Toxicology letters最新文献

{"title":"A battery of assays for chasing ricin and its activity","authors":"Shivani Dixit ,&nbsp;Ram Kumar Dhaked ,&nbsp;Greeshma TS ,&nbsp;Anjali Yadav ,&nbsp;Jagrati Parashar ,&nbsp;Nandita Saxena","doi":"10.1016/j.toxlet.2025.04.003","DOIUrl":"10.1016/j.toxlet.2025.04.003","url":null,"abstract":"<div><div>Ricin, a type-2 Ribosome-Inactivating Protein (RIP), is a dangerous biotoxin derived from castor plant seeds. It is classified as a Schedule 1 agent by the Chemical Weapon Convention (CWC) and a Category B agent by the Biological and Toxin Weapon Convention (BTWC). Despite their high toxicity, castor seed plants are widely used for the production of castor oil and in folk medicine systems for the treatment of various diseases. Due to the lack of a Food and Drug Administration (FDA) approved medication, early detection of biologically active ricin is critical for implementing suitable countermeasures in time to avert casualties. It is required to employ an integrated approach to distinguish between pure and crude ricin as well as active/inactive ricin. In the present study, a series of bioassays were performed to identify biologically active ricin and its different forms. This assessment included both field and lab-based assays to detect and differentiate different isoforms of ricin. The assays used are the lateral flow assay (LFA), hemagglutination assay (HA), In-vitro translational system (IVTS), cytotoxicity assay (CA), and mouse protection assay (MPA). Considering the ricin-contaminated scenario, the first step was to qualitatively determine the presence of ricin using LFA. Following that, a HA was optimized to differentiate between crude and pure ricin. In addition to this, the assay was also able to differentiate various cultivars and isoforms. IVTS assay was used to identify the enzymatic activity of the ricin A chain that inhibited translational machinery with IC₅₀ (50 % inhibitory concentration) of 11.2 ng/ml. Further neutralization with anti-ricin rabbit polyclonal antibodies (RPAb) confirmed the ricin-mediated translation inhibition and excluded the use of other RIPs (abrin, saproin, and viscumin). Cytotoxicity in HeLa cells was used as a cellular model with an estimated CC₅₀ value (50 % cytotoxic concentration) of 36 ng/ml. The neutralization experiment with RPAb specifically reversed the ricin-induced cytotoxicity. A mouse protection assay was done using 5X LD₅₀ of ricin, which caused mortality within 48 h. RPAb increased the survival, verdict the presence of ricin, and eliminated the presence of related RIPs. All the proposed assays suffice the requirement during ricin exposure scenario from the field to the laboratory. These assays are also capable of distinguishing crude/pure/cultivars, and isoforms of ricin. During an emergency, a combination of these assays will help us to make faster decisions and increase the therapeutic time window for treatment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 43-53"},"PeriodicalIF":2.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835049","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":"6PPD impairs immune responses and fin regeneration in zebrafish","authors":"Xiaoyu Mao ,&nbsp;Dashuang Mo ,&nbsp;Yuqin Cheng ,&nbsp;Mengzhu Lv","doi":"10.1016/j.toxlet.2025.04.001","DOIUrl":"10.1016/j.toxlet.2025.04.001","url":null,"abstract":"<div><div><em>N</em>-(1,3-Dimethylbutyl)-<em>N</em>′-phenyl-<em>p</em>-phenylenediamine (6PPD), a commonly used antioxidant in tire manufacturing, has been widely detected in the environment and shown to exhibit acute toxicity in several organs. However, the effects of 6PPD on immune responses, particularly following injury, remain poorly understood. In this study, we investigated the impact of 6PPD exposure on immune responses using zebrafish as a model. 6PPD exposure disrupted caudal fin regeneration at various stages of the regenerative process. Further analysis revealed that 6PPD impaired immune responses following fin amputation, as evidenced by the reduced number of lyz⁺/mpx⁺ neutrophils and the downregulation of key immune-related genes. Besides, the morphology of neutrophils was changed upon 6PPD exposure, indicating the defective migration of immune cells. The incubation of zebrafish larvae with lipopolysaccharide (LPS), which induces global immune responses, also exhibited impaired immune function when combined with 6PPD exposure. Additionally, the injection of LPS into the egg yolk or trunk exacerbated immune responses at the injury site, yet 6PPD exposure significantly reduced neutrophil accumulation and downregulated the expression of immune-related genes, confirming the toxicity of 6PPD in immune responses. These findings provide new insights into the toxic effects of 6PPD on immune responses during injury, highlighting its potential to impair immune function in animals and human.