591, p <； 0.001）、全身疲劳（β = 0.476, p = 0.001）和FVC降低（β = -0.353, p = 0.014）。结论职业性铅暴露与运动能力和肺功能受损有关。虽然氧化应激会导致这种损伤，但累积暴露时间是最一致的预测因素。这是第一个综合评估铅对最大运动能力以及生化和呼吸参数影响的研究，为其系统生理负担提供了新的见解。
{"title":"Occupational lead exposure induces oxidative stress, pulmonary dysfunction, and reduced exercise capacity: A cross-sectional study","authors":"Ukbe Sirayder, Cihangir Acik","doi":"10.1016/j.toxlet.2026.111828","DOIUrl":"10.1016/j.toxlet.2026.111828","url":null,"abstract":"<div><h3>Aim</h3><div>This study aimed to evaluate the effects of occupational lead exposure on exercise capacity, oxidative stress, and pulmonary function using a multisystemic approach.</div></div><div><h3>Methods</h3><div>A total of 48 lead-exposed and 51 control male workers participated in this cross-sectional study. Incremental Shuttle Walk Test (ISWT), spirometry, blood lead levels (ICP-MS), and oxidative stress markers (MDA, FRAP) were assessed. Correlation and stepwise linear regression analyses were performed.</div></div><div><h3>Results</h3><div>The exposed group showed significantly lower ISWT distances (p < 0.001, Cohen’s d = 0.93), higher dyspnea and fatigue scores (p < 0.01), elevated MDA (d = 2.99), and reduced FRAP levels (d = 0.64). FVC (%) was significantly lower (p < 0.001, d = 1.48), while FEV₁/FVC ratio was higher (p < 0.001, d = 1.46). Regression analyses revealed that lead exposure duration significantly predicted reduced ISWT distance (β = –0.299, p = 0.039), increased dyspnea (β = 0.591, p < 0.001), general fatigue (β = 0.476, p = 0.001), and lower FVC (β = –0.353, p = 0.014).</div></div><div><h3>Conclusion</h3><div>Occupational lead exposure is associated with impaired exercise performance and pulmonary function. While oxidative stress contributes to this impairment, cumulative exposure duration emerged as the most consistent predictor. This is the first study to integratively evaluate the impact of lead on maximal exercise capacity alongside biochemical and respiratory parameters, offering novel insights into its systemic physiological burden.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111828"},"PeriodicalIF":2.9,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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