Toxicology letters最新文献

{"title":"Characterization of cell membrane fragments containing muscle type nAChR from Tetronarce californica after preparation using high pressure homogenization","authors":"Fabian Springer ,&nbsp;Marian Freisleben ,&nbsp;Sebastian Muschik ,&nbsp;Franz Worek ,&nbsp;Thomas Seeger ,&nbsp;Lorenz Meinel ,&nbsp;Karin Veronika Niessen","doi":"10.1016/j.toxlet.2024.12.008","DOIUrl":"10.1016/j.toxlet.2024.12.008","url":null,"abstract":"<div><div>The nicotinic acetylcholine receptor (nAChR) is a pentameric ligand-gated ion channel (pLGIC) commonly used as a model for receptors belonging to the Cys-loop superfamily. Members of pLGICs are standardly used in numerous toxicological investigations e.g., GABA and nAChR in the context of nerve agent poisoning. Organophosphorus compounds inhibit AChE, leading to accumulation of acetylcholine in the synaptic cleft and subsequently to a cholinergic crisis, in part through desensitization of nAChR. Due to the limitations of standard therapy, studies concerning functional ligand-receptor interactions of therapeutically active substances are of high importance. Therefore, we developed a novel method to obtain muscle type nAChR-containing membrane fragments from native tissue using high-pressure homogenization. The obtained microsomal fragments were characterized using Dynamic Light Scattering, laser Doppler electrophoresis and protein concentration. The microsomal membrane fragments were further purified, and the plasma membrane fraction was enriched using different density gradients. <em>K</em>_D and <em>B</em>_Max values were determined using a scintillation proximity assay (SPA) with [³H]epibatidine as reporter ligand. Measurement data showed that the ideal conditions to obtain microsomal membrane fragments with high pressure homogenization were four runs at 400 bar. For density gradient centrifugation the under layering of the microsomal membrane fragments (bottom-up method) is to be preferred for further purification. Sucrose seems to be more efficient compared to xylitol or iodixanol density gradients. The nAChR-containing plasma membrane fractions resulting from the developed purification protocol achieve a high degree of quality and reproducibility, making them suitable to model physiological conditions. This system has the potential to be used in both bead- and filtration-based assays probing affinity parameters for ligand binding or functional experiments. The protocol can be easily modified for other LGICs or transmembrane proteins, allowing for further expansion of its use.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"404 ","pages":"Pages 58-66"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979967","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":"Evaluation of the causal effects of perfluorooctanesulfonate on COVID-19 and its associated mechanisms: Integrated Mendelian randomization and network toxicology analyses","authors":"Wenting Tao ,&nbsp;Liang Chen","doi":"10.1016/j.toxlet.2025.01.008","DOIUrl":"10.1016/j.toxlet.2025.01.008","url":null,"abstract":"<div><div>Observational reports have suggested that exposure to perfluorooctanesulfonate (PFOS) can influence COVID-19 infection-related parameters. This study thus sought to use integrated Mendelian randomization (MR) and network toxicology approaches to clarify the potential causal link between PFOS exposure and COVID-19 severity and the molecular mechanisms underlying this relationship. Inverse-variance-weighted analyses highlighted a causal link between plasma PFOS concentrations and a greater risk of sCOVID-19 (<em>OR</em> 1.293<em>, 95 % CI</em> 1.077–1.552, p = 0.006), but not of SARS-CoV-2 infection (p = 0.257) or COVID-19 hospitalization (p = 0.516). No causal link between PFOS concentration and sCOVID-19 was found by reverse MR. In total, 65 targets were tentatively linked to the relationship between PFOS exposure and sCOVID-19. GO and KEGG analyses highlighted involvement in pathways associated with kinase activity, inflammatory responses, and epithelial and endothelial cell migration. In molecular docking analyses, PFOS was confirmed to readily bind to all five analyzed core targets (<em>IL10, ALB, NOTCH1, PPARG,</em> and <em>NFE2L2</em>). These results suggest that PFOS exposure is causally linked to sCOVID-19 risk, while also offering promising insights into the mechanisms that may underlie this association and candidate targets for treatments aimed at limiting the negative effects of PFOS on COVID-19 severity.