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 32-42"},"PeriodicalIF":2.9,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796331","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":"Exploring gadolinium deposition in maternal and offspring mice: Impacts of gestational and lactational exposure","authors":"Ying Kong ,&nbsp;Kai Liu ,&nbsp;Shi Qiu ,&nbsp;Jiali Wang ,&nbsp;Shuai Zhang ,&nbsp;Kai Xu","doi":"10.1016/j.toxlet.2025.03.010","DOIUrl":"10.1016/j.toxlet.2025.03.010","url":null,"abstract":"<div><div>To investigate the gadolinium deposition induced by repeated administration of gadolinium-based contrast agents (GBCAs) in multi-organ/tissue of mother and pup mice during pregnancy and lactation, two hundred and seventy ICR mice were divided into three groups (non-pregnant, pregnant, and lactating; n = 90/group) and received gadodiamide, gadoterate meglumine, or saline intravenously (2.5 mmol Gd/kg once every two days for a total of 10 doses) throughout the entire gestation or lactation period. Gadolinium concentration detection, histological analyses, and transmission electron microscopy were performed on mother and pup mice at the completion of the injection, one month later, and three months later. Our results showed that (i)exposure to GBCAs during pregnancy resulted in gadolinium deposition in fetal organs more significantly with gadodiamide, with the greatest deposition observed in the kidneys and the least in the brain, interestingly, the fetal body was found with no detectable gadolinium deposits one month after birth, that (ii) exposure to GBCAs during lactation did not result in detectable gadolinium deposition in the organs/tissues of the unweaned pups, and that (iii)gadolinium deposition decreased more rapidly in the first month in all tissues examined from all maternal and non-pregnant mice, and gadolinium deposition was found to be lower in the kidneys of both pregnant and lactating mice than in non-pregnant mice. Collectively, exposure to GBCAs during pregnancy resulted in gadolinium deposition in their fetuses with no significant organ toxicity found, and breastfeeding continued after exposure to GBCAs during lactation may not pose a risk of gadolinium deposition to the pups.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 13-22"},"PeriodicalIF":2.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789029","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 urinary metabolites reflect occupational exposure to organophosphate flame retardants? A case study in electronic waste recycling workers.","authors":"Sabrina Gravel ,&nbsp;Inna Tata Traore ,&nbsp;Miriam L. Diamond ,&nbsp;Liisa Jantunen ,&nbsp;Joseph Zayed ,&nbsp;France Labrèche ,&nbsp;Marc-André Verner","doi":"10.1016/j.toxlet.2025.03.012","DOIUrl":"10.1016/j.toxlet.2025.03.012","url":null,"abstract":"<div><div>Organophosphate esters (OPEs) are commonly used in electronic devices to meet safety standards, but electronic-waste recycling (e-recycling) workers may face significant exposure to those potentially hazardous compounds in their workplace. We examined the relationship between urinary OPE metabolites and their parent compounds in the air, in Canadian e-recycling facilities. We collected personal air samples and end-of-shift urine samples from workers at six e-recycling facilities. We employed linear and Tobit regression models to assess associations between air concentrations of triphenyl phosphate (TPhP) and three metabolites, of tris (2-chloroethyl) phosphate (TCEP) and two metabolites, of tris (2-chloroisopropyl) phosphate (TCPP) and two metabolites, of tris (1,3-dichloro-2-propyl) phosphate (TDCPP), and of tris (2-butoxyethyl) phosphate (TBOEP) and one metabolite each. The 85 participants, mostly male (78 %) and aged between 25 and 54, had concentrations of OPEs detected in 90–100 % of air samples, with geometric means of TPhP, TCEP, TBOEP and TDCPP, of 351, 404, 261 and 250 picomoles per cubic metre respectively. The proportion of detection of their corresponding metabolites varied between 32 % and 98 %. Regression models including the urinary flow rate as a covariate showed that a doubling of the air concentration of TCEP was associated with a 42–107 % increase in its metabolites, and a doubling of air concentration of TBOEP, with a 77 % increase. The paucity of data on the toxicokinetics of OPEs limits the determination of appropriate urinary metabolites to monitor OPE occupational exposure. Such additional data, in combination with workplace contextual information, may help clarify the major routes of exposure and the corresponding contributing sources.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 23-31"},"PeriodicalIF":2.