Toxicology letters最新文献

{"title":"Rosuvastatin exposure during adulthood increases ovarian follicular atresia and reduces reproductive performance in female mice","authors":"Amanda Rebonatto Oltramari ,&nbsp;Alice Santos Da Silva ,&nbsp;Marina Machado Cabrera ,&nbsp;Geisson Marcos Nardi ,&nbsp;Fátima Regina Mena Barreto Silva ,&nbsp;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}

{"title":"Tributyl phosphate disrupts hepatic lipid metabolism via cGAS-STING signal pathway mediated inflammation","authors":"Liwei Yang,&nbsp;Zhili Ge,&nbsp;Xuehan Ding,&nbsp;Jingjing Shi,&nbsp;Jiaxin Zhang,&nbsp;Tianyou Wang,&nbsp;Huibin Jiang,&nbsp;Xinyu Zhang,&nbsp;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> &lt; 0.05). TBP exposure enhanced interleukin-6 (IL-6) production and this effect is reversed by aspirin treatment(<em>P</em> &lt; 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> &lt; 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}

{"title":"Transcript-protein discrepancy of glutamatergic receptor subunits in human iPSC-derived neurons: Implications for neurotoxicity testing","authors":"Melania Maria Serafini ,&nbsp;Miriam Midali ,&nbsp;Giacomo Grumelli ,&nbsp;Alessandro Cutarelli ,&nbsp;Marina Marinovich ,&nbsp;Luciano Conti ,&nbsp;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}

{"title":"Busulfan plus cyclophosphamide induced spermatogenic dysfunction and recovery: A dynamic change perspective","authors":"Tianyu Li ,&nbsp;Zhichen Tang ,&nbsp;Yaping Song ,&nbsp;Min Su ,&nbsp;Xiao Liu ,&nbsp;Fuping Li ,&nbsp;Xing Wei ,&nbsp;Xiaolei Luo ,&nbsp;Bin Zhou ,&nbsp;Yanyun Wang ,&nbsp;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}

{"title":"MicroRNA-based discrimination of hepatotoxic and non-hepatotoxic drugs using a humanized liver mouse model","authors":"Naoto Okada ,&nbsp;Hatsune Enomoto ,&nbsp;Ryota Goto ,&nbsp;Hidehisa Tachiki ,&nbsp;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}

{"title":"Role of mitochondrial biogenesis in methanol-induced neurobehavioral changes in rats","authors":"Guoping Li ,&nbsp;Xiaohong Du ,&nbsp;Xinqiao Wang ,&nbsp;Xiaojie Han ,&nbsp;Mengnan Peng ,&nbsp;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&amp;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 &lt; 0.05). OFT results demonstrated reduced central zone activity duration, total distance traveled, and central zone entries (P &lt; 0.05). H&amp;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 &lt; 0.05). Western blot analysis confirmed downregulation of COX IV, PGC-1α, NRF1, and TFAM (P &lt; 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}

{"title":"Occupational lead exposure induces oxidative stress, pulmonary dysfunction, and reduced exercise capacity: A cross-sectional study","authors":"Ukbe Sirayder,&nbsp;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 &lt; 0.001, Cohen’s d = 0.93), higher dyspnea and fatigue scores (p &lt; 0.01), elevated MDA (d = 2.99), and reduced FRAP levels (d = 0.64). FVC (%) was significantly lower (p &lt; 0.001, d = 1.48), while FEV₁/FVC ratio was higher (p &lt; 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 &lt; 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}

{"title":"The novel PFOS substitute OBS induces visual developmental toxicity in zebrafish embryos via ferroptosis","authors":"Xing Liu ,&nbsp;Xinyi Wu ,&nbsp;Mingzhu Xia,&nbsp;Yi Fan,&nbsp;Yichun Zhao,&nbsp;Junjie Han,&nbsp;Ruobing Chen,&nbsp;Yuting Peng,&nbsp;Man Qu","doi":"10.1016/j.toxlet.2026.111830","DOIUrl":"10.1016/j.toxlet.2026.111830","url":null,"abstract":"<div><div>Sodium p-perfluorous nonenoxybenzenesulfonate (OBS), a widely used substitute for perfluorooctanesulfonic acid, may threaten ocular development, but its mechanisms remain unclear. In this study, zebrafish embryos were exposed to OBS (0, 0.01, 0.1, 1 mg/L) for 120 h. OBS exposure resulted in pronounced ocular developmental abnormalities, including lens deformation, reduced retinal layer thickness, and a significant decrease in eye size. Mechanistic analyses revealed that OBS induced oxidative stress and ferroptosis-associated alterations: the number of early apoptotic cells increased in a dose-dependent manner, accompanied by marked downregulation of key eye development genes (<em>lhx4, pax6, rx1,</em> and <em>vsx1</em>). Additionally, elevated Fe^2 + and malondialdehyde levels, abnormally increased superoxide dismutase activity, and reduced catalase activity and glutathione content were observed. Expression levels of ferroptosis-related genes (<em>gpx4, slc7a11, fth,</em> and <em>tfr</em>) were also significantly altered. Notably, treatment with the ferroptosis-specific inhibitor Ferrostatin-1 (Fer-1) effectively alleviated OBS-induced ocular damage, further supporting ferroptosis as a central regulatory mechanism. Collectively, this study provides the first evidence that ferroptosis plays a pivotal role in OBS-induced ocular developmental defects in zebrafish embryos, offering insights into PFOS alternatives' risks and therapeutic targets.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111830"},"PeriodicalIF":2.9,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990842","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}