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"405 ","pages":"Pages 1-8"},"PeriodicalIF":2.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079937","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":"Activation of Wnt/β-catenin signaling to increase B lymphoma Moloney murine leukemia virus insertion region 1 by lithium chloride attenuates the toxicity of cisplatin in the HEI-OC1 auditory cells","authors":"Chen Lu ,&nbsp;Chao Chen ,&nbsp;Yingpeng Xu ,&nbsp;Dingyuan Dai ,&nbsp;Chen Sun ,&nbsp;Qi Li","doi":"10.1016/j.toxlet.2024.11.009","DOIUrl":"10.1016/j.toxlet.2024.11.009","url":null,"abstract":"<div><div>Cisplatin is widely used in anti-tumor therapy, but the ototoxicity caused by high-dose cisplatin often limits its efficacy, and the specific mechanism of cisplatin-induced cochlear damage is still not perfect. The Wnt/β-catenin signaling pathway is closely related to aging, embryonic development, and apoptosis. Meanwhile, B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1) plays a certain role in the evolution and development of the inner ear and the occurrence and development of inner ear-related diseases. Our study intends to explore the role and specific mechanism of the Wnt/β-catenin signaling pathway and BMI1 in improving cisplatin ototoxicity. The appropriate experimental concentrations for each drug were selected by CCK-8 cell proliferation assay and Western Blot to detect apoptosis. The lentivirus transfection of HEI-OC1 cochlear hair cells was used to overexpress BMI1. Western Blot, qPCR, and immunofluorescence detected the activation of each component of BMI1 and Wnt/β-catenin signaling pathway in each experimental model. Wnt/β-catenin signaling pathway and BMI1 are jointly involved in cisplatin-induced cell injury. Low lithium chloride (LiCl) concentrations activated the Wnt/β-catenin pathway, increased BMI1 expression, and reduced cisplatin-induced hair cell injury. In contrast, overexpression of BMI1 inhibited the Wnt/β-catenin pathway and reduced hair cell injury. Meanwhile, the increased cisplatin-induced damage to hair cells by inhibiting BMI1 could not be rescued by LiCl. In conclusion, LiCl can ameliorate cisplatin ototoxicity by elevating BMI1 expression through activation of the Wnt/β-catenin pathway. Overexpression of BMI1 inhibits the Wnt/β-catenin pathway and reduces cisplatin-induced hair cell damage.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"403 ","pages":"Pages 50-65"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751750","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":"Do Delta-9-tetrahydrocannabinol and Cannabidiol have opposed effects on male fertility?","authors":"Olivia L.M. Scandlan,&nbsp;Laura A. Favetta","doi":"10.1016/j.toxlet.2024.12.003","DOIUrl":"10.1016/j.toxlet.2024.12.003","url":null,"abstract":"<div><div><em>Cannabis sativa</em> is a complex plant, renowned for its diverse array of bioactive compounds, the most prominent of which are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These compounds exhibit markedly opposing pharmacological effects, with THC being primarily psychoactive and CBD known for its non-psychoactive properties. In recent years, there has been growing interest in the potential health implications of these compounds, particularly concerning male reproductive health. Accumulating evidence over the past decade has alluded to the potential negative effects of THC, including its association with reduced sperm quality, altered hormone levels, changes in genetic and epigenetic profiles, and potential impacts on fertility. Conversely, emerging studies suggest that CBD may exert protective and beneficial effects on male reproductive health, possibly through its anti-inflammatory and antioxidant properties. This review aims to provide a comprehensive analysis of the current scientific literature, delineating the mechanisms by which THC and CBD influence male reproductive health, highlighting the disparities in their effects, and discussing the clinical and therapeutic implications of these findings.