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788961","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":"Using explainable machine learning to predict the irritation and corrosivity of chemicals on eyes and skin","authors":"Yingxu Liu ,&nbsp;Yang Liu ,&nbsp;Simeng Zhang ,&nbsp;Chen Zeng ,&nbsp;Qing Zhang ,&nbsp;Yunya Jiang ,&nbsp;Xi Yang ,&nbsp;Lidan Zheng ,&nbsp;Qian Ge ,&nbsp;Yanmin Zhang ,&nbsp;Yadong Chen ,&nbsp;Mengyi Lu ,&nbsp;Haichun Liu","doi":"10.1016/j.toxlet.2025.03.008","DOIUrl":"10.1016/j.toxlet.2025.03.008","url":null,"abstract":"<div><div>Contact with specific chemicals often results in corrosive and irritative responses in the eyes and skin, playing a pivotal role in assessing the potential hazards of personal care products, cosmetics, and industrial chemicals to human health. While traditional animal testing can provide valuable information, its high costs, ethical controversies, and significant demand for animals limit its extensive use, particularly during preliminary screening stages. To address these issues, we adopted a computational modeling approach, integrating 3316 experimental data points on eye irritation and 3080 data points on skin irritation, to develop various machine learning and deep learning models. Under the evaluation of the external validation set, the best-performing models for the two tasks achieved balanced accuracies (BAC) of 73.0 % and 75.1 %, respectively. Furthermore, interpretability analyses were conducted at the dataset level, molecular level, and atomic level to provide insights into the prediction outcomes. Analysis of substructure frequencies identified structural alert fragments within the datasets. This information serves as a reference for identifying potentially irritating chemicals. Additionally, a user-friendly visualization interface was developed, enabling non-specialists to easily predict eye and skin irritation potential. In summary, our study provides a new avenue for the assessment of irritancy potential in chemicals used in pesticides, cosmetics, and ophthalmic drugs.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"408 ","pages":"Pages 1-12"},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143767481","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":"Extended sub-chronic exposure to heavy metal mixture induced multidrug resistance against chemotherapy agents in ovarian cancer cells","authors":"Gözde Sahin ,&nbsp;Zeynep Banu Doğanlar","doi":"10.1016/j.toxlet.2025.03.006","DOIUrl":"10.1016/j.toxlet.2025.03.006","url":null,"abstract":"<div><div>Recent scientific findings suggest that persistent, minimal quantity exposure to heavy metals combinations can instigate negative reactions across various cell types, tissues, and organs. However, the interplay between heavy metals present in blood and cancerous cells remains largely unclear. We aimed to examine the capability of a Pb, Cd, and Co at very low concentrations blend to trigger multidrug resistance against chemotherapeutic remedies such as cisplatin, 5-fluorouracil, and doxorubicin in the NIH-Ovcar3 human ovarian cancer cell line. Additionally, we sought to dissect the molecular mechanisms bolstering this resistance. Our results illustrate that consistent administration of the heavy metal mixture at extraordinarily low concentrations fosters pronounced chemotherapy resistance in Ovcar3 cells via cross resistance. This resistance endured and was propagated through ensuing cell generations. We observed that ATP-binding cassette (ABC) membrane transporters, specifically P-gp/ABCB1, BRCP/ABCG2, and ABCC1-type cellular detoxification functions, were markedly overexpressed, playing a crucial role in multidrug resistance. This finding supports the molecular evidence of the acquired multidrug resistance phenotype and provides preliminary insights into the potential resistance mechanism. We also found decreased mortality rates in the resistant ovarian cancer cells, with the mitochondrial apoptosis pathway activating at a reduced rate post-chemotherapy relative to the non-resistant control cells. Furthermore, multidrug-resistant cells exhibited increased motility and enhanced wound-healing abilities, hinting at a higher metastatic potential. These findings suggest that analysing P-gp, BRCP, and ABCC1 multidrug resistance gene expression and/or protein levels within biopsy samples from ovarian cancer patients at risk of heavy metal exposure could prove advantageous in determining chemotherapy dosage and prolonging patient lifespan.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"407 ","pages":"Pages 50-62"},"PeriodicalIF":2.