{"title":"Piecing together the puzzles: Aryl hydrocarbon receptor-mediated genetic and epigenetic signatures in dioxin-induced carcinogenicity- A systematic review and meta-analysis","authors":"Hefnawy Ahmad A. ,&nbsp;Siam Mohamed ,&nbsp;Mofarih Y. Alkhaldi ,&nbsp;Hassan A. Asiri ,&nbsp;Atheer M. Ali ,&nbsp;Faisal A. Shaher ,&nbsp;Mubarak Sultan Al-Shahrani ,&nbsp;Mohammed Ahmed Al-Qarni ,&nbsp;Hossam M. El-Hawary","doi":"10.1016/j.toxlet.2026.111827","DOIUrl":"10.1016/j.toxlet.2026.111827","url":null,"abstract":"<div><h3>Background</h3><div>Dioxins, are highly potent environmental carcinogens. Their toxic effects are mediated primarily by the Aryl Hydrocarbon Receptor (AhR). A comprehensive understanding of how AhR-induced genetic and epigenetic alterations drive carcinogenesis, especially through effects on cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) and transgenerational inheritance, remains imperative.</div></div><div><h3>Objectives</h3><div>This study investigated the interplay between AhR signaling and some molecular modifications in dioxin-induced carcinogenicity. We aimed to characterize resultant gene expression signatures, cell-specific responses, identify novel AhR targets and susceptible organs, and develop a molecular profile for biomarker and therapeutic development.</div></div><div><h3>Methods</h3><div>We searched databases for peer-reviewed experimental and epidemiological studies on AhR activation by dioxins and its effects on genetic/epigenetic mechanisms, cancer pathways, EMT/CSCs, or transgenerational impacts. Two reviewers performed selection, data extraction, and bias assessment.</div></div><div><h3>Results</h3><div>From 7510 records, 39 studies were incorporated in the qualitative synthesis including 19 in the meta-analyses. Dioxin/AhR significantly increased the expression of certain DNA methylating enzymes. AhR upregulates Gadd45b and LAT1/SLC7A5, induces IL-6, promotes cell cycle progression and interacts with key cancer pathways. AhR signaling alters DNA methylation at promoters, modulates histone modifications, dysregulates ncRNAs, facilitates EMT, influences CSCs, and elicits cell-specific liver responses. Evidence for transgenerational epigenetic inheritance of disease susceptibility was identified.</div></div><div><h3>Conclusion</h3><div>Dioxin-induced carcinogenicity involves intricate AhR-mediated genetic damage and profound epigenetic reprogramming. These alterations, which are often cell-type and species-specific, disrupt critical cellular processes, including EMT and CSC biology, and are susceptible to transgenerational inheritance. The identified molecular signatures offer a foundation for improved biomarkers and targeted therapeutic interventions.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111827"},"PeriodicalIF":2.9,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960459","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}

{"title":"Cadmium interferes with the antiproliferative effect of fulvestrant in endocrine therapy-resistant estrogen receptor α-positive breast cancer cells","authors":"Koki Kanameda ,&nbsp;Masayo Hirao-Suzuki ,&nbsp;Shuso Takeda","doi":"10.1016/j.toxlet.2026.111829","DOIUrl":"10.1016/j.toxlet.2026.111829","url":null,"abstract":"<div><div>Fulvestrant (FUL), an estrogen receptor α (ERα)-degradative anti-estrogen, is used alone or in combination with cyclin-dependent kinase 4/6 inhibitors for the treatment of advanced ERα-positive breast cancer (BC) in postmenopausal women. Cadmium (Cd), an environmental pollutant and metalloestrogen, binds to ERα as a ligand. Patients with BC may experience disease progression despite FUL treatment, suggesting potential interactions between FUL and Cd in long-term estrogen-deprived (LTED) cells. Therefore, the effect of FUL and Cd interaction in LTED cells, a model of postmenopausal BC, was investigated. LTED cells were treated with FUL and Cd at therapeutically or physiologically relevant concentrations, both simultaneously and sequentially (either with FUL treatment followed by Cd or Cd pre-treatment followed by FUL). FUL treatment alone decreased LTED cell viability; however, Cd pre/post-treatment attenuated the antiproliferative effect of FUL. Western blotting showed that Cd pre/post-treatment did not affect FUL-induced ERα degradation. Hence, Cd could suppress the antiproliferative effect of FUL in LTED cells.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111829"},"PeriodicalIF":2.9,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960442","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}