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"403 ","pages":"Pages 94-104"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the relationship among zinc status, blood manganese levels, and enzymatic markers of tissue damage: an epidemiological study using NHANES 2013-2016 data","authors":"Afnan Alandanoosi ,&nbsp;Florence George ,&nbsp;Juan Liuzzi","doi":"10.1016/j.toxlet.2024.11.011","DOIUrl":"10.1016/j.toxlet.2024.11.011","url":null,"abstract":"<div><div>Manganese is an essential trace element required for various physiological processes. However, excessive exposure to this metal can lead to health issues. This study aims to evaluate whether adequate zinc intake can influence the relationship between blood manganese levels and markers indicating damage to the liver and other organs in populations using epidemiological data. We conducted a comprehensive analysis utilizing 2013–2016 data from the National Health and Nutrition Examination Survey (NHANES). The findings indicated that blood manganese exhibits a significant positive association with the serum levels of enzymatic markers of liver damage alkaline phosphatase and aspartate aminotransferase. However, when investigating the interaction between blood manganese and zinc intake at the second quartile, a significant negative association was found with alkaline phosphatase in three different linear regression models. A similar association was found between the fourth quartile of zinc intake and lactate dehydrogenase activity in all three models of the study. The findings suggest that unhealthy high levels of manganese in populations may lead to tissue injury and disease. Nevertheless, having an adequate zinc intake could help mitigate manganese toxicity.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"403 ","pages":"Pages 76-83"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780775","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":"ARC protects cochlear hair cells from neomycin-induced ototoxicity via the Ras/JNK signaling pathway","authors":"Xiaoyu Yu ,&nbsp;Hanbing Gao ,&nbsp;Jie Zhang ,&nbsp;Qiaojun Fang ,&nbsp;Wenjie Kang ,&nbsp;Haiqiong Shang ,&nbsp;Xiangyu Lou ,&nbsp;Ming Guan","doi":"10.1016/j.toxlet.2024.12.005","DOIUrl":"10.1016/j.toxlet.2024.12.005","url":null,"abstract":"<div><div>The present study was designed to investigate the role and mechanism of the Apoptosis repressor with caspase recruitment domain (ARC) in protecting the neomycin-induced hair cell damage. HEI-OC1 cells and basilar membrane culture were applied to determine the effect of ARC. Plasmid transfection was used to regulate the ARC or Ras expression. We have found the ARC overexpression in HEI-OC1 cells can increase the cell viability and decrease cell apoptosis after neomycin injury. The cleaved caspase 3 was reduced in ARC overexpression group after neomycin treatment. The p-CREB expression was increased in ARC overexpression group, while the p-c-Jun expression was decreased after neomycin incubation. In HEI-OC1 cells and basilar membranes, JNK and Ras inhibitions both can reduce ARC expression, and Ras overexpression can increase the ARC expression. This study indicates that ARC can protect the hair cells from neomycin-induced apoptosis through Ras/JNK signaling pathway. Our findings provide new insights in preventing cochlear HC death after drug-induced ototoxicity.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"403 ","pages":"Pages 111-119"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819332","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":"Steroid hormones, vitamin D and melatonin in rapidly rotating shift female hospital workers","authors":"Silvia Fustinoni ,&nbsp;Rosa Mercadante ,&nbsp;Elisa Polledri ,&nbsp;Dario Consonni ,&nbsp;Laura Campo ,&nbsp;Gianfranco Frigerio ,&nbsp;Eleonora Crespi ,&nbsp;Giovanni Costa","doi":"10.1016/j.toxlet.2024.11.013","DOIUrl":"10.1016/j.toxlet.2024.11.013","url":null,"abstract":"<div><div>Disruption of circadian rhythm caused by night-shift work has been associated with several disorders, including cancer. Health care personnel often works at night to insure the continuity of care. Aim of this study was to evaluate the influence of night-shift work on serum and saliva levels of steroid hormones, vitamin D, and melatonin in hospital female workers. Ninety-seven female hospital workers were recruited: 46 nurses performing