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738319","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":"Environmental pesticide exposure and its association with hematological parameters and inflammation indices among school-aged children in Mexico","authors":"Miguel Alfonso Ruiz-Arias ,&nbsp;Yael Yvette Bernal-Hernández ,&nbsp;Irma Martha Medina-Díaz ,&nbsp;Ana M. Mora ,&nbsp;José Francisco Herrera-Moreno ,&nbsp;Briscia Socorro Barrón-Vivanco ,&nbsp;Cyndia Azucena González-Arias ,&nbsp;Francisco Alberto Verdín-Betancourt ,&nbsp;José Antonio Aguilar-Bañuelos ,&nbsp;Juan Manuel Agraz-Cibrián ,&nbsp;José Francisco Zambrano-Zaragoza ,&nbsp;Pedro de Jesús Bastidas-Bastidas ,&nbsp;Aurora Elizabeth Rojas-García","doi":"10.1016/j.toxlet.2025.03.009","DOIUrl":"10.1016/j.toxlet.2025.03.009","url":null,"abstract":"<div><div>Few studies have investigated the association between pesticide exposure and immune-inflammatory indices in children. We conducted a cross-sectional study of 369 school-aged children from three Mexican communities with varying levels of agricultural production. Blood samples were collected to calculate immune-inflammatory indices, and pooled hand-washing samples from 30 randomly selected children per community were analyzed for pesticide metabolites. Urinary dialkylphosphates (DAP) were determined in pooled samples per community. Multivariable logistic regression models assessed associations between pesticide exposure and immune-inflammatory indices (&gt;median vs. &lt;median). We detected ten classes of pesticides in hand-washing samples, including benzimidazoles, carbamates, neonicotinoids, organochlorines, organophosphates, and N-(phosphonomethyl)glycine. Total pesticide residue concentrations were 6.6 µg/L and 5.5 µg/L in the two highest production communities, compared to 0.3 µg/L in the reference community. Bifenthrin, chlorpyrifos, malathion, and carbendazim were present across all communities, with AMPA (a glyphosate metabolite) in the highest concentrations in agricultural areas. Urinary DAP were significantly higher in children from agricultural communities. Children in the largest agricultural community had lower hemoglobin and lymphocyte counts but higher neutrophil and eosinophil counts. Regression models showed increased odds of elevated systemic inflammation indices, particularly in children from the two highest production areas. Our adjusted models revealed significant associations between pesticide exposure and platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and eosinophil-to-lymphocyte ratio (ELR), in community B compared to community C, emphasizing the need for targeted interventions in high-exposure communities.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"407 ","pages":"Pages 83-94"},"PeriodicalIF":2.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754772","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":"Dose-dependent effects of chlorpyrifos on liver injury, intestinal dysbiosis, and metabolic perturbations in C57BL/6J mice","authors":"Shuilin Wei ,&nbsp;Mengjing Wu ,&nbsp;Quanzhi Qin ,&nbsp;Chunxia Chen,&nbsp;Huan Huang,&nbsp;Zhongqing Wen,&nbsp;Junli Huang,&nbsp;Xixiang Xie,&nbsp;Rixiang Su,&nbsp;Xing Zhou,&nbsp;Jian Qin,&nbsp;Xiaoxia Liu,&nbsp;Xiaoyu Chen","doi":"10.1016/j.toxlet.2025.03.011","DOIUrl":"10.1016/j.toxlet.2025.03.011","url":null,"abstract":"<div><div>The organophosphorus pesticide chlorpyrifos (CPF) is widely utilized in agriculture to protect crops from pests and diseases. Concerns regarding its extensive use have emerged due to the substance's persistence, bioaccumulation, endocrine disruption, and associated toxicity, which may lead to various adverse reactions. In this study, 32 male C57BL/6 J mice were orally administered varying doses of CPF over a period of two weeks. Metabolic perturbations resulting from subacute exposure to CPF were assessed using LC-MS/MS-based untargeted metabolomics, alongside biochemical analysis and histopathological techniques. The 16S rRNA gene sequencing method was employed to evaluate changes in the gut microbial community within the cecal contents of mice exposed to CPF. In vivo studies have shown that CPF exposure induced dose-dependent damage and dysregulation of the intestinal microbiota in mouse colonic tissues. This was characterized by significant alterations in the gut microbiota, increased intestinal permeability and elevated levels of lipopolysaccharides. These changes may have compromised intestinal barrier function and facilitated the transfer of intestinal microbial metabolites and endotoxins to the liver, subsequently leading to liver injury. Collectively, this study elucidates a potential mechanism by which CPF triggers liver injury through alterations in the intestinal microbial community and increased intestinal permeability. These findings not only enhance our understanding of the toxicological effects of CPF but also contribute to the assessment of health risks associated with CPF exposure.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"407 ","pages":"Pages 73-82"},"PeriodicalIF":2.