clockwise rapid rotating shift schedule on a 5-day cycle, including one night, and 51 day workers. Thirteen steroid hormones and vitamin D were assessed in morning serum samples; cortisol, cortisone and melatonin were assessed in morning and evening saliva samples. We fitted multiple regression models adjusted for age, BMI, sampling month, ovarian cycle phase, and use of oral contraceptives (OC). Rapidly rotating clockwise shift work was associated with increased levels of serum corticosterone, 11-deoxycortisol, dehydroepiandrosterone (DHEA), and androstenedione, and decreased levels of estradiol and vitamin D. OC modulated the association between serum cortisol, corticosterone and 11-deoxycortisol and work shift. The normal circadian phase of salivary melatonin, cortisol and cortisone was not affected by shift work. In female hospital nurses, the clockwise rapid rotating shift schedule increases the level of some hormones, likely associated with stress. No increase of estradiol, nor modification of salivary hormones was observed.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"403 ","pages":"Pages 32-39"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early developmental effects of propofol exposure in different stages of zebrafish embryos","authors":"Luís Félix ,&nbsp;Sónia Campos ,&nbsp;Paula Guedes de Pinho ,&nbsp;Luís Antunes ,&nbsp;Ana M. Valentim","doi":"10.1016/j.toxlet.2024.12.002","DOIUrl":"10.1016/j.toxlet.2024.12.002","url":null,"abstract":"<div><div>The mechanism of action of propofol, a common intravenous anaesthetic, in early life stages is not well understood with contradictory studies showing neurotoxic and neurogenic effects in the developing brain. Zebrafish early life stages have been established as an alternative model for animal experimentation with propofol toxicological effects reported following chronic exposure. Yet, the acute exposure to other anaesthetics has been shown to induce early life stage-dependent toxicological outcomes. Therefore, the present study aimed to evaluate the teratogenic effects of propofol at the 256-cell, 50 % epiboly and 1–4 somite stages following a 20 min exposure. Embryos were exposed after primarily assessment of propofol acute toxicity (24h-LC₅₀=9.82 μg mL⁻¹) and absorption at different developmental stages by chromatography. Embryos (2 hours post-fertilization, hpf) were treated with an anaesthetic and toxicological concentration of propofol (2.5 and 10 μg mL⁻¹, respectively) for 20-min. Mortality and developmental toxicity were then evaluated until 144 hpf, when the behaviour and oxidative-stress-related biomarkers were assessed. Exposure at the 256-cell stage resulted in a concentration-dependent increased number of abnormalities in head, fins and tail and a decreased body length as well as in changes in ATPase activity for the lowest concentration. On the other hand, exposure at later stages resulted in a decreased survival while no significant malformations were detected. Yet, exposure during the 50 % epiboly stage resulted in the increase of ROS levels as well as glutathione (GST and GSSG) levels while exposure at 1–4 somite stage resulted in increased DNA damage and ATPase alterations. The behaviour of zebrafish was similar among treatments. Overall, these findings show highlight the stage-dependent teratogenic potential of short propofol exposures during zebrafish early development. The alterations observed may be linked to the activation of the zygotic transcription in embryos, requiring further studies to delve into the molecular changes underlying the observed effects.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"403 ","pages":"Pages 84-93"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Introducing the OECD guidance document on occupational biomonitoring: A harmonized methodology for deriving occupational biomonitoring levels (OBL)","authors":"Nancy B. Hopf ,&nbsp;Jos Bessems ,&nbsp;Tiina Santonen ,&nbsp;Susana Viegas ,&nbsp;Ludwine Casteleyn ,&nbsp;Devika Poddalgoda ,&nbsp;Farida Lamkarkach ,&nbsp;Thomas Göen ,&nbsp;Maryam Zare Jeddi ,&nbsp;Michael Koller ,&nbsp;Christophe Rousselle ,&nbsp;Kate Jones ,&nbsp;Kaspar Schmid ,&nbsp;Rex FitzGerald ,&nbsp;Michael Bader ,&nbsp;Koki Takaki ,&nbsp;Patience Browne ,&nbsp;Virpi Väänänen ,&nbsp;Radu Corneliu Duca ,&nbsp;Robert Pasanen-Kase","doi":"10.1016/j.toxlet.2024.12.006","DOIUrl":"10.1016/j.toxlet.2024.12.006","url":null,"abstract":"<div><div>Derivation of occupational biomonitoring levels (OBLs) is needed to effectively utilize biomonitoring for assessing exposures to chemical substances, and consequently, implement risk reduction measures to reduce health risks among workers. OBLs are the appropriate option for chemical substances that can be absorbed through the skin. This methodology for derivation of OBLs has been developed in collaboration with scientific and regulatory experts from more than 40 institutes in 15 countries within the Organization for Economic Cooperation and Development (OECD) framework. This manuscript provides a summary of the guidance on derivation of OBLs destined for scientists, risk assessors, and regulators who are tasked with establishing OBLs for regulatory purposes and implementing occupational biomonitoring programs. The derivation methodology follows a tiered approach based on the strength of evidence and quality of the data that we have labeled level of confidence. The tiered approach serves as a practical framework in occupational health risk assessment and management. We distinguish between four OBL levels depending on the strength of scientific evidence and confidence level: health-based derivation of OBL based on robust epidemiological data showing causal exposure-health effect relationship and Provisional OBL (POBL) based on robust toxicological animal data showing dose-response relationship as well as two assessment values which are not health based: reference levels in the general population (Reference OBL or (ROBL)), and Technical achievable OBL or (TOBL). Four case studies illustrating the derivation methods for OBLs and POBLs are also provided. Using this state-of-the-art approach (OECD guidance document no. 370) will lead to a harmonized derivation of OBLs and subsequently to evidence-based risk management measures.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"403 ","pages":"Pages 132-143"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142839769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N6-methyladenosine mediated-NRF2 signaling pathway attenuates cadmium cytotoxicity by inhibiting oxidative damage in bronchial epithelial cells","authors":"Nan Zhang ,&nbsp;Yuan Zhao ,&nbsp;Jie Yang ,&nbsp;Yifei Sun ,&nbsp;Rongxian Li ,&nbsp;Zuoshun He ,&nbsp;Shiyan Gu","doi":"10.1016/j.toxlet.2024.12.007","DOIUrl":"10.1016/j.toxlet.2024.12.007","url":null,"abstract":"<div><div>Although N⁶-methyladenosine (m⁶A) and its regulatory proteins were involved in multiple cellular damage processes, the roles of m⁶A and its regulatory proteins in cadmium-induced pulmonary cell damage remain largely unknown. Our present data indicated that cadmium exposure caused serious damage in bronchial epithelial cells, as evidenced by reduction of cell viability and elevation of oxidative damage and apoptosis. These processes were accompanied by alterations of m⁶A modification and its regulatory proteins (FTO, ALKBH5, YTHDC2). It is noteworthy that pretreatment with the m⁶A agonist entacapone (ENT) markedly attenuated the detrimental effects of cadmium, including cell death, oxidative damage, and the activation of the nuclear factor erythroid 2-related factor 2 (NRF2）signalling pathway. Conversely, the detrimental effects of CdSO₄ were significantly exacerbated when m⁶A levels were inhibited by 3-deazidyladenosine (DAA). Further prediction result revealed that multiple m⁶A-modified sites occur on <em>NRF2</em> mRNA with high confidence level, implicating that m⁶A modification on <em>NRF2</em> mRNA may affect the protein expression of NRF2. In conclusion, our data together suggest that m⁶A modification play critical roles in cadmium-induced bronchial epithelial cell damage, during which NRF2 signaling pathway may act as an important bridge for m⁶A modification to regulate cellular damage. This study offer a promising avenue for further investigation into the mechanisms underlying cadmium-induced bronchial epithelial cell damage from the perspective of RNA epigenetics.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"403 ","pages":"Pages 144-158"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898339","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}