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754760","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":"Toxic effects of sterigmatocystin on porcine oocyte maturation and subsequent embryo development","authors":"Yumin Lee ,&nbsp;Dabin Cha ,&nbsp;Seunghyun Choi ,&nbsp;Jongki Cho ,&nbsp;Sanghoon Lee","doi":"10.1016/j.toxlet.2025.03.007","DOIUrl":"10.1016/j.toxlet.2025.03.007","url":null,"abstract":"<div><div>Sterigmatocystin (STE), a precursor of aflatoxin B1, is one of the mycotoxins that easily contaminates feed. Although previous studies have suggested the toxic effects of aflatoxin B1 on oocyte maturation, little attention has been given to the effects of STE. Therefore, we investigated the effects of STE on porcine oocyte maturation. In this study, porcine oocytes were subjected to <em>in vitro</em> maturation supplemented with various concentrations of STE (0, 5, 10, and 25 μM). The results showed that the cumulus cell expansion indexes of all STE-treated groups were significantly decreased compared to the control group, with 10 μM significantly decreasing the transcript expression of cumulus expansion-related genes. Regarding nuclear maturation, metaphase II rates in all STE-treated groups were significantly lower than in the control group, with 10 μM significantly decreasing the transcript expression of oocyte competence-, mitogen-activated protein kinase-, and maturation-promoting factor-related genes. While cleavage rates showed no significant differences, the blastocyst formation rates significantly declined in groups treated with more than 10 μM of STE. Based on these findings, the 10 μM STE group was selected for subsequent experiments. STE supplementation significantly increased reactive oxygen species levels and decreased glutathione levels in oocytes compared to the control group. Furthermore, STE significantly decreased mitochondrial quantity and membrane potential, while increasing the percentage of γ-H2AX-positive oocytes. The number of LC3-positive dots and Annexin-V-positive oocytes was also significantly higher in the STE-treated group than in the control group. In conclusion, STE impairs porcine oocyte maturation and subsequent embryo development by inducing oxidative stress, mitochondrial dysfunction, DNA damage, excessive autophagy, and early apoptosis.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"407 ","pages":"Pages 63-72"},"PeriodicalIF":2.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738320","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":"Cigarette smoking modulates m6A modification, affecting the induction of CYP1A1 mRNA by regulating human ARNT and AHRR in A549 cells","authors":"Takumi Nakano ,&nbsp;Masataka Nakano ,&nbsp;Tatsuki Fukami ,&nbsp;Miki Nakajima","doi":"10.1016/j.toxlet.2025.03.005","DOIUrl":"10.1016/j.toxlet.2025.03.005","url":null,"abstract":"<div><div><em>N</em>⁶-Methyladenosine (m⁶A) modification is a common epitranscriptomic mark of eukaryotic RNAs. This modification is installed by a methyltransferase like 3 (METTL3)-METTL14 complex and is eliminated by fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5). Aberrant m⁶A modification is associated with the development and progression of cancer. Cigarette smoking is a major lifestyle habit and risk factor for lung cancer. This study aimed to clarify the effects of cigarette smoking on the expression of m⁶A modification-regulating enzymes and the significance of m⁶A modification in the biological responses to cigarette smoking. Treatment of cigarette smoke extract (CSE) significantly decreased METTL3 and METTL14 protein levels in human lung adenocarcinoma-derived A549 cells. The induction of CYP1A1 mRNA by 2,3,7,8-tetrachlorodibenzo-<em>p</em>-dioxin, a typical ligand of the aryl hydrocarbon receptor (AHR), was attenuated by the knockdown (KD) of METTL3 or ALKBH5, whereas it was enhanced by the KD of FTO. As the underlying mechanisms, significantly decreased expression of AHR nuclear translocator (ARNT) by the KD of METTL3 or ALKBH5, and significantly decreased expression of AHR repressor (AHRR) by the KD of FTO were demonstrated. Formaldehyde-assisted isolation of regulatory elements assay revealed that the KD of METTL3 or ALKBH5 resulted in the compaction of the chromatin structure of <em>ARNT</em> promoter, suggesting that METTL3 and ALKBH5 promote the transcription of ARNT through the rearrangement of chromatin structure. Collectively, we found that CSE treatment decreased METTL3 and METTL14 protein levels, and m⁶A modification have impact on the induction of CYP1A1 by modulating ARNT and AHRR expression.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"407 ","pages":"Pages 41-49"},"PeriodicalIF":2